Jay S. Skyler

The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes.We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose.At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab.A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)

Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20-50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups.

Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.

Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1C value) and risk of complications was log-linear and extended down to the normal A1C range (<6%) with no threshold noted. In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1C, with no glycemic threshold. On the basis of these two large controlled trials, along with smaller studies and numerous epidemiologic reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing that more or less stringent goals may be appropriate for certain patients. Whereas many epidemiologic studies and meta-analyses …

Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes.We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26-50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes.Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) > or =80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015).It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.

<h2>Summary</h2><h3>Background</h3> The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. <h3>Methods</h3> In this multicentre, double-blind, randomised controlled trial, patients aged 6–45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375. <h3>Findings</h3> 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1–112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47–15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept <i>vs</i> 15 [43%] on placebo) or neutropenia (seven [9%] <i>vs</i> five [14%]). <h3>Interpretation</h3> Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. <h3>Funding</h3> US National Institutes of Health.

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” on 10–12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.

The underlying cause of type 1 diabetes, loss of beta-cell function, has become the therapeutic target for a number of interventions in patients with type 1 diabetes. Even though insulin therapies continue to improve, it remains difficult to achieve normal glycemic control in type 1 diabetes, especially long term. The associated risks of hypoglycemia and end-organ diabetic complications remain. Retention of beta-cell function in patients with type 1 diabetes is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. To facilitate the development of therapies aimed at altering the type 1 diabetes disease process, an American Diabetes Association workshop was convened to identify appropriate efficacy outcome measures in type 1 diabetes clinical trials. The following consensus emerged: While measurements of immune responses to islet cells are important in elucidating pathogenesis, none of these measures have directly correlated with the decline in endogenous insulin secretion. HbA(1c) is a highly valuable clinical measure of glycemic control, but it is an insensitive measure of beta-cell function, particularly with the currently accepted standard of near-normal glycemic control. Rates of severe hypoglycemia and diabetic complications ultimately will be improved by therapies that are effective at preserving beta-cell function but as primary outcomes require inordinately large and protracted trials. Endogenous insulin secretion is assessed best by measurement of C-peptide, which is cosecreted with insulin in a one-to-one molar ratio but unlike insulin experiences little first pass clearance by the liver. Measurement of C-peptide under standardized conditions provides a sensitive, well accepted, and clinically validated assessment of beta-cell function. C-peptide measurement is the most suitable primary outcome for clinical trials of therapies aimed at preserving or improving endogenous insulin secretion in type 1 diabetes patients. Available data demonstrate that even relatively modest treatment effects on C-peptide will result in clinically meaningful benefits. The development of therapies for addressing this important unmet clinical need will be facilitated by trials that are carefully designed with beta-cell function as determined by C-peptide measurement as the primary efficacy outcome.

The purpose of this study was to explore possible calculations using oral glucose tolerance test (OGTT) values in order to develop a simple measure of insulin sensitivity. We devised a formula for an insulin sensitivity index, ISI(0,120), that uses the fasting (0 min) and 120 min post-oral glucose (OGTT) insulin and glucose concentrations. It appears to be generalizable across a spectrum of glucose tolerance and obesity. Most importantly, our data show that ISI(0,120) correlates well, when applied prospectively in comparative studies, with the insulin sensitivity index obtained from the euglycemic hyperinsulinemic clamp (r = 0.63, P < 0.001). This correlation was demonstrably superior to other indices of insulin sensitivity such as the HOMA formula presented by Matthews, and performed comparably to the computerized HOMA index. Measurement of insulin sensitivity has traditionally been possible only in research settings because of the invasiveness and expense of the methods used. Clinical investigators have therefore sought more practical methods to obtain an index of insulin sensitivity. Such an index should approximate insulin sensitivity as measured by the euglycemic hyperinsulinemic clamp (M). We present ISI(0,120), a simple yet sensitive measure of insulin sensitivity which is adaptable for use in clinical settings as well as large epidemiologic studies.

Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a 2- to 4-fold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 11,2 and type 2 diabetes.3–5 In the Diabetes Control and Complications Trial (DCCT), there was an ≈60% reduction in the development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1c, <6.05%; mean achieved A1c, ≈7%) and the standard group (A1c, ≈9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1c value) and risk of complications was log-linear and extended down to the normal A1c range (<6%) with no threshold noted. In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed up for 10 years, and intensive control (median A1c, 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1c, 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1c, with no glycemic threshold. On the basis of these 2 large controlled trials, along with smaller studies and numerous epidemiological reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1c goal of <7% for most adults with diabetes,6 recognizing that more or less stringent …

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.

Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes.Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399.145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups.Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge.US National Institutes of Health.

Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes.We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34.Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group.Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders.National Institutes of Health and Juvenile Diabetes Research Foundation.

D iabetes is defined by its association with hyperglycemia- specific microvascular complications; however, it also imparts a 2-to 4-fold risk of cardiovascular disease (CVD).Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD.4][5] In the Diabetes Control and Complications Trial (DCCT), there was an Ϸ60% reduction in the development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A 1c , Ͻ6.05%; mean achieved A 1c , Ϸ7%) and the standard group (A 1c , Ϸ9%) over an average of 6.5 years.The relationship between glucose control (as reflected by the mean on-study A 1c value) and risk of complications was log-linear and extended down to the normal A 1c range (Ͻ6%) with no threshold noted.In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed up for 10 years, and intensive control (median A 1c , 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A 1c , 7.9%).Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A 1c , with no glycemic threshold.

Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was −0.0245 pmol/mL/month (95% CI −0.0271 to −0.0215) through the first 12 months and −0.0079 (−0.0113 to −0.0050) from 12 to 24 months (P &amp;lt; 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.

OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (&amp;gt;70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were −0.28% (95% CI −0.42, −0.15) for 2.5 mg, −0.54% (−0.65, −0.42) for 10 mg, and −0.53% (−0.65, −0.42) for 25 mg (all P &amp;lt; 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by −1.8/−3.0/−3.4 kg (all P &amp;lt; 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P &amp;lt; 0.0001 for 10 and 25 mg); lowered total daily insulin dose by −6.4/−13.3/−12.7% (all P &amp;lt; 0.0001); and decreased systolic blood pressure by −2.1/−3.9/−3.7 mmHg (all P &amp;lt; 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo. CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.Eighty-seven subjects (aged 8-40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome-baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year-showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (P = 0.03). Odds ratio for loss of C-peptide to <0.2 nmol/L following rituximab was 0.565 (P = 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

Effective glycaemic control in type 1 diabetes mellitus usually requires two or more insulin injections daily. Inhaled intrapulmonary delivery of insulin offers a potential new way to deliver meal-related insulin, eliminating the need for preprandial injections.73 patients with type 1 diabetes mellitus were studied in an open-label, proof-of-concept, parallel-group randomised trial. Patients in the experimental group received preprandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection. Patients in the control group received their usual insulin regimen of two to three injections per day. Participants monitored their blood glucose four times daily, and adjusted insulin doses weekly to achieve preprandial glucose targets of 5.6-8.9 mmol/L. The primary outcome measure was change in glycosylated haemoglobin (HbA1c) after 12 weeks. Secondary outcomes were fasting and postprandial glucose response to a mixed meal; hypoglycaemia frequency and severity; pulmonary function; and patients' satisfaction.Changes in HbA1c were indistinguishable between groups (difference 0.2% [95% CI -0.2 to 0.5]). Changes in fasting and postprandial glucose concentrations, and occurrence and severity of hypoglycaemia were also similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function (ie, spirometry, lung volumes, diffusion capacity, and oxygen saturation).This proof-of-concept study shows that preprandial insulin can be given by inhalation in individuals with insulin-deficient type 1 diabetes as a less invasive alternative to conventional preprandial insulin injections.

Despite the demonstrated benefits of glycemic control, patient acceptance of basal/bolus insulin therapy for type 1 diabetes has been slow. We investigated whether a basal/bolus insulin regimen involving rapid-acting, dry powder, inhaled insulin could provide glycemic control comparable with a basal/bolus subcutaneous regimen.Patients with type 1 diabetes (ages 12-65 years) received twice-daily subcutaneous NPH insulin and were randomized to premeal inhaled insulin (n = 163) or subcutaneous regular insulin (n = 165) for 6 months.Mean glycosylated hemoglobin (A1C) decreased comparably from baseline in the inhaled and subcutaneous insulin groups (-0.3 and -0.1%, respectively; adjusted difference -0.16% [CI -0.34 to 0.01]), with a similar percentage of subjects achieving A1C <7%. Although 2-h postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group (adjusted difference -39.5 mg/dl [CI -57.5 to -21.6]). Inhaled insulin was associated with a lower overall hypoglycemia rate but higher severe hypoglycemia rate. The overall hypoglycemia rate (episodes/patient-month) was 9.3 (inhaled) vs. 9.9 (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91-0.97]), and the severe hypoglycemia rate (episodes/100 patient-months) was 6.5 vs. 3.3 (RR 2.00 [CI 1.28-3.12]). Increased insulin antibody serum binding without associated clinical manifestations occurred in the inhaled insulin group. Pulmonary function between the groups was comparable, except for a decline in carbon monoxide-diffusing capacity in the inhaled insulin group without any clinical correlates.Inhaled insulin may provide an alternative for the management of type 1 diabetes as part of a basal/bolus strategy in patients who are unwilling or unable to use preprandial insulin injections.

OBJECTIVE There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AND METHODS Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA+). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA+). RESULTS In both cohorts autoantibody number was highly predictive of type 1 diabetes (P &amp;lt; 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P &amp;lt; 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P &amp;lt; 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes. CONCLUSIONS The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking.High selenium yeast supplementation (200 mug/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean +/- SD.Of the 450 HIV-1-seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0% +/- 24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change (Delta) in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (Delta = 32.2 +/- 24.5 vs 0.5 +/- 8.8 microg/L; P<.001), and greater levels predicted decreased HIV-1 viral load (P<.02), which predicted increased CD4 count (P<.04). Findings remained significant after covarying age, sex, ethnicity, income, education, current and past cocaine and other drug use, HIV symptom classification, antiretroviral medication regimen and adherence, time since HIV diagnosis, and hepatitis C virus coinfection. Follow-up analyses evaluating treatment effectiveness indicated that the nonresponding selenium-treated subjects whose serum selenium change was less than or equal to 26.1 microg/L displayed poor treatment adherence (56.8% +/- 29.8%), HIV-1 viral load elevation (Delta = +0.29 +/- 1.1 log(10) units), and decreased CD4 count (Delta = -25.8 +/- 147.4 cells/microL). In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 microg/L evidenced excellent treatment adherence (86.2% +/- 13.0%), no change in HIV-1 viral load (Delta = -0.04 +/- 0.7 log(10) units), and an increase in CD4 count (Delta = +27.9 +/- 150.2 cells/microL).Daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease. Trial Registration isrctn.org Identifier: ISRCTN22553118.

