Birger Thorsteinsson

Abstract Background Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. Methods Cross‐sectional Danish–British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self‐reported rate of severe hypoglycaemia during the preceding year. Results The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient‐year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient‐year and only retinopathy was a significant risk marker together with state of awareness. Conclusion Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia. Copyright © 2004 John Wiley & Sons, Ltd.

The frequency of symptomatic hypoglycaemic episodes was studied in 411 randomly selected conventionally treated Type 1 diabetic out‐patients. Between two consecutive visits to the out‐patient clinic each patient filled in a questionnaire at home. The number of hypoglycaemic episodes was then recorded prospectively in a diary for 1 week. From the questionnaires, the (retrospective) frequencies of mild and severe symptomatic hypoglycaemia were 1.6 and 0.029 episodes patient −1 week −1 . From the diaries, the (prospective) frequencies of mild and severe hypoglycaemic episodes were 1.8 and 0.027 patient −1 week −1 . Symptomatic hypoglycaemia was more frequent on working days than during weekends (1.8:1) and more frequent in the morning than during the afternoon, evening, and night (4.5:2.2:1.4:1). The symptoms of hypoglycaemia were non‐specific, heterogeneous, and weakened with increasing duration of diabetes. During their diabetic life, 36 % of the patients had experienced hypoglycaemic coma. The frequency of hypoglycaemia was positively, but only weakly, correlated with insulin dose, number of injections, percentage unmodified insulin of the total dose, and HbA 1c (mild hypoglycaemia only). The frequency was also negatively, but weakly, correlated with age and HbA 1c (episodes with coma only), but not correlated with sex, duration of diabetes, or patients' ratings of worries about mild and severe hypoglycaemia.

Background: Many patients with poorly controlled type 2 diabetes mellitus (DM) receive, as initial insulin treatment, the addition of a basal formulation to an existing regimen of oral antidiabetic drug (OAD) therapy. Used this way, the insulin analogue detemir has been associated with improved glycemic control of a magnitude similar to neutral protamine Hagedorn (NPH), with lower rates of hypoglycemia and weight gain. Initial studies investigated detemir administered BID, but pharmacologic data suggest that detemir might be effective with QD administration. Objectives: The aims of this study were to compare the effectiveness and tolerability of detemir versus NPH administered QD together with ?1 OAD in poorly controlled type 2 DM, and to compare different administration times of detemir. Methods: This 20-week, multicenter, randomized, open-label, 3-arm, parallel-group trial was conducted at 91 centers across Europe and the United States. Men and women were eligible for participation if they were aged ≥18 years, had a body mass index (BMI) ≤40 kg/m2, had a diagnosis of type 2 DM of at least 12 months' duration, and were insulin naive. Eligible patients also had a glycosylated hemoglobin (HbA1c) concentration value not outside the range of 7.5% to 11.0% following at least 3 months' treatment with ≥10 AD. Patients were randomly assigned to receive an evening SC injection of detemir, a prebreakfast injection of detemir, or an evening injection of NPH insulin (1:1:1), administered at initial doses of 10 IU (U). Results: A total of 504 patients were enrolled 5 men, 219 women; mean [SD] age, 59 [11] years; mean [SD] BMI, 30 [5] kg/m2; insulin detemir before breakfast, 168; insulin detemir evening, 170; NPH insulin evening, 166). The intent-to-treat population comprised 498 patients. Morning and evening detemir were associated with reductions in HbA1c similar to those with evening NPH (raw mean decreases, -1.58%, −1.48%, and −1.74%, respectively). Nine-point profile and fasting and predinner plasma glucose data found morning detemir to be associated with a different diurnal glycemic profile compared with the evening regimens. Compared with evening NPH, 24-hour and nocturnal hypoglycemia were reduced by 53% (P = 0.019) and 65% (P = 0.031), respectively, with evening detemir. Incidences of hypoglycemia did not differ significantly between groups that received morning and evening detemir, but nocturnal hypoglycemia was reduced further, by 87%, with morning detemir compared with evening NPH (P < 0.001). Weight gain was 1.2, 0.7, and 1.6 kg with morning detemir, evening detemir, and NPH, respectively (P = 0.005 for evening detemir vs NPH). No between-treatment differences were seen in other tolerability end points. Conclusions: The results of this study in patients whose type 2 DM was poorly controlled with ≥1 OAD suggest that insulin detemir QD in the morning or evening can be used to improve glycemic control. Compared with NPH, insulin detemir may offer some tolerability advantages in this role.