Background: Despite demonstrated benefits, intensive insulin therapy has not gained widespread clinical acceptance for several reasons: Multiple daily injections are inconvenient, adherence is a concern, and the time-activity profile may not mimic normal insulin secretion. As such, alternate means of administering insulin are being evaluated. Objective: To assess the efficacy and safety of pulmonary delivery of insulin in type 2 diabetic patients who require insulin. Design: Randomized, open-label, 3-month study consisting of a screening visit, a 4-week baseline lead-in phase, and a 12-week treatment phase. Setting: General clinical research center and outpatient research clinics. Patients: 26 patients (16 men, 10 women) with type 2 diabetes (average age, 51.1 years; average duration of diabetes, 11.2 years). Intervention: Patients received inhaled insulin before each meal plus a bedtime injection of ultralente insulin, performed home glucose monitoring, and had weekly adjustment of insulin dose; target level for preprandial plasma glucose was 5.55 to 8.88 mmol/L (100 to 160 mg/dL). Measurements: Glycemic control (hemoglobin A1c level) obtained at baseline and monthly for 3 months. Pulmonary function tests were done at baseline and at the end of the study. Results: Inhaled insulin treatment for 3 months significantly improved glycemic control compared with baseline: Mean hemoglobin A1c levels decreased by 0.0071 ± 0.0072 (0.71% ± 0.72%). Patients experienced an average of 0.83 mild to moderate hypoglycemic event per month; no severe events were recorded. Patients showed no significant weight gain or change in pulmonary function compared with baseline. Conclusions: Pulmonary delivery of insulin in type 2 diabetic patients who require insulin improved glycemic control, was well tolerated, and demonstrated no adverse pulmonary effects. Larger-scale studies are ongoing to provide long-term efficacy and safety data. *For members of the Inhaled Insulin Study Group, see Appendix.

In the United States (US), diabetes mellitus is a serious and costly public health problem, affecting more than 16 million people. Its incidence will continue to grow, as indicated by high rates of impaired fasting glucose levels, increased rates of obesity, and the trend toward more sedentary lifestyles. The prevalence of diabetes increases with age and varies by gender, race, and ethnicity. Diabetes also presents an enormous economic burden in the US. In 1996, total health care costs were $1 trillion, $120 million of which was for diabetes. A large proportion of the per-person costs associated with diabetes is for treating diabetic complications. Morbidity and mortality rates are higher in patients with diabetes than in patients without diabetes. There has been some recent improvement in type 2 diabetes treatment with the availability of newer medications, including secretagogues, metformin, acarbose, and the ‘glitazones’. More patients are now using oral combination therapy, and fewer patients are using insulin. Unfortunately, many patients with type 2 diabetes are delaying the use of insulin, even when it is indicated for their treatment. Moreover, even with the new classes of oral antidiabetic agents, glycemic control remains suboptimal and patients still are not reaching the recommended target values for HbA1c (<7%). Primary medical care for diabetes patients is also less than optimal and must be improved. On an arbitrary gradient scale of 1 to 4 (with 1 being primitive and 4 being comprehensive), the US is only at stage 2 for diabetes care systems, indicating a pressing need for improvement in diabetes care. Copyright © 2002 John Wiley & Sons, Ltd.

The most important question for clinicians caring for diabetic patients, and for the patient themselves, is whether the risk of complications can be altered by careful control of glycemia. Epidemiologic studies showed a strong relationship between glycemia and diabetic complications, in both type I and type II diabetes. There is a continuous relationship between prevailing glycemia and risk of progression of complications, implying that any improvement in glycemic control is beneficial. The debate of the question has ended--glucose control is important.

TrialNet's goal to test preventions for type 1 diabetes has created an opportunity to gain new insights into the natural history of pre-type 1 diabetes. The TrialNet Natural History Study (NHS) will assess the predictive value of existing and novel risk markers for type 1 diabetes and will find subjects for prevention trials.The NHS is a three-phase, prospective cohort study. In phase 1 (screening), pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512, and islet cell antibodies) are measured. Phase 2 (baseline risk assessment) includes oral glucose tolerance tests (OGTTs) in antibody-positive subjects and estimation of 5-yr diabetes risks according to the OGTT and number of confirmed positive antibody tests. Phase 3 (follow-up risk assessments) requires OGTTs every 6 months. In phases 2 and 3, samples are collected for future tests of T-lymphocyte function, autoantibody isotypes, RNA gene expression, and proteomics. The primary outcome is diabetes onset.Of 12 636 relatives screened between March 2004 and December 2006, 605 (4.8%) were positive for at least one biochemical antibody. Of these, 322 were confirmed antibody positive and completed phase 2, of whom 296 subjects were given preliminary 5-yr diabetes risks of <25% (n = 132), > or =25% (n = 36), and > or =50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, > or =25%; 3 or more, > or =50%) and/or an abnormal OGTT (> or =50%).The NHS is identifying potential prevention trial subjects and is assembling a large cohort that will provide new natural history information about pre-type 1 diabetes. Follow-up to diabetes will help establish the biological significance and clinical value of novel type 1 diabetes risk markers.

OBJECTIVE—There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial–Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis. RESEARCH DESIGN AND METHODS—Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points. RESULTS—Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P &amp;lt; 0.001 for all indexes). Area under the curve (AUC) C-peptide (P &amp;lt; 0.05) and AUC C-peptide–to–AUC glucose ratio (P &amp;lt; 0.001) values decreased in the oral group; peak C-peptide–to–2-h glucose ratio values decreased in both groups (P &amp;lt; 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P &amp;lt; 0.05) and peak C-peptide (oral group, P &amp;lt; 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide–to–glucose ratio values decreased in both groups (P &amp;lt; 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P &amp;lt; 0.01). Fasting C-peptide–to–fasting glucose ratio values remained constant throughout the 30-month follow-up. CONCLUSIONS—These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.

OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.

Recent advances in insulins, insulin pumps, continuous glucose-monitoring systems, and control algorithms have resulted in an acceleration of progress in the development of artificial pancreas devices. This review discusses progress in the development of external systems that are based on subcutaneous drug delivery and subcutaneous continuous glucose monitoring. There are two major system-level approaches to achieving closed-loop control of blood glucose in diabetic individuals. The unihormonal approach uses insulin to reduce blood glucose and relies on complex safety mitigation algorithms to reduce the risk of hypoglycemia. The bihormonal approach uses both insulin to lower blood glucose and glucagon to raise blood glucose, and also relies on complex algorithms to provide for safety of the user. There are several major strategies for the design of control algorithms and supervision control for application to the artificial pancreas: proportional-integral-derivative, model predictive control, fuzzy logic, and safety supervision designs. Advances in artificial pancreas research in the first decade of this century were based on the ongoing computer revolution and miniaturization of electronic technology. The advent of modern smartphones has created the ability to utilize smartphone technology as the engineering centerpiece of an artificial pancreas. With these advances, an artificial or bionic pancreas is within reach.

Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and beta-cell function contribute to the progression to the disease.In 328 islet cell autoantibody-positive, nondiabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range 8], sequential OGTTs (2,143 in total) were performed at baseline, every 6 months, and 2.7 years [2.7] later, when 115 subjects became diabetic. Beta-cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses.In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas beta-cell glucose sensitivity was impaired (median 48 pmol/min per m2 per mmol/l [interquartile range 36] vs. 87 pmol/min per m2 per mmol/l [67]; P < 0.0001) and predicted incident diabetes (P < 0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-h glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (approximately 13 mmol x l(-1) x year(-1)); glucose sensitivity began to decline significantly (P < 0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable.In high-risk relatives, beta-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, with a slow linear increase followed by a rapid surge, and are anticipated by a further deterioration of beta-cell glucose sensitivity.

OBJECTIVE A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration &amp;lt;100 days). RESEARCH DESIGN AND METHODS A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value &amp;lt; 0.025. RESULTS The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. CONCLUSIONS Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.

We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D).TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity.The ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23-3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78-0.90] at 2 years, 0.81 [0.74-0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88-0.98] at 2 years, 0.91 [0.83-0.99] at 3 years) than either the DPTRS or the ABRS alone (P ≤ 0.01 for all comparisons).These findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.

Type 1 diabetes—or, more accurately, type 1A diabetes—is thought to arise from selective immunologically mediated destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans with consequent insulin deficiency (1). This occurs in individuals in whom genetic susceptibility outweighs genetic protection and is probably initiated by environmental factors not yet clearly defined. The disease arises via a cellular-mediated immune process, presumably a specific reaction to one or more β-cell proteins (autoantigens). There is consequent progressive impairment of β-cell function and apparent decline in β-cell mass. A secondary humoral immune response is characterized by the appearance of autoantibodies that serve as markers of the immune damage to β-cells. This insidious type 1 diabetes disease process generally evolves over a variable period of years (Fig. 1). The decline in β-cell function—and presumably in mass—is evidenced metabolically by loss of first-phase insulin response to an intravenous glucose challenge and later by the appearance of impairment in glycemic regulation, which is manifested as dysglycemia either as impaired glucose tolerance, impaired fasting glucose, or “indeterminate” glucose levels (values >200 mg/dl [11.1 mmol/l] at 30, 60, or 90 min during an oral glucose tolerance test). Ultimately, the clinical syndrome of type 1 diabetes becomes evident when the majority of β-cell function has been lost and presumably most β-cells have been destroyed; at this juncture, frank hyperglycemia supervenes. Although that broad sequence can be articulated, there are still gaps in many of the details. Further understanding of the nature of the disease process will facilitate the design of intervention strategies aimed at abrogating β-cell destruction and ultimately at prophylaxis of type 1 diabetes. FIG. 1. Progression of the type 1 diabetes disease process. This is a cellular autoimmune process occurring in individuals with a genetic predisposition to the disease, presumably triggered by some environmental factor. Humoral antibodies indicate …

To assess the safety, tolerability, and feasibility of adult allogeneic bone marrow-derived mesenchymal precursor cells (MPCs) in type 2 diabetes inadequately controlled with metformin either alone or with one additional oral antidiabetic agent.The study was a dose-escalating randomized placebo-controlled trial assessing one intravenous (IV) infusion of MPCs (rexlemestrocel-L; Mesoblast Inc.) 0.3 × 10(6)/kg (n = 15), 1.0 × 10(6)/kg (n = 15), or 2.0 × 10(6)/kg (n = 15) or placebo (n = 16). Study duration was 12 weeks.Subjects (21 women, 40 men) with a mean ± SD baseline HbA1c 8.3 ± 1.0% (67 ± 10.9 mmol/mol), BMI 33.5 ± 5.5 kg/m(2), and diabetes duration 10.1 ± 6.0 years were enrolled at 18 U.S. sites. No acute adverse events (AEs) were associated with infusion. No serious AEs, serious hypoglycemia AEs, or discontinuations due to AEs over 12 weeks were found. No subjects developed donor-specific anti-HLA antibodies or became sensitized. The safety profile was comparable among treatment groups. Compared with placebo, a single IV infusion of rexlemestrocel-L reduced HbA1c at all time points after week 1. The adjusted least squares mean ± SE dose-related differences in HbA1c from placebo in the rexlemestrocel-L groups ranged from -0.1 ± 0.2% (-1.1 ± 2.2 mmol/mol) to -0.4 ± 0.2% (4.4 ± 2.2 mmol/mol) at 8 weeks and from 0.0 ± 0.25% to -0.3 ± 0.25% (-3.3 ± -2.7 mmol/mol) at 12 weeks (P < 0.05 for 2.0 × 10(6)/kg dose at 8 weeks). The clinical target HbA1c <7% (53 mmol/mol) was achieved by 33% (5 of 15) of the subjects who received the 2.0 × 10(6)/kg dose vs. 0% of those who received placebo (P < 0.05).This short-term study demonstrates the safety and feasibility of up to 246 million MPCs in subjects with type 2 diabetes.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize-potentially even reverse-the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in β-cell function compared with randomized control groups, while others have failed to slow the decline in β-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.

OBJECTIVE Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P &amp;lt; 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P &amp;lt; 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

This study evaluated gender differences in glycemic control among adolescents with insulin-dependent diabetes mellitus (IDDM). Drawing upon a conceptual model, the role of diabetes-specific and psychological variables in predicting gender differences in adolescents' glycemic control was examined. Following routine appointments for medical care, 42 adolescents with IDDM completed several measures: Test of Diabetes Knowledge and Problem Solving-Revised; Self-Care Inventory; Beck Depression Inventory; and the State-Trait Anxiety Inventory. Metabolic control was assessed via HbA[sub 1c] assays. Findings revealed that girls were in worse metabolic control than boys and reported more symptoms of depression and anxiety. Furthermore, gender differences in metabolic control could be explained by the greater depressive symptomatology reported by adolescent girls. Possible reasons for the linkage between depression and poor metabolic control are discussed, as well as directions for future research and clinical implications.

Objective To provide an overview of U-500 regular insulin action, review published clinical studies with U- 500 regular insulin, and offer guidance to practicing endocrinologists for identifying patients for whom U-500 regular insulin may be appropriate. Methods This review has been produced through a synthesis of relevant published literature compiled via a literature search (MEDLINE search of the English-language literature published between January 1969, and July 2008, related to U-500, insulin resistance, concentrated insulin, high-dose insulin, insulin pharmacokinetics, and diabetes management) and the authors’ collective clinical experience. Results The obesity epidemic is contributing to an increase in the prevalence of type 2 diabetes, as well as to increasing insulin requirements in insulin-treated patients. Many of these patients exhibit severe insulin resistance, manifested by daily insulin requirements of 200 units or greater or more than 2 units/kg. Delivering an appropriate insulin volume to these patients can be difficult and inconvenient and may be best accomplished with U-500 regular insulin by multiple daily injections or with continuous subcutaneous insulin infusion, rather than with standard U-100 insulin. Implementation of U-500 regular insulin in patients previously on other insulin formulations is described with a treatment algorithm covering dosage requirements ranging from 150 to more than 600 units per day on the basis of the authors’ experience. Conclusion Regimen conversion of appropriately selected patients from high-dose, U-100 insulin to U-500 regular insulin therapy on the basis of the recommendations presented in this article may potentially result in improved glycemic control and lower cost. (Endocr Pract. 2009;15:71-79)

The accurate prediction of type 1 diabetes is essential for appropriately identifying prevention trial participants. Thus, we have developed a risk score for the prediction of type 1 diabetes.Diabetes Prevention Trial-Type 1 (DPT-1) participants, islet cell autoantibody (ICA)-positive relatives of type 1 diabetic patients (n = 670), were randomly divided into development and validation samples. Risk score values were calculated for the validation sample from development sample model coefficients obtained through forward stepwise proportional hazards regression.A risk score based on a model including log-BMI, age, log-fasting C-peptide, and postchallenge glucose and C-peptide sums from 2-h oral glucose tolerance tests (OGTTs) was derived from the development sample. The baseline risk score strongly predicted type 1 diabetes in the validation sample (chi(2) = 82.3, P < 0.001). Its strength of prediction was almost the same (chi(2) = 83.3) as a risk score additionally dependent on a decreased first-phase insulin response variable from intravenous glucose tolerance tests (IVGTTs). Biochemical autoantibodies did not contribute significantly to the risk score model. A final type 1 diabetes risk score was then derived from all participants with the same variables as those in the development sample model. The change in the type 1 diabetes risk score from baseline to 1 year was in itself also highly predictive of type 1 diabetes (P < 0.001).A risk score based on age, BMI, and OGTT indexes, without dependence on IVGTTs or additional autoantibodies, appears to accurately predict type 1 diabetes in ICA-positive relatives.

Type 1 Diabetes TrialNet is an international consortium of clinical research centers aimed at the prevention or delay of type 1 diabetes (T1D). The fundamental goal of TrialNet is to counter the T1D disease process by immune modulation and/or enhancement of β cell proliferation and regeneration. To achieve this goal, TrialNet researchers are working to better understand the natural history of the disease, to identify persons at risk, and to clinically evaluate novel therapies that balance potential risks and benefits. The particular focus is on studies of preventive measures. In addition, TrialNet evaluates therapies in individuals with newly diagnosed T1D with preserved β cell function to help determine the risk/benefit profile and gain an initial assessment of potential efficacy in preservation of β cell function, so that promising agents can be studied in prevention trials. In addition, TrialNet evaluates methodologies that enhance the conduct of its clinical trials, which includes tests of outcome assessment methodology, the evaluation of surrogate markers, and mechanistic studies laying the foundation for future clinical trials.

BackgroundB-lymphocyte depletion with rituximab has been shown to benefit patients with various autoimmune diseases. We have previously demonstrated that this benefit is also apparent in patients with newly diagnosed type 1 diabetes.ObjectivesThe effect of rituximab on in vivo antibody responses, particularly during the period of B-lymphocyte depletion, is incompletely determined. This study was designed to assess this knowledge void.MethodsIn patients with recent-onset type 1 diabetes treated with rituximab (n = 46) or placebo (n = 29), antibody responses to neoantigen phiX174 during B-lymphocyte depletion and with hepatitis A (as a second neoantigen) and tetanus/diphtheria (as recall antigens) after B-lymphocyte recovery were studied. Anti- tetanus, diphtheria, mumps, measles, and rubella titers were measured before and after treatment by means of ELISA. Antibody titers and percentage IgM versus percentage IgG to phiX174 were measured by means of phage neutralization. B-lymphocyte subsets were determined by means of flow cytometry.ResultsNo change occurred in preexisting antibody titers. Tetanus/diphtheria and hepatitis A immunization responses were protective in the rituximab-treated subjects, although significantly blunted compared with those seen in the controls subjects, when immunized at the time of B-lymphocyte recovery. Anti-phiX174 responses were severely reduced during the period of B-lymphocyte depletion, but with B-lymphocyte recovery, anti-phiX174 responses were within the normal range.ConclusionsDuring the time of B-lymphocyte depletion, rituximab recipients had a decreased antibody response to neoantigens and significantly lower titers after recall immunization with diphtheria and tetanus toxoid. With recovery, immune responses return toward normal. Immunization during the time of B-lymphocyte depletion, although ineffective, does not preclude a subsequent response to the antigen. B-lymphocyte depletion with rituximab has been shown to benefit patients with various autoimmune diseases. We have previously demonstrated that this benefit is also apparent in patients with newly diagnosed type 1 diabetes. The effect of rituximab on in vivo antibody responses, particularly during the period of B-lymphocyte depletion, is incompletely determined. This study was designed to assess this knowledge void. In patients with recent-onset type 1 diabetes treated with rituximab (n = 46) or placebo (n = 29), antibody responses to neoantigen phiX174 during B-lymphocyte depletion and with hepatitis A (as a second neoantigen) and tetanus/diphtheria (as recall antigens) after B-lymphocyte recovery were studied. Anti- tetanus, diphtheria, mumps, measles, and rubella titers were measured before and after treatment by means of ELISA. Antibody titers and percentage IgM versus percentage IgG to phiX174 were measured by means of phage neutralization. B-lymphocyte subsets were determined by means of flow cytometry. No change occurred in preexisting antibody titers. Tetanus/diphtheria and hepatitis A immunization responses were protective in the rituximab-treated subjects, although significantly blunted compared with those seen in the controls subjects, when immunized at the time of B-lymphocyte recovery. Anti-phiX174 responses were severely reduced during the period of B-lymphocyte depletion, but with B-lymphocyte recovery, anti-phiX174 responses were within the normal range. During the time of B-lymphocyte depletion, rituximab recipients had a decreased antibody response to neoantigens and significantly lower titers after recall immunization with diphtheria and tetanus toxoid. With recovery, immune responses return toward normal. Immunization during the time of B-lymphocyte depletion, although ineffective, does not preclude a subsequent response to the antigen.

OBJECTIVE We assessed diabetes risk associated with zinc transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma-associated protein 2 antigen (IA-2A). RESEARCH DESIGN AND METHODS For this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody-negative relatives. RESULTS ZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA+ vs. 8 of 911 [0.8%] BAA−, P &amp;lt; 0.001) and BAA number (177 of 1,683 [10.5%] single-, 221 of 384 [57.6%] double-, and 150 of 189 [79.4%] triple-BAA positivity, P &amp;lt; 0.001). The 4-year diabetes risk was higher in single BAA+ relatives with ZnT8A than ZnT8A− relatives (31 vs. 7%, P &amp;lt; 0.001). In multivariable analysis, age ≤20 years (hazard ratio 2.13, P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not (P = 0.81 and 0.86, respectively). CONCLUSIONS In relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies.

Abstract Since type 1 diabetes is an immunologically mediated disease, immune intervention should alter the natural history of the disease. This article reviews prevention studies undertaken either prior to any evidence of autoimmunity (primary prevention) or after the development of islet autoantibodies (secondary prevention). Most immune intervention studies have been conducted in recent‐onset type 1 diabetes (tertiary prevention), and these are not reviewed herein. The goal of primary and secondary intervention is to arrest the immune process and thus prevent or delay clinical disease. Primary prevention studies have been conducted in infants with high genetic risk. Interventions tested include several dietary manipulations, including infant formulas free of either cow's milk or of bovine insulin, infant formula supplemented with the omega‐3‐fatty acid docosahexaenoic acid, delayed introduction of gluten‐containing foods, and vitamin D supplementation. Secondary prevention studies have been conducted in both children and adults with diabetes autoantibodies. Interventions tested include nicotinamide, insulin injections, oral insulin, nasal insulin, glutamic acid decarboxylase, and cyclosporine. Underway are secondary prevention studies with teplizumab and with abatacept.

We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis.

OBJECTIVE We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. RESEARCH DESIGN AND METHODS Diabetes Prevention Trial–Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose &amp;lt;200 mg/dL (Ind60+Only) were compared with Index60 &amp;lt;2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. RESULTS Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P &amp;lt; 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range −22 to −34% in DPT-1 and −14 to −27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. CONCLUSIONS An approach based on prediction and natural history appears to have utility for diagnosing T1D.

Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes.FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months' duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-< 5000 mg/g (≥ 22.6-< 565 mg/mmol) and eGFR of ≥ 25-< 90 ml/min/1.73 m2.The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia.FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years.ClinicalTrials.gov NCT05901831.

The purpose of this study was to evaluate the 2-year pulmonary safety of inhaled human insulin (Exubera [EXU]) in 635 nonsmoking adults with type 2 diabetes.Patients were randomly assigned to receive prandial EXU or subcutaneous insulin (regular or short-acting) plus basal (intermediate- or long-acting) insulin. The primary end points were the annual rate of decline in forced expiratory volume in 1 s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)).Small differences in FEV(1) favoring subcutaneous insulin developed during the first 3 months but did not progress. Adjusted treatment group differences in FEV(1) annual rate of change were -0.007 l/year (90% CI -0.021 to 0.006) between months 0 and 24 and 0.000 l/year (-0.016 to 0.016) during months 3-24. Treatment group differences in DL(CO) annual rate of change were not significant. Both groups sustained similar reductions in A1C by month 24 (last observation carried forward) (EXU 7.7-7.3% vs. subcutaneous insulin 7.8-7.3%). Reductions in fasting plasma glucose (FPG) were greater with EXU than with subcutaneous insulin (adjusted mean treatment difference -12.4 mg/dl [90% CI -19.7 to -5.0]). Incidence of hypoglycemia was comparable in both groups. Weight increased less with EXU than with subcutaneous insulin (-1.3 kg [-1.9 to -0.7]). Adverse events were comparable, except for a higher incidence of mild cough and dyspnea with EXU.Two-year prandial EXU therapy showed a small nonprogressive difference in FEV(1) and comparable sustained A1C improvement but lower FPG levels and less weight gain than seen in association with subcutaneous insulin in adults with type 2 diabetes.