The E23K polymorphism of the pancreatic β-cell ATP-sensitive K+ (KATP) channel subunit Kir6.2 (KCNJ11) is associated with type 2 diabetes in whites, and a recent in vitro study of the E23K variant suggests that the association to diabetes might be explained by a slight inhibition of serum insulin release. In a study comprising 519 unrelated glucose-tolerant subjects, we addressed the question as to whether the E23K variant was related to reduced serum insulin release during an oral glucose tolerance test (OGTT). Furthermore, the polymorphism was examined in a case-control study comprising 803 type 2 diabetic patients and 862 glucose-tolerant control subjects. The E23K variant was associated with significant reductions in the insulinogenic index (P = 0.022) and serum insulin levels under the response curve during an OGTT (0–120 min) (P = 0.014) as well as with an increase in BMI (P = 0.013). In the present study, the association of the E23K polymorphism with type 2 diabetes was not significant (P = 0.26). However, the K23K genotype significantly associated with type 2 diabetes in a meta-analysis of white case and control subjects (n = 2,824, odds ratio [OR] 1.49, P = 0.00022). In conclusion, the widespread E23K polymorphism may have a diabetogenic effect by impairing glucose-induced insulin release and increasing BMI.

To study prevalence and incidence of diabetes mellitus in patients with cystic fibrosis.Five year prospective study with annual oral glucose tolerance tests.CF Center Copenhagen, Denmark.191 patients with cystic fibrosis aged above 2 years.Glucose tolerance, plasma glucose concentrations after fasting and after glucose loading, and haemoglobin A1c levels.Prevalence of diabetes increased from 11% (n = 21) to 24% (n = 46) during study, with annual age dependent incidence of 4-9%. Diabetes was diagnosed at median age of 21 (range 3-40). At diagnosis of diabetes, symptoms of hyperglycaemia were present in 33% of patients, fasting hyperglycaemia (> or = 7.8 mmol/l) was seen in 16%, and increased haemoglobin A1c levels (> 6.4%) were seen in 16%. Impaired glucose tolerance implied higher risk for development of diabetes than normal glucose tolerance (odds ratio 5.6). In 58% of cases with impaired glucose tolerance, however, glucose tolerance was normal at next annual test. Normal glucose tolerance was found in only 37% of patients at all five tests. Within this group of patients, median plasma glucose concentrations after fasting and after glucose loading and haemoglobin A1c levels increased by 6-8% during study.Prevalence and incidence of diabetes in cystic fibrosis patients was high and increased with age. Since hyperglycaemic symptoms, fasting hyperglycaemia, and increased levels of glycated haemoglobin did not reliably identify diabetes mellitus, we recommend annual oral glucose tolerance tests in all cystic fibrosis patients aged over 10 years.

The ability of people with insulin-treated diabetes to remember severe hypoglycaemia and the consistency of their self-estimated awareness of hypoglycaemia are not well documented but are important in clinical practice. The aim of this study is to assess recall of severe hypoglycaemia in patients with type 1 diabetes and to evaluate the feasibility of a simple method for clinical classification of the awareness of hypoglycaemia.A one-year prospective study was performed on a cohort of patients with type 1 diabetes (n = 230). The rate of severe hypoglycaemia reported retrospectively at the end of the study was compared to the prospectively recorded rate during the study period. Self-estimated awareness was explored in questionnaires at baseline and at the end, and assessments were evaluated by the occurrence of severe hypoglycaemic episodes.Almost 90% of the participants correctly recalled whether they had had severe hypoglycaemia. However, those with high prospectively recorded numbers had incomplete recall, resulting in a 15% underestimation of the overall rate. On the basis of the answer to the question "Do you recognise symptoms when you have a hypo?", the population was classified into three groups: 40% with normal awareness, 47% with impaired awareness and 13% with unawareness. The groups with impaired awareness and unawareness had 5.1 and 9.6 times higher rates of severe hypoglycaemia, respectively, compared to the group with normal awareness (p < 0.001).People with type 1 diabetes generally remember severe hypoglycaemic episodes during a one-year period. A simple method is proposed for classifying the state of awareness of hypoglycaemia in clinical practice.

The effect of insulin therapy on lung function and lung infections was studied in a retrospective case‐control design in 18 diabetic cystic fibrosis (CF) patients; 18 non‐diabetic CF patients, matched for sex, age and presence of chronic Pseudomonas aeruginosa lung infection. served as controls. Parameters of CF clinical status were collected for six years before and two years after the onset of insulin therapy in the diabetic patients. Before onset of insulin therapy, body mass index (BMI) and forced vital capacity (FVC) in (pre)diabetic patients deviated increasingly from those in control patients. Decreases in BMI and lung function during the past three months before onset of insulin therapy were reverted within three months of insulin therapy. From three months to two years after onset of insulin therapy, differences in BMI and lung function diminished between diabetic and control patients. After two years of insulin therapy, BMI was similar in diabetic and non‐diabetic patients and the percentage differences in forced expiratory volume in 1s (FEV 1 ) and FVC between the two groups were similar to those found six years before the onset of insulin therapy. The finding that insulin therapy improves lung function in diabetic CF patients suggests strongly that the insidious decline in lung function seen during the years before the diagnosis of diabetes mellitus results from the pre‐diabetic condition. After onset of insulin therapy, the percentages of sputum examinations positive for Haemophilus infuenzae and Streptococcus pneumoniae decreased in the diabetic patients, whereas parameters of lung infections with P. aeruginosa and Staphylococcus aureus remained unchanged. In conclusion, since insulin therapy improves lung function and reduces the number of infections with H. influenzae and S. pneumoniae in diabetic CF patients, we suggest that insulin therapy should be started when diabetes mellitus is diagnosed.