Type 1 diabetes mellitus (T1D) arises from selective immunologically mediated destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans with consequent insulin deficiency.1,2 This occurs in genetically susceptible individuals and is a cellular-mediated process, presumably a specific reaction to one or more β-cell proteins (autoantigens), although probably initiated by some environmental factor(s). There is consequent progressive impairment of β-cell function and decline in β-cell mass. A secondary humoral immune response is characterized by the appearance of autoantibodies that serve as markers of the immune damage to β-cells.3,4,5 This insidious T1D disease process evolves over a period of years.6 The decline in β-cell function and mass is evidenced metabolically by loss of first-phase insulin response to an intravenous glucose challenge,7,8 and later by the appearance of impairment in glycemic regulation, manifested as dysglycemia—usually as impaired glucose tolerance, but occasionally as impaired fasting glucose.9 Ultimately, the clinical syndrome of T1D becomes evident when the majority of β-cells have been destroyed and frank hyperglycemia supervenes. Given this sequence of events, for which it is possible to envision intervention to interdict the process, it is not surprising that much research effort has been expended to identify individuals at risk of the disease. Clinical Pharmacology & Therapeutics (2007) 81, 768–771. doi:10.1038/sj.clpt.6100179; published online 28 March 2007

OBJECTIVE—We examined metabolic changes in the period immediately after the diagnosis of type 1 diabetes and in the period leading up to its diagnosis in Diabetes Prevention Trial–Type 1 (DPT-1) participants. RESEARCH DESIGN AND METHODS—The study included oral insulin trial participants and parenteral insulin trial control subjects (n = 63) in whom diabetes was diagnosed by a 2-h diabetic oral glucose tolerance test (OGTT) that was confirmed by another diabetic OGTT within 3 months. Differences in glucose and C-peptide levels between the OGTTs were assessed. RESULTS—Glucose levels increased at 90 (P = 0.006) and 120 min (P &amp;lt; 0.001) from the initial diabetic OGTT to the confirmatory diabetic OGTT (mean ± SD interval 5.5 ± 2.8 weeks). Peak C-peptide levels fell substantially between the OGTTs (median change −14.3%, P &amp;lt; 0.001). Among the 55 individuals whose last nondiabetic OGTT was ∼6 months before the initial diabetic OGTT, peak C-peptide levels decreased between these two OGTTs (median change −14.0%, P = 0.052). Among those same individuals the median change in peak C-peptide levels from the last normal OGTT to the confirmatory OGTT (interval 7.5 ± 1.3 months) was −23.8% (P &amp;lt; 0.001). Median rates of change in peak C-peptide levels were 0.00 ng · ml−1 · month−1 (P = 0.468, n = 36) from ∼12 to 6 months before diagnosis, −0.10 ng · ml−1 · month−1 (P = 0.059, n = 55) from 6 months before diagnosis to diagnosis, and −0.43 ng · ml−1 · month−1 (P = 0.002, n = 63) from the initial diabetic OGTT to the confirmatory diabetic OGTT. CONCLUSIONS—It seems that postchallenge C-peptide levels begin to decrease appreciably in the 6 months before diagnosis and decrease even more rapidly within 3 months after diagnosis.

Summary The Diabetes Control and Complications Trial (DCCT) led to considerable improvements in the management of type 1 diabetes, with the wider adoption of intensive insulin therapy to reduce the risk of complications. However, a large gap between evidence and practice remains, as recently shown by the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, in which 30-year rates of microvascular complications in the 'real world' EDC patients were twice that of DCCT patients who received intensive insulin therapy. This gap may be attributed to the many challenges that patients and practitioners face in the day-to-day management of the disease. These barriers include reaching glycaemic goals, overcoming the reality and fear of hypoglycaemia, and appropriate insulin therapy and dose adjustment. As practitioners, the question remains: how do we help patients with type 1 diabetes manage glycaemia while overcoming barriers? In this article, the Global Partnership for Effective Diabetes Management provides practical recommendations to help improve the care of patients with type 1 diabetes.

Understanding the relationship between age and islet autoantibody (Ab) seroconversion can establish the optimal screening interval(s) to assess risk for type 1 diabetes, identify subjects who can participate in prevention trials, and determine associated costs. This study assessed the rates of seroconversion to glutamic acid decarboxylase positive (GAD65(+)), insulin positive (mIAA(+)), and insulinoma-associated protein 2 positive (ICA512(+)) in a large cohort of relatives of type 1 diabetes probands undergoing Ab rescreening in the TrialNet Natural History Study.Of 32,845 children aged <18 years screened for Abs, 1,287 (3.9%) were GAD65(+), 778 (2.4%) were mIAA(+), 677 (2.1%) were ICA512(+), and 31,038 were Ab-negative. Ab-negative children were offered annual rescreening up to 18 years of age. Cox regression was used to estimate the risk for GAD65, mIAA, and ICA512 seroconversion. RESULTS There were 205 children who seroconverted to GAD65(+), 155 who seroconverted to mIAA(+), and 53 who seroconverted to ICA512(+) over 5.8 years of follow-up. The risk of mIAA (hazard ratio 0.89 [95% CI 0.85-0.92]) and GAD65 (0.96 [0.93-0.99]) seroconversion significantly decreased with increasing age (i.e., for each 1-year increase in age, the risk of seroconversion decreased by 11% [P < 0.0001] for mIAA and 4% [P = 0.04] for GAD65) across all ages. The cumulative Ab seroconversion was 2% for those <10 years of age versus 0.7% for those ≥10 years of age.The risk of development of islet Abs declines with increasing age in type 1 diabetes relatives. These data support annual screening for children <10 years of age and one additional screening in adolescence.

Type 1 diabetes (T1D) is often first recognized when signs and symptoms occur, yet the pathogenetic development of T1D usually begins years before that. Pancreatic autoantibodies commonly become elevated long before diagnosis (1). Although data indicate that the first-phase insulin response (FPIR) is also abnormal well before diagnosis (2–5), the development and progression of metabolic abnormalities had not been well characterized until the recent performance of T1D prevention trials (6–8). The unique designs of these trials provided the opportunity to perform longitudinal studies that have yielded new insights into metabolic changes that occur during the progression to T1D. This review will describe what we have learned about the metabolic natural history of T1D from the Diabetes Prevention Trial–Type 1 (DPT-1). ### A description of DPT-1. DPT-1 included two separate trials, the parenteral and oral insulin trials (6,7). The objective of both trials was to delay or prevent the occurrence of T1D by interfering with the immunologic processes that result in the disorder. The parenteral insulin trial consisted of an intervention group that received subcutaneous ultralente insulin at a dose of 0.125 units/kg twice daily and a control group that received no insulin. The intervention group was admitted annually to a unit for 4 days during which a continuous infusion of recombinant human regular insulin was administered. The oral insulin trial included an intervention group, which received a once-daily dose of 7.5 mg recombinant human insulin crystals, and a placebo control group. In both trials, individuals were required to be nondiabetic, aged 1–45 years, and first- or second-degree relatives of T1D patients. Two phases determined further eligibility for the trials. In the screening phase, the relatives were tested for islet cell autoantibody (ICA) positivity. Those positive then participated in a risk assessment phase. This included an intravenous glucose tolerance test …

Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.

Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic beta cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of beta cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of beta cell function have established a predictive relationship between stimulated C-peptide as a measure of beta cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of beta cell function, but also as a specific, sensitive, feasible, and clinically meaningful outcome defining beta cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes.

To examine the correlates of plasma leptin, including fasting insulin, adiposity, and several health habits and behaviors among a nondiabetic multiethnic population.A cross-sectional study was conducted among 25-44 year old African-Americans (n = 126), Cuban-Americans (n = 107), and non-Hispanic whites (n = 189) randomly selected from Dade County Florida. Fasting leptin levels were correlated with fasting insulin, percent body fat, smoking, alcohol use, and physical activity within each sex. Multiple linear regression and analysis of covariance were used to estimate the independent determinants of plasma leptin concentration separately among men and women.Stepwise linear regression analyses revealed statistically significant associations of leptin with percent body fat, fasting insulin, cigarette smoking, and physical activity (both inversely) among men (p < 0.05 for each). Among women, percent body fat, fasting insulin (both positively), cigarette smoking, and alcohol use (inversely) were independent predictors of leptin levels explaining over 70% of the variance. Analyses of covariance revealed that women had higher adjusted mean leptin levels than men (13.1 ng/ml vs. 5.9 ng/ml; p < 0.001), whereas no separate effect of ethnicity was noted.Although adiposity was the strongest correlate of leptin levels, fasting insulin and several health habits and behaviors were independently associated with leptin. After adjustment for these factors, women had significantly higher mean leptin levels than men. The independent association among leptin and insulin levels is intriguing and suggests additional avenues for epidemiologic research.

This paper reviews worldwide efforts to interdict the type 1 diabetes (T1D) disease process, during the stage of evolution of the disease prior to the time of disease onset. The goal of intervention before disease onset is to arrest immune destruction and thus prevent or delay clinical disease. In this regard, there have been several large-scale multicenter randomized controlled clinical trials designed to prevent T1D. These have tested nicotinamide, parenteral insulin, oral insulin, nasal insulin, and the elimination of cow's milk from infant feeding.

We assessed the extent to which both standard and alternative indexes from 2-h oral glucose tolerance testing predict type 1 diabetes and whether oral glucose tolerance tests (OGTTs) predict type 1 diabetes in individuals with normal glucose tolerance.The prediction of type 1 diabetes from baseline OGTTs was studied in 704 Diabetes Prevention Trial-Type 1 participants (islet-cell autoantibody [ICA]-positive relatives of type 1 diabetic patients). The maximum follow-up was 7.4 years. Analyses utilized receiver-operator curves (ROCs), proportional hazards models, and survival curves.ROC areas under the curve (ROCAUCs) for both the AUC glucose (0.73 +/- 0.02) and an OGTT prediction index (0.78 +/- 0.02) were higher (P < 0.001) than those for the fasting (0.53 +/- 0.02) and 2-h glucose (0.66 +/- 0.02). ROCAUCs for the 60- and 90-min glucose (0.71 +/- 0.02 and 0.72 +/- 0.02, respectively) were also higher (P < 0.01) than those for the fasting and 2-h glucose. Among individuals with normal glucose tolerance, OGTTs were highly predictive, with 4th versus 1st quartile hazard ratios for the 2-h glucose, AUC glucose, and OGTT prediction index ranging from 3.77 to 5.30 (P < 0.001 for all).Certain alternative OGTT indexes appear to better predict type 1 diabetes than standard OGTT indexes in ICA-positive relatives of type 1 diabetic patients. Moreover, even among those with normal glucose tolerance, OGTTs are strongly predictive. This suggests that subtle metabolic abnormalities are present several years before the diagnosis of type 1 diabetes.

OBJECTIVE We studied the incidence of dysglycemia and its prediction of the development of type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, we assessed whether dysglycemia was sustained. RESEARCH DESIGN AND METHODS Participants (n = 515) in the Diabetes Prevention Trial–Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for type 1 diabetes prediction. RESULTS Of 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month visit was highly predictive of the development of type 1 diabetes, both in those aged &amp;lt;13 years (P &amp;lt; 0.001) and those aged ≥13 years (P &amp;lt; 0.01). Those aged &amp;lt;13 years with dysglycemia at the 6-month visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis. CONCLUSIONS ICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is strongly predictive of type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of type 1 diabetes.

OBJECTIVE We studied the C-peptide response to oral glucose with progression to type 1 diabetes in Diabetes Prevention Trial-Type 1 (DPT-1) participants. RESEARCH DESIGN AND METHODS Among 504 DPT-1 participants <15 years of age, longitudinal analyses were performed in 36 progressors and 80 nonprogressors. Progressors had oral glucose tolerance tests (OGTTs) at baseline and every 6 months from 2.0 to 0.5 years before diagnosis; nonprogressors had OGTTs over similar intervals before their last visit. Sixty-six progressors and 192 nonprogressors were also studied proximal to and at diagnosis. RESULTS The 30-0 min C-peptide difference from OGTTs performed 2.0 years before diagnosis in progressors was lower than the 30-0 min C-peptide difference from OGTTs performed 2.0 years before the last visit in nonprogressors (P < 0.01) and remained lower over time. The 90-60 min C-peptide difference was positive at every OGTT before diagnosis in progressors, whereas it was negative at every OGTT before the last visit in nonprogressors (P < 0.01 at 2.0 years). The percentage whose peak C-peptide occurred at 120 min was higher in progressors at 2.0 years (P < 0.05); this persisted over time (P < 0.001 at 0.5 years). However, the peak C-peptide levels were only significantly lower at 0.5 years in progressors (P < 0.01). The timing of the peak C-peptide predicted type 1 diabetes (P < 0.001); peak C-peptide levels were less predictive (P < 0.05). CONCLUSIONS A decreased early C-peptide response to oral glucose and an increased later response occur at least 2 years before the diagnosis of type 1 diabetes.

OBJECTIVE In this investigation we evaluated nine metabolic indexes from intravenous glucose tolerance tests (IVGTTs) and oral glucose tolerance tests (OGTTs) in an effort to determine their prognostic performance in predicting the development of type 1 diabetes in those with moderate risk, as defined by familial relation to a type 1 diabetic individual, a positive test for islet cell antibodies and insulin autoantibody, but normal glucose tolerance. RESEARCH DESIGN AND METHODS Subjects (n = 186) who had a projected risk of 25–50% for developing type 1 diabetes within 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial–Type 1. Prognostic performance of the metabolic indexes was determined using receiver operating characteristic (ROC) curve and survival analyses. RESULTS Two-hour glucose from an OGTT most accurately predicted progression to disease compared with all other metabolic indicators with an area under the ROC curve of 0.67 (95% CI 0.59–0.76), closely followed by the ratio of first-phase insulin response (FPIR) to homeostasis model assessment of insulin resistance (HOMA-IR) with an area under the curve value of 0.66. The optimal cutoff value for 2-h glucose (114 mg/dl) maintained sensitivity and specificity values &amp;gt;0.60. The hazard ratio for those with 2-h glucose ≥114 mg/dl compared with those with 2-h glucose &amp;lt;114 mg/dl was 2.96 (1.67–5.22). CONCLUSIONS The ratio of FPIR to HOMA-IR from an IVGTT provided accuracy in predicting the development of type 1 diabetes similar to that of 2-h glucose from an OGTT, which, because of its lower cost, is preferred. The optimal cutoff value determined for 2-h glucose provides additional guidance for clinicians to identify subjects for potential prevention treatments before the onset of impaired glucose tolerance.

Diabetes Technology & TherapeuticsVol. 11, No. S1 Continuous Glucose Monitoring (CGM) SupplementContinuous Glucose Monitoring: An Overview of Its DevelopmentJay S. SkylerJay S. SkylerSearch for more papers by this authorPublished Online:26 May 2009https://doi.org/10.1089/dia.2009.0045AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byTransdermal amperometric biosensors for continuous glucose monitoring in diabetesTalanta, Vol. 253Artificial pancreasUseful Measurement of Glucose Variability by Flash Glucose Monitoring (FGM) with the Efficacy of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor6 January 2020 | Diabetes Research: Open Access, Vol. 2, No. S1Clinical effect for diabetic pregnant female by Low Carbohydrate Diet (LCD) and Continuous Glucose Monitoring (CGM)28 August 2019 | Obstetrics & Gynecology International Journal, Vol. 10, No. 4FPGA Based Smart System for Non Invasive Blood Glucose Sensing Using Photoplethysmography and Online Correction of Motion Artifact28 October 2016Electrochemical Glucose Biosensors for Diabetes Care28 June 2016Brief Review on Integrated Planar Waveguide-Based Optical Sensor31 August 2016FPGA based system for blood glucose sensing using photoplethysmography and online motion artifact correction using adalineTherapeutic transdermal drug innovation from 2000 to 2014: current status and outlookDrug Discovery Today, Vol. 20, No. 11Design and Development of a Mechatronic System for Noninvasive Refilling of Implantable Artificial PancreasIEEE/ASME Transactions on Mechatronics, Vol. 20, No. 3Noninvasive Blood Glucose Sensing Using Near Infra-Red Spectroscopy and Artificial Neural Networks Based on Inverse Delayed Function Model of Neuron11 December 2014 | Journal of Medical Systems, Vol. 39, No. 1Continuous Glucose Monitoring in Insulin-Treated Patients in Non-ICU Settings13 August 2014 | Journal of Diabetes Science and Technology, Vol. 8, No. 5Is the Masked Continuous Glucose Monitoring System Clinically Useful for Predicting Hemoglobin A1C in Type 1 Diabetes? Elizabeth Duran-Valdez, Mark R. Burge, Paula Broderick, Lynda Shey, Virginia Valentine, Ronald Schrader, and David S. Schade23 April 2014 | Diabetes Technology & Therapeutics, Vol. 16, No. 5A Micromachined Glucose Monitoring Sensor with Diffusion Control1 April 2014 | Key Engineering Materials, Vol. 609-610Magnitude of the Dawn Phenomenon and Its Impact on the Overall Glucose Exposure in Type 2 Diabetes13 November 2013 | Diabetes Care, Vol. 36, No. 12Predicting Glucose Sensor Behavior in Blood Using Transport Modeling: Relative Impacts of Protein Biofouling and Cellular Metabolic Effects1 November 2013 | Journal of Diabetes Science and Technology, Vol. 7, No. 6Towards Smart Tattoos: Implantable Biosensors for Continuous Glucose Monitoring26 November 2012 | Advanced Healthcare Materials, Vol. 2, No. 1La variabilité glycémique en réanimationAnnales Françaises d'Anesthésie et de Réanimation, Vol. 31, No. 12Comparative Analysis of the Efficacy of Continuous Glucose Monitoring and Self-Monitoring of Blood Glucose in Type 1 Diabetes Mellitus1 September 2012 | Journal of Diabetes Science and Technology, Vol. 6, No. 5Micromachined biosensor system for interstitial fluid sampling and glucose monitoringArtificial PancreasUsing a Stochastic Model to Detect Unusual Continuous Glucose Monitor Behaviour in Newborn InfantsIFAC Proceedings Volumes, Vol. 45, No. 18Management of Type 1 Diabetes2 November 2011Amperometric Biosensors8 February 2012A New Index to Optimally Design and Compare Continuous Glucose Monitoring Glucose Prediction Algorithms Andrea Facchinetti, Giovanni Sparacino, Emanuele Trifoglio, and Claudio Cobelli1 February 2011 | Diabetes Technology & Therapeutics, Vol. 13, No. 2From pancreatic extracts to artificial pancreas: History, science and controversies about the discovery of the pancreatic antidiabetic hormoneAvances en Diabetología, Vol. 27, No. 1Modeling the relative impact of capsular tissue effects on implanted glucose sensor time lag and signal attenuation28 August 2010 | Analytical and Bioanalytical Chemistry, Vol. 398, No. 4Mesure du glucose en continu et insulinothérapie en boucle fermée : une alternative à l’autosurveillance glycémique ?Médecine des Maladies Métaboliques, Vol. 4Current World LiteratureCurrent Opinion in Endocrinology, Diabetes & Obesity, Vol. 17, No. 4Use of Sensors in the Treatment and Follow-up of Patients with Diabetes Mellitus9 August 2010 | Sensors, Vol. 10, No. 8“Smart” Continuous Glucose Monitoring Sensors: On-Line Signal Processing Issues12 July 2010 | Sensors, Vol. 10, No. 7Microdialysis based device for continuous extravascular monitoring of blood glucose26 January 2010 | Biomedical Microdevices, Vol. 12, No. 3Long-term calibration considerations during subcutaneous microdialysis sampling in mobile ratsBiomaterials, Vol. 31, No. 16Monitorización de la glucosa en tiempo real. ¿Panacea o mera distracción?Avances en Diabetología, Vol. 26, No. 2Role of continuous glucose monitoring in diabetes managementAvances en Diabetología, Vol. 26, No. 2Glucose response of dissolved-core alginate microspheres: towards a continuous glucose biosensorThe Analyst, Vol. 135, No. 10How accurately do we measure blood glucose levels in intensive care unit (ICU) patients?Best Practice & Research Clinical Anaesthesiology, Vol. 23, No. 4Initiation of Prandial Insulin Therapy with AIR Inhaled Insulin or Insulin Lispro in Patients with Type 2 Diabetes: A Randomized Noninferiority Trial Jorge L. Gross, Masako Nakano, Gildred Colon-Vega, Ramon Ortiz-Carasquillo, Jeffrey A. Ferguson, Sandra Althouse, Janet A. Tobian, Pierre-Yves Berclaz, and Zvonko Milicevic22 September 2009 | Diabetes Technology & Therapeutics, Vol. 11, No. s2Efficacy and Safety of AIR Inhaled Insulin Compared to Insulin Lispro in Patients with Type 1 Diabetes Mellitus in a 6-Month, Randomized, Noninferiority Trial Angel L. Comulada, Eric Renard, Masako Nakano, Nadeem Rais, Xuejing Mao, David M. Webb, and Zvonko Milicevic22 September 2009 | Diabetes Technology & Therapeutics, Vol. 11, No. s2The Future of Continuous Glucose Monitoring Satish K. Garg26 May 2009 | Diabetes Technology & Therapeutics, Vol. 11, No. S1 Volume 11Issue S1Jun 2009 InformationCopyright 2009, Mary Ann Liebert, Inc.To cite this article:Jay S. Skyler.Continuous Glucose Monitoring: An Overview of Its Development.Diabetes Technology & Therapeutics.Jun 2009.S-5-S-10.http://doi.org/10.1089/dia.2009.0045Published in Volume: 11 Issue S1: May 26, 2009PDF download

We assessed the accuracy of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), developed from the Diabetes Prevention Trial-Type 1 (DPT-1), in the TrialNet Natural History Study (TNNHS).Prediction accuracy of the DPTRS was assessed with receiver-operating characteristic curve areas. The type 1 diabetes cumulative incidence within the DPTRS intervals was compared between the TNNHS and DPT-1 cohorts.Receiver-operating characteristic curve areas for the DPTRS were substantial in the TNNHS (P < 0.001 at both 2 and 3 years). The type 1 diabetes cumulative incidence did not differ significantly between the TNNHS and DPT-1 cohorts within DPTRS intervals. In the TNNHS, 2-year and 3-year risks were low for DPTRS intervals <6.50 (<0.10 and <0.20, respectively). Thresholds ≥7.50 were indicative of high risk in both cohorts (2-year risks: 0.49 in the TNNHS and 0.51 in DPT-1).The DPTRS is an accurate and robust predictor of type 1 diabetes in autoantibody-positive populations.

OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants. RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991). It was also compared between individuals with DPTRS values <7.00 or >7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS. DPTRS values >7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants. The reliability of DPTRS values >7.00 was compared with dysglycemia in the TNNHS. RESULTS The cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values >7.00 was comparable to those with dysglycemia. Among those with dysglycemia, the cumulative incidence was much higher (P < 0.001) for those with DPTRS values >7.00 than for those with values <7.00 (3-year risks: 0.16 for <7.00 and 0.46 for >7.00). Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P < 0.001); there was no significant difference in risk between the studies among those with DPTRS values >7.00. The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values >7.00 to values <7.00 (36 vs. 23%). CONCLUSIONS DPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals. The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.