In pregnancy with type 1 diabetes, we evaluated occurrence of mild and severe hypoglycemia and analyzed the influence of strict metabolic control, nausea, vomiting, and other potential predictors of occurrence of severe hypoglycemia.A prospective observational study of 108 consecutive pregnant women with type 1 diabetes was conducted. At 8, 14, 21, 27, and 33 weeks of gestation, patients performed self-monitored plasma glucose (SMPG) (eight/day) for 3 days and completed a questionnaire on nausea, vomiting, hypoglycemia awareness, and history of mild (managed by the patient) and severe (requiring assistance from others) hypoglycemia.Forty-nine (45%) women experienced 178 severe hypoglycemic events, corresponding to 5.3, 2.4, and 0.5 events/patient-year in the first, second, and third trimesters, respectively. The incidence of mild hypoglycemia was 5.5 events/patient-week in early pregnancy and decreased throughout pregnancy (P < 0.0001), regardless of presence of severe hypoglycemia. Prevalence of nausea and vomiting, mild hypoglycemia, and fraction of SMPG readings </=3.9 mmol/l did not differ between women with and without severe hypoglycemia. A1C, median SMPG, and fluctuations in SMPG decreased during pregnancy, with no differences between women with and without severe hypoglycemia. Logistic regression analysis identified history of severe hypoglycemia the year preceding pregnancy (odds ratio 3.3 [95% CI 1.2-9.2]) and impaired awareness or unawareness (3.2 [1.2-8.2]) as independent predictors for severe hypoglycemia.In pregnancy with type 1 diabetes, the incidence of mild and severe hypoglycemia was highest in early pregnancy, although metabolic control was tighter in the last part of pregnancy. Predictors for severe hypoglycemia were history of severe hypoglycemia and impaired awareness.

Neuropsychological testing was carried out in 16 insulin dependent (type I) diabetic men during four periods when mean blood glucose concentrations were (A) 6.3 (SEM 0.13) mmol/l (113.5 (SEM 2.3) mg/100 ml), (B) 2.9 (0.05) mmol/l (52.3 (0.9) mg/100 ml), and (C) 1.8 (0.03) mmol/l (32.4 (0.05) mg/100 ml), all measured during intravenous insulin infusion, and (D) 6.1 (0.13) mmol/l (109.9 (2.3) mg/100 ml), measured after intravenous glucose. The total neuropsychological test score decreased between periods A and B, A and C, and B and C, whereas improvement occurred between periods C and D (all p less than 0.02). These results were not due to changes in individual subjects alone but were consistent for the whole group. During hypoglycaemia there were changes in the patients' estimates of elapsed time, which were underestimated at period C as compared with the estimates at periods A, B, and D (all p less than 0.05). None of the 16 patients noticed symptoms of hypoglycaemia at period A or B, 12 reported symptoms at C, and one at D. Patients with type I diabetes may show a deterioration in neuropsychological skills during periods of asymptomatic subnormal or hypoglycaemic blood glucose concentrations.

Background Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin. Methods In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996. Findings Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0·51 episodes (95% CI 0·19–0·84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11–48; p=0·010). Interpretation Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins. Funding Novo Nordisk A/S.

This study investigated the efficacy and safety of once-daily liraglutide 1.2 mg versus placebo as add-on to insulin treatment in normal-weight patients with poorly controlled type 1 diabetes.In a randomized (1:1), double-blind, placebo-controlled design, 40 patients with type 1 diabetes (HbA1c ≥8% [64 mmol/mol]) received once-daily liraglutide 1.2 mg or placebo for 12 weeks. Continuous glucose monitoring was performed before and at the end of treatment. The primary end point was change in HbA1c. Secondary end points included change in insulin dose, weight, glycemic excursions, heart rate, and blood pressure.Baseline HbA1c was similar in the liraglutide and placebo group (8.8 ± 0.2 and 8.7 ± 0.1% [72.5 ± 2.2 and 71.8 ± 1.5 mmol/mol]). Change in HbA1c from baseline was -0.6 ± 0.2% (-6.22 ± 1.71 mmol/mol) with liraglutide and -0.5 ± 0.2% (-5.56 ± 1.67 mmol/mol) with placebo (P = 0.62). Variation in glycemic excursions did not change in either group. Change in body weight was -3.13 ± 0.58 and +1.12 ± 0.42 kg (P < 