OBJECTIVE Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone. RESEARCH DESIGN AND METHODS The study was conducted worldwide in 465 subjects, with baseline HbA1c of 7–10% (53–86 mmol/mol) and fasting serum glucose of 130–240 mg/dL, randomized to placebo versus ranolazine. RESULTS Compared with placebo, there was a greater decline in HbA1c at week 24 from baseline (primary end point) in subjects taking ranolazine (mean difference −0.56% [−6.1 mmol/mol]; P &amp;lt; 0.0001). Moreover, the proportion of subjects achieving an HbA1c &amp;lt;7.0% was greater with ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference −8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference −19 mg/dL; P = 0.0008 vs. placebo). Subjects taking ranolazine trended toward a greater decrease from baseline in fasting insulin (P = 0.0507), a greater decrease in fasting glucagon (P = 0.0003), and a lower postprandial 3-h glucagon area under the curve (P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated. CONCLUSIONS Compared with placebo, use of ranolazine monotherapy over 24 weeks, in subjects with type 2 diabetes and inadequate glycemic control on diet and exercise alone, significantly reduced HbA1c and other measures of glycemic control.

Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic β-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D.This was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell (RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide (LPS), 1 µg/mL.The levels of RBC DHA were increased by 61-100% in treated compared to control infants at ages 6-36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1β, TNFα, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein (hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing ≥two persistently positive biochemical islet autoantibodies.This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced.

OBJECTIVE Metabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies. RESEARCH DESIGN AND METHODS Baseline 2-h oral glucose tolerance test data from 6,620 TrialNet Pathway to Prevention Study (TNPTP) autoantibody-positive participants (relatives of individuals with type 1 diabetes) were used to form 25 zones from five area under the curve glucose (AUCGLU) rows and five area under the curve C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data. RESULTS As AUCGLU increased, changes of glucose and C-peptide response curves (from mean glucose and mean C-peptide values at 30, 60, 90, and 120 min) were similar within the five AUCPEP columns. Among the zones, 5-year risk for type 1 diabetes was highly correlated with islet antigen 2 antibody prevalence (r = 0.96, P &amp;lt; 0.001). Disease risk decreased markedly in the highest AUCGLU row as AUCPEP increased (0.88–0.41; P &amp;lt; 0.001 from lowest AUCPEP column to highest AUCPEP column). AUCGLU correlated appreciably less with Index60 (an indicator of insulin secretion) in the highest AUCPEP column (r = 0.33) than in other columns (r ≥ 0.78). AUCGLU was positively related to “fasting glucose × fasting insulin” and to “fasting glucose × fasting C-peptide” (indicators of insulin resistance) before and after adjustments for Index60 (P &amp;lt; 0.001). CONCLUSIONS Phenotypes of 25 zones formed from AUCGLU and AUCPEP were used to gain insights into type 1 diabetes heterogeneity. Zones were used to examine GCRC changes with increasing AUCGLU, associations between risk and autoantibody prevalence, the dependence of glucose as a predictor of risk according to C-peptide, and glucose heterogeneity from contributions of insulin secretion and insulin resistance.

Whether serum leptin levels are associated with insulin resistance independent of the effects of hyperinsulinemia and adiposity is an important unanswered question. We examined the relationship between the rate of insulin-mediated glucose uptake and serum leptin concentrations among nondiabetic men and women.A cross-sectional analysis was performed among 49 young to middle-aged men and women who participated in the Miami Community Health Study. All participants had measures of insulin resistance (euglycemic-hyperinsulinemic clamp), postchallenge insulin levels, fasting serum leptin levels, and several measures of adiposity.The rate of insulin-mediated glucose uptake (M in milligrams per kilogram per minute) was significantly associated with leptin concentrations in both men (r = -0.83; P < 0.001) and women (r = -0.59; P < 0.001). M was also inversely related to percent body fat and to the 2-h insulin area under the curve (AUC). After covariate adjustment for sex, percent body fat, and AUC, leptin remained a significant correlate of M (P = 0.04).Cross-sectionally, leptin was significantly associated with insulin resistance in this nondiabetic sample of men and women. There may be a different physiological mechanism to explain the leptin/insulin resistance association apart from the insulin/adiposity link. Confirmatory evidence awaits the results of clinical trials.

FreeStyle accurately measures the concentration of glucose in a 300-nL volume of capillary blood obtained with significantly reduced pain from the forearm where the density of capillaries is much lower than in the fingertips. The readings are independent of temperature, of altitude (O2 pressure) and of hematocrit in the 0%-60% range. At their physiological levels, none of the often interfering constituents of blood affect the readings.

The purpose of this study was to examine characteristics associated with the insulin metabolic syndrome, including insulin resistance, abnormal glucose tolerance, dyslipidemia, obesity, and elevated blood pressure, among women who have experienced gestational diabetes. 39 nondiabetic, young (20-42 years), postpartum (3-18 months) white women were recruited from obstetrical clinics. Twenty-one women had a history of gestational diabetes; 18 had uncomplicated pregnancies. Multivariate analyses revealed a significant difference between groups in insulin resistance (M, measured by euglycemic clamp) and insulin levels (from an oral glucose tolerance test), with insulin resistance showing a statistically stronger difference than insulin levels. Groups also differed significantly when compared on a set of variables associated with insulin metabolic syndrome: glucose tolerance, triglycerides, blood pressure, and body-mass index. Using insulin resistance as a covariate eliminated these group differences, suggesting that insulin resistance is the key factor underlying insulin metabolic syndrome. The higher risk of later developing type 2 diabetes and hypertension in women who have a history of gestational diabetes is explicable by their poorer profile on variables associated with insulin metabolic syndrome, and appears to be attributable to insulin resistance. Thus, insulin resistance appears to distinguish young women at risk for cardiovascular disease.

Diabetes Technology & TherapeuticsVol. 11, No. 8 EditorialInsulin Glargine and Cancer—An Unsubstantiated AllegationSatish K. Garg, Irl B. Hirsch, and Jay S. SkylerSatish K. GargBarbara Davis Center for Childhood Diabetes, Aurora, Colorado.Search for more papers by this author, Irl B. HirschUniversity of Washington Medical Center–Roosevelt, Seattle, Washington.Search for more papers by this author, and Jay S. SkylerDiabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida.Search for more papers by this authorPublished Online:21 Aug 2009https://doi.org/10.1089/dia.2009.1705AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byThe systematic case-referent methodTherapies, Vol. 74, No. 2Préparations insuliniques au cours de la dernière décennie.Médecine des Maladies Métaboliques, Vol. 12, No. 2Insulin, insulin receptors, and cancer1 July 2016 | Journal of Endocrinological Investigation, Vol. 39, No. 12Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies6 January 2016 | Diabetes Care, Vol. 39, No. 3Metabolic, anabolic, and mitogenic insulin responses: A tissue-specific perspective for insulin receptor activatorsMolecular and Cellular Endocrinology, Vol. 415The Impact of Technology on Current Diabetes ManagementPediatric Clinics of North America, Vol. 62, No. 4Differential Pathway Coupling of the Activated Insulin Receptor Drives Signaling Selectivity by XMetA, an Allosteric Partial Agonist Antibody22 January 2015 | Journal of Pharmacology and Experimental Therapeutics, Vol. 353, No. 1Traitement du diabète et cancer : enquête à propos de deux controversesMédecine des Maladies Métaboliques, Vol. 8, No. 4Risk of Cancer in Diabetes: The Effect of MetforminISRN Endocrinology, Vol. 2013The Future of Basal Insulin Viral N. Shah, Emily G. Moser, Aaron Blau, Megha Dhingra, and Satish K. Garg28 August 2013 | Diabetes Technology & Therapeutics, Vol. 15, No. 9Diabetes and Risk of CancerISRN Oncology, Vol. 2013Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry5 July 2012 | Diabetes/Metabolism Research and Reviews, Vol. 28, No. 5Optimizing treatment strategies with insulin glargine in Type 2 diabetes10 January 2014 | Expert Review of Endocrinology & Metabolism, Vol. 7, No. 4Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence4 April 2012 | Diabetologia, Vol. 55, No. 6Protected Graft Copolymer (PGC) Basal Formulation of Insulin as Potentially Safer Alternative to Lantus® (Insulin-Glargine): A Streptozotocin-Induced, Diabetic Sprague Dawley Rats Study28 December 2011 | Pharmaceutical Research, Vol. 29, No. 4Type 2 Diabetes in Adults3 November 2011Intensieve glucoseregulering en het risico op kanker bij type 2 diabetes: een meta-analyse van belangrijke trials14 March 2015 | Nederlands Tijdschrift voor Diabetologie, Vol. 9, No. 2Intensive glucose control and risk of cancer in patients with type 2 diabetes21 April 2011 | Diabetologia, Vol. 54, No. 7Overall Mortality in Diabetes Mellitus: Where Do We Stand Today? George Dailey13 June 2011 | Diabetes Technology & Therapeutics, Vol. 13, No. S1Traitements hypoglycémiants et cancerMédecine des Maladies Métaboliques, Vol. 5, No. 1Controversies in the use of insulin analogues10 January 2011 | Expert Opinion on Biological Therapy, Vol. 11, No. 2Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials20 October 2010 | Diabetologia, Vol. 54, No. 1Diabetes Mellitus and Increased Risk of Cancer: Focus on Metformin and the Insulin AnalogsPharmacotherapy, Vol. 30, No. 11Glucose-lowering therapies and cancer risk: the trials and tribulations of trials and observations4 June 2010 | Diabetologia, Vol. 53, No. 9Contemporary Management of Patients with Type 1 DiabetesEndocrinology and Metabolism Clinics of North America, Vol. 39, No. 3Insulin Glargine and Cancer Risk: An Opinion Statement of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical PharmacyPharmacotherapy, Vol. 30, No. 9Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling28 April 2010 | Diabetologia, Vol. 53, No. 8Epidemiological aspects of neoplasms in diabetes8 April 2010 | Acta Diabetologica, Vol. 47, No. 2Diabetes mellitus, hyperglycaemia and cancerDiabetes & Metabolism, Vol. 36, No. 3Associations of Hyperglycemia and Insulin Usage With the Risk of Cancer in Type 2 Diabetes: The Hong Kong Diabetes Registry25 February 2010 | Diabetes, Vol. 59, No. 5Insufficient evaluation of adverse events is not a proof of safety. Reply to LG Hemkens, U Grouven, R Bender, et al. [letter]19 January 2010 | Diabetologia, Vol. 53, No. 4Insulin, insulin analogues and cancer: no cause for panicInternational Journal of Clinical Practice, Vol. 64, No. 5New insulins and the risk of cancerInternational Journal of Clinical Practice, Vol. 64The Role of Basal Insulin and Glucagon-Like Peptide-1 Agonists in the Therapeutic Management of Type 2 Diabetes—A Comprehensive Review Satish K. Garg18 January 2010 | Diabetes Technology & Therapeutics, Vol. 12, No. 1Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin PumpsExperimental Diabetes Research, Vol. 2010Insulin Glargine Controversy: A Tribute to the Editorial Team at DiabetologiaDiabetes, Vol. 58, No. 11Insulina glargina y riesgo de cáncerEndocrinología y Nutrición, Vol. 56, No. 8Insulin glargine and cancer: cause and effect unproven2 September 2009 | Practical Diabetes International, Vol. 26, No. 7 Volume 11Issue 8Aug 2009 InformationCopyright 2009, Mary Ann Liebert, Inc.To cite this article:Satish K. Garg, Irl B. Hirsch, and Jay S. Skyler.Insulin Glargine and Cancer—An Unsubstantiated Allegation.Diabetes Technology & Therapeutics.Aug 2009.473-476.http://doi.org/10.1089/dia.2009.1705Published in Volume: 11 Issue 8: August 21, 2009Online Ahead of Print:July 10, 2009PDF download

Preservation of -cell function as measured by stimulated C-peptide has recently been accepted as a therapeutic target for subjects with newly diagnosed type 1 diabetes. In recently completed studies conducted by the Type 1 Diabetes Trial Network (TrialNet), repeated 2-hour Mixed Meal Tolerance Tests (MMTT) were obtained for up to 24 months from 156 subjects with up to 3 months duration of type 1 diabetes at the time of study enrollment. These data provide the information needed to more accurately determine the sample size needed for future studies of the effects of new agents on the 2-hour area under the curve (AUC) of the C-peptide values. The natural log(), log(+1) and square-root transformations of the AUC were assessed. In general, a transformation of the data is needed to better satisfy the normality assumptions for commonly used statistical tests. Statistical analysis of the raw and transformed data are provided to estimate the mean levels over time and the residual variation in untreated subjects that allow sample size calculations for future studies at either 12 or 24 months of follow-up and among children 8–12 years of age, adolescents (13–17 years) and adults (18+ years). The sample size needed to detect a given relative (percentage) difference with treatment versus control is greater at 24 months than at 12 months of follow-up, and differs among age categories. Owing to greater residual variation among those 13–17 years of age, a larger sample size is required for this age group. Methods are also described for assessment of sample size for mixtures of subjects among the age categories. Statistical expressions are presented for the presentation of analyses of log(+1) and transformed values in terms of the original units of measurement (pmol/ml). Analyses using different transformations are described for the TrialNet study of masked anti-CD20 (rituximab) versus masked placebo. These results provide the information needed to accurately evaluate the sample size for studies of new agents to preserve C-peptide levels in newly diagnosed type 1 diabetes.

We evaluated the effects of hyperbaric oxygen therapy (HOT) on autoimmune diabetes development in nonobese diabetic (NOD) mice. Animals received no treatment or daily 60-min HOT 100% oxygen (HOT-100%) at 2.0 atmospheres absolute and were monitored for diabetes onset, insulitis, infiltrating cells, immune cell function, and β-cell apoptosis and proliferation. Cyclophosphamide-induced diabetes onset was reduced from 85.3% in controls to 48% after HOT-100% (P < 0.005) and paralleled by lower insulitis. Spontaneous diabetes incidence reduced from 85% in controls to 65% in HOT-100% (P = 0.01). Prediabetic mice receiving HOT-100% showed lower insulitis scores, reduced T-cell proliferation upon stimulation in vitro (P < 0.03), increased CD62L expression in T cells (P < 0.04), reduced costimulation markers (CD40, DC80, and CD86), and reduced major histocompatibility complex class II expression in dendritic cells (DCs) (P < 0.025), compared with controls. After autoimmunity was established, HOT was less effective. HOT-100% yielded reduced apoptosis (transferase-mediated dUTP nick-end labeling-positive insulin-positive cells; P < 0.01) and increased proliferation (bromodeoxyuridine incorporation; P < 0.001) of insulin-positive cells compared with controls. HOT reduces autoimmune diabetes incidence in NOD mice via increased resting T cells and reduced activation of DCs with preservation of β-cell mass resulting from decreased apoptosis and increased proliferation. The safety profile and noninvasiveness makes HOT an appealing adjuvant therapy for diabetes prevention and intervention trials.

To establish and compare the prognostic accuracy of immunologic and metabolic markers in predicting onset of type 1 diabetes in those with high risk in a prospective study.A total of 339 subjects from the Diabetes Prevention Trial-Type 1 (DPT-1) parenteral study, who were islet cell antibody (ICA)-positive, with low first-phase insulin response (FPIR) and/or abnormal glucose tolerance at baseline, were followed until clinical diabetes onset or study end (5-year follow-up). The prognostic performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis and compared with nonparametric testing of ROC curve areas. Pearson correlation was used to assess the relationship between the markers.Individually, insulin autoantibody titer, ICA512A titer, peak C-peptide, 2-h glucose, FPIR, and FPIR/homeostasis model assessment of insulin resistance provided modest but significant prognostic values for 5-year risk with a similar level of area under ROC curve ranging between 0.61 and 0.67. The combination of 2-h glucose, peak C-peptide, and area under the curve C-peptide significantly improved the prognostic accuracy compared with any solitary index (P < 0.05) with an area under ROC curve of 0.76 (95% CI 0.70-0.81). The addition of antibody titers and/or intravenous glucose tolerance test (IVGTT) markers did not increase the prognostic accuracy further (P = 0.46 and P = 0.66, respectively).The combination of metabolic markers derived from the oral glucose tolerance test improved accuracy in predicting progression to type 1 diabetes in a population with ICA positivity and abnormal metabolism. The results indicate that the autoimmune activity may not alter the risk of type 1 diabetes after metabolic function has deteriorated. Future intervention trials may consider eliminating IVGTT measurements as an effective cost-reduction strategy for prognostic purposes.

We assessed the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for identifying individuals who are highly likely to progress to type 1 diabetes (T1D) within 2 years.The DPTRS was previously developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and was subsequently validated in the TrialNet Natural History Study (TNNHS). DPTRS components included C-peptide and glucose indexes from oral glucose tolerance testing, along with age and BMI. The cumulative incidence of T1D was determined after DPTRS thresholds were first exceeded and after the first occurrences of glucose abnormalities.The 2-year risks after the 9.00 DPTRS threshold was exceeded were 0.88 and 0.77 in DPT-1 (n = 90) and the TNNHS (n = 69), respectively. In DPT-1, the 2-year risks were much lower after dysglycemia first occurred (0.37; n = 306) and after a 2-h glucose value between 190 and 199 mg/dL was first reached (0.64; n = 59). Among those who developed T1D in DPT-1, the 9.00 threshold was exceeded 0.81 ± 0.53 years prior to the conventional diagnosis. Postchallenge C-peptide levels were substantially higher (P = 0.001 for 30 min; P < 0.001 for other time points) when the 9.00 threshold was first exceeded compared with the levels at diagnosis.A DPTRS threshold of 9.00 identifies individuals who are very highly likely to progress to the conventional diagnosis of T1D within 2 years and, thus, are essentially in a preclinical diabetic state. The 9.00 threshold is exceeded well before diagnosis, when stimulated C-peptide levels are substantially higher.

We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants.Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 <1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia.The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- (P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- (P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- (P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive (P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P < 0.01 for all]).The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points.

We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion.Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders.The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p < 0.001), which persisted after adjustments for age, sex, BMI z score and number of autoantibodies (p < 0.001). Among the monophasic group, the risk of type 1 diabetes was greater for those with a glucose peak at 90 min than for those with a peak at 30 min; the difference persisted after adjustments (p < 0.001). Compared with the biphasic group, the monophasic group had a lower early C-peptide (30-0 min) response, a lower C-peptide index (30-0 min C-peptide/30-0 min glucose), as well as a greater 2 h C-peptide level (p < 0.001 for all).Those with biphasic glucose curves have a lower risk of progression to type 1 diabetes than those with monophasic curves, and the risk among the monophasic group is increased when the glucose peak occurs at 90 min than at 30 min. Differences in glucose curve shapes between the monophasic and biphasic groups appear to be related to C-peptide responses.

We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial–Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial–Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P &amp;lt; 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P &amp;lt; 0.01 with or without adjustment for age). For a DPTRS &amp;lt;6.75, oral insulin groups did not differ from placebo groups in the AUC Ratio. The findings suggest that 1 year of treatment with oral insulin slows metabolic deterioration in individuals at high risk for type 1 diabetes. Moreover, the findings further suggest that metabolic end points can be useful adjuncts to the diagnostic end point in assessments of preventive treatments for the disorder.

BackgroundMetabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of β-cell function and metabolic outcomes in new-onset type 1 diabetes.Methods21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test.Findings6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2–3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods.InterpretationInterventions that preserve β-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials.FundingJDRF and Diabetes UK.

This article discusses type 1 diabetes mellitus, which results from insulin deficiency caused by autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The autoimmune response against islet beta-cells is believed to result from a disorder of immunoregulation. According to this concept, T lymphocytes (T cells) autoreactive to certain beta-cell constituents exist normally but are restrained by regulatory (suppressor) T cells. Activation of beta-cell autoreactive T cells together with deficient regulatory T cell responses is believed to result in clonal expansion of autoreactive T cells, and these cells may elicit a cascade of beta-antigen specific (T cell) immune and nonspecific inflammatory responses that destroy islet beta-cells. Islet beta-cells autoreactive T cells seem to secrete type 1 cytokines, whereas regulatory T cells may secrete type 2 and type 3 cytokines; therefore, type 1 diabetes may result from a relative dominance of type 1 cytokines over type 2 and type 3 cytokines. These concepts derive mainly from studies in animal models with spontaneous autoimmune diabetes, and the evidence in humans with type 1 diabetes is sparse. Nevertheless, the concept of type 1 diabetes as a disorder of immunoregulation has spurred clinical trials of diabetes prevention based on strategies directed at diverting the immune response from autoimmunity to self-tolerance, for example, by administration of beta-cell autoantigens, and by attempting to tip the immune balance in favor of the production or action of type 2 and type 3 cytokines over type 1 cytokines.

Diabetic retinopathy and diabetic nephropathy extract an enormous toll on patients with diabetes and an enormous burden on the health care system. With aggressive control of glycemia and blood pressure, coupled with aggressive use of laser photocoagulation and treatment of microalbuminuria, these problems can largely be eliminated. In the future, specific interventions may emerge that will allow interdiction of the pathophysiologic processes that lead to initiation and progression of these microvascular complications. The challenge for the primary care physician and diabetologist is to attain excellent glycemic control and aggressive control of blood pressure, while assuring that every patient has appropriate dilated fundus examinations at least annually, preferably by an ophthalmologist or retinal specialist, and regular screening for microalbuminuria. With such medical management, appropriate intervention can occur to reduce the risk of blindness and renal failure and to lessen the burden from diabetic retinopathy and nephropathy.

IN BRIEF Insulin pump therapy is becoming a preferred treatment modality of diabetes specialists for the management of patients with diabetes. As a result,internists, general practitioners, nurse practitioners, and allied health care professionals will more frequently encounter patients using, or desiring to use, these devices. This article serves as an introduction to the principles that guide patient selection, patient education of self-management skills, and the practical aspects of pump management that everyone assisting patients on pump therapy should be aware of.

We characterized fluctuations between states of glycemia in progressors to type 1 diabetes and studied whether those fluctuations are related to the early C-peptide response to oral glucose.Oral glucose tolerance tests (OGTTs) from differing states of glycemia were compared within individuals for glucose and C-peptide. Dysglycemic OGTTs (DYSOGTTs) were compared with normal OGTTs (NLOGTT), while transient diabetic OGTTs (TDOGTTs) were compared with subsequent nondiabetic OGTTs and with OGTTs performed at diagnosis.Of 135 progressors with four or more OGTTs, 30 (22%) went from NLOGTTs to DYSOGTTs at least twice. Area under the curve (AUC) glucose values from the second NLOGTT were higher (P < 0.001) than values from the first NLOGTT. Among 98 progressors whose DYSOGTTs and NLOGTTs were synchronized for the time before diagnosis, despite higher glucose levels (P < 0.01 at all time points) in the DYSOGTTs, 30- to 0-min C-peptide difference values changed little. Likewise, 30- to 0-min C-peptide difference values did not differ between TDOGTTs and subsequent (within 3 months) nondiabetic OGTTs in 55 progressors. In contrast, as glucose levels increased overall from the first to last OGTTs before diagnosis (P < 0.001 at every time point, n = 207), 30- to 0-min C-peptide difference values decreased (P < 0.001).Glucose levels fluctuate widely as they gradually increase overall with progression to type 1 diabetes. As glucose levels increase, the early C-peptide response declines. In contrast, glucose fluctuations are not related to the early C-peptide response. This suggests that changes in insulin sensitivity underlie the glucose fluctuations.

OBJECTIVE We examined changes in GAD65 and ICA-512 autoantibodies (GADA and IA-2A) during progression to type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Diabetes Prevention Trial–Type 1 (DPT-1) participants were assessed for changes in positivity and titers of GADA and IA-2A during the progression to T1D. RESULTS Among 99 progressors to T1D with GADA and IA-2A measurements at baseline and diagnosis (mean interval = 3.3 ± 1.5 years), GADA positivity changed little and GADA titers decreased (P &amp;lt; 0.01). In contrast, both IA-2A positivity and titers increased substantially (P &amp;lt; 0.001). Even among those positive at baseline, IA-2A titers increased from baseline to diagnosis (n = 57; P &amp;lt; 0.001), whereas GADA titers decreased (n = 80; P &amp;lt; 0.01). The same patterns of change were also evident among those positive for both autoantibodies (n = 48) at baseline. CONCLUSIONS IA-2A titers increase during the years before the diagnosis of T1D, even among those positive for IA-2A. In contrast, GADA titers tend to decline during those years.

A recent autopsy analysis asserted that incretin drugs have the potential of increasing the risk for pancreatic cancer and for pancreatic neuroendocrine tumors. We examined the Network for Pancreatic Organ Donors with Diabetes (nPOD) database from which that analysis was derived. Our findings raise important questions about the comparability of the two groups of diabetes patients used for the analysis. Our review of the data available on the nPOD Web site and our reading of the earlier article lead us to the conclusion that the data, and the implications of the data, as expressed by the authors of the autopsy analysis are vastly overstated and are a misrepresentation of the information available.

There is a need for biomarkers to monitor the development and progression of type 1 DM. We analyzed mRNA expression levels for granzyme B, perforin, fas ligand, TNF-α, IFN-γ, Foxp3, IL-10, TGF-β, IL-4, IL-6, IL-17, Activation-induced cytidine deaminase (AID) and Immunoglobulin G gamma chain (IgG<gamma>) genes in peripheral blood of at-risk, new-onset and long-term type 1 DM , and healthy controls. The majority of the genes were suppressed in long-term type 1 DM compared to controls and new-onset patients. IFN-γ, IL-4 and IL-10 mRNA levels were significantly higher in new-onset compared to at-risk and long-term groups. There was decreased mRNA expression for AID and IgG<gamma> and up-regulation of IFN-γ with age in controls. Data suggest an overall depressed immunity in long-term type 1 DM. Increased gene expression levels for IFN-γ, IL-4 and IL-10 in new-onset patients from at-risk patients might be used as potential markers for progression of the disease.

Decreased treatment adherence in patients with diabetes mellitus type 1 (type 1 DM) may reflect impairments in decision-making and underlying associated deficits in working memory and executive functioning. Other factors, including comorbid major depression, may also interfere with decision-making. The authors sought to review the clinically relevant characteristics of decision-making in type 1 DM by surveying the literature on decision-making by patients with type 1 DM. Deficiencies in decision-making in patients with type 1 DM or their caregivers contribute to treatment nonadherence and poorer metabolic control. Animal models of type 1 DM reveal deficits in hippocampal-dependent memory tasks, which are reversible with insulin. Neurocognitive studies of patients with type 1 DM reveal lowered performance on ability to apply knowledge to solve problems in a new situation and acquired scholarly knowledge, psychomotor efficiency, cognitive flexibility, visual perception, speed of information-processing, and sustained attention. Other factors that might contribute to poor decision-making in patients with type 1 DM, include "hypoglycemia unawareness" and comorbid major depression (given its increased prevalence in type 1 DM). Future studies utilizing novel treatment strategies to help patients with type 1 DM make better decisions about their disease may improve their glycemic control and quality of life, while minimizing the impact of end-organ disease.

Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies.TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL+) were compared with those ECL negative (ECL-) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D.The progression to multiple autoantibodies was significantly higher for those GADA/ECL+ (n = 107) than those GADA/ECL- (n = 78) (P = 0.001) and for those mIAA/ECL+ (n = 24) than those mIAA/ECL- (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58-7.39; P < 0.01) for GADA and 8.15 (3.02-22.00; P < 0.001) for mIAA. GADA/ECL+ and mIAA/ECL+ participants had significantly higher PS6M values than their ECL- counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL+, 14% progressed to T1D; of those mIAA/ECL+, 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL- progressed to T1D (median follow-up: 5 years).ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL+ are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL- are at very low risk.

Background/Objective The extent of influence of BMI and age on C-peptide at the diagnosis of type 1 diabetes (T1D) is unknown. We thus studied the impact of body mass index Z-scores (BMIZ) and age on C-peptide measures at and soon after the diagnosis of T1D. Methods Data from Diabetes Prevention Trial-Type 1 (DPT-1) participants <18.0 years at diagnosis was analyzed. Analyses examined associations of C-peptide measures with BMIZ and age in 2 cohorts: oral glucose tolerance tests (OGTTs) at diagnosis (n = 99) and mixed meal tolerance tests (MMTTs) <6 months after diagnosis (n = 80). Multivariable linear regression was utilized. Results Fasting and area under the curve (AUC) C-peptide from OGTTs (n = 99) at diagnosis and MMTTs (n = 80) after diagnosis were positively associated with BMIZ and age (P < .001 for all). Associations persisted when BMIZ and age were included as independent variables in regression models (P < .001 for all). BMIZ and age explained 31%-47% of the variance of C-peptide measures. In an example, 2 individuals with identical AUC C-peptide values had an approximate 5-fold difference in values after adjustments for BMIZ and age. The association between fasting glucose and C-peptide decreased markedly when fasting C-peptide values were adjusted (r = 0.30, P < .01 to r = 0.07, n.s.). Conclusions C-peptide measures are strongly and independently related to BMIZ and age at and soon after the diagnosis of T1D. Adjustments for BMIZ and age cause substantial changes in C-peptide values, and impact the association between glycemia and C-peptide. Such adjustments can improve assessments of β-cell impairment at diagnosis.

The purpose of this review study was to determine and categorize common causes of intermittent hyperglycemia and suggest potential measures to prevent and treat the identified causes.A literature review was conducted to obtain relevant information on hyperglycemia and continuous subcutaneous insulin infusion (CSII). Medical departments from Novo/Nordisk, Eli Lilly and Company, and Sanofi/Aventis were contacted requesting information on their insulin temperature stability, the compatibility of insulin with insulin/pump reservoirs, and tubing sets/catheters. Endocrinologists, Certified Diabetes Educators, and pump manufacturing company trainers were interviewed for their clinical observations and to determine the incidence of reported hyperglycemia and relationships to pump failures.Causes of intermittent hyperglycemia in CSII patients included problems with mechanical evaluation of the pump, basal/bolus review, reservoir/tubing, catheter site selection/placement, and insulin compatibility/stability.As more patients and health care providers strive to improve control of diabetes, use of insulin pump therapy will continue to increase. Unexplained hyperglycemia will continue to occur, which can lead to increased health care costs due to complications such as diabetic ketoacidosis. Evaluation of patient techniques and pump programming can uncover many potential causes, and the health care provider can assist in patient education to prevent further episodes.

Immunotherapy trials in recent-onset type 1 diabetes (T1D) have had mixed results, with some therapies—anti-CD3 monoclonal antibodies targeting T cells (1–7), anti-CD20 monoclonal antibodies targeting B cells (8), and costimulation blockade (9)—showing promise, with at least transient improvement in β-cell function compared with randomized control groups. In the current issue, Herold et al. (10) from the Immune Tolerance Network (ITN) report the results of the Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes (AbATE) trial. This is the fifth trial with anti-CD3, the fourth with the monoclonal antibody teplizumab, demonstrating preservation of β-cell function. The article describes a group of “responders” to treatment, identified by the label “responders” for those who maintained C-peptide better than the randomized but untreated comparison group at 24 months. Responders, defined in this way, constituted 45% of the subjects treated with anti-CD3. When examining β-cell function over time in the trial, it was evident that the responders had maintained β-cell function for 2 years, whereas the nonresponders had lost β-cell function at a rate similar to the control group. This is a crucial observation, because in an analysis that includes both responders and nonresponders, the profound retention of C-peptide in nearly half of subjects can be missed. The fundamental question is why some subjects failed to respond. It could be that the immunotherapy was …

The cardiometabolic syndrome (CMS) has been an organizing conceptual framework for subclinical cardiovascular pathophysiology. Using cross‐sectional data from 338 healthy men and women aged 18 to 55 years, the study examined the role of central adiposity and insulin sensitivity and assessed potential relationships with other metabolic indices (insulin sensitivity, glucose tolerance, fibrinolysis, lipidemia, endothelial function, and inflammation) and measures of cardiac structure and function (cardiac mass, compliance and contractility, myocardial oxygen demand, and blood pressure). Structural equation modeling analyses, which controlled for sex, age, and race, demonstrated good fit to the data. The derived relationships provided a physiologically consistent model of CMS, with an initiating role for central adiposity and insulin resistance. The model accounted for 30% and 82% of the variance in diastolic blood pressure and myocardial oxygen demand, respectively. The findings suggest predominant pathways through which subclinical metabolic processes may exert pathogenic impact on the heart and vasculature.

The objective of this study was to describe a pilot trial of using an omega-3 fatty acid (docosahexaenoic acid [DHA]) to prevent islet cell autoimmunity in infants with an increased risk for developing type 1 diabetes (T1D). Infants from pregnant mothers who either have T1D (or the father or a previous child has T1D) and who entered the study in the third trimester or infants younger than age 5 months having a first-degree family member with T1D were eligible for the study. Infants from either group also had to have an increased genetic (HLA) risk for T1D (or multiple first-degree relatives with T1D) to be eligible. The study is a multicenter, 2-arm, randomized, double-masked clinical trial that will last 4 years (1 year of recruitment and 3 years of treatment). Treatment with DHA (or control) began in the last trimester of pregnancy or in the first 5 months after birth. Inflammatory mediators, including cytokines, chemokines, eicosanoids, and C-reactive protein, are being measured along with fatty acids in maternal and infant blood. Ninety-eight infants were enrolled (41 during pregnancy and 57 in the 5 months after birth). HLA results of the 97 eligible infants (1 infant had a protective 0602 allele and was thus ineligible) showed that 90 have DR3 and/or DR4. Seven infants were enrolled without DR3/4 but who instead had multiple first-degree relatives with T1D. Compliance has been excellent, and no families have discontinued participation. Intervention trials in this high-risk group are feasible but require significant effort to identify potential participants.

To assess pulmonary safety during discontinuation and readministration of inhaled human insulin (EXU; Exubera((R)) insulin human [rDNA origin]) Inhalation Powder) therapy in adults with type 1 diabetes.Patients were randomized to receive basal insulin plus either pre-meal EXU (n=290) or a short-acting subcutaneous (SC) insulin (n=290) for 2 years (comparative phase), followed by 6 months of SC insulin (washout) and 6 months of their original therapy (readministration). Highly standardized lung function tests were performed throughout.Small treatment group differences favoring SC insulin in change from baseline forced expiratory volume in 1s (FEV(1)) and carbon monoxide diffusing capacity (DL(CO)) occurred early and were non-progressive. These differences resolved during washout and recurred at the same magnitude during readministration. Both groups maintained glycemic control, and hypoglycemic event rates were similar. In the EXU group, insulin antibody (IAb) levels plateaued at 12 months, declined to near baseline levels during washout and increased during readministration to levels observed in the comparative phase.FEV(1) and DL(CO) changes observed during discontinuation and readministration of EXU therapy are consistent with a reversible, non-progressive and non-pathological effect on lung function. EXU readministration is not associated with an augmented IAb response.

Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the beta-cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions. Preventive interventions mandate the identification of well-defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against beta-cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field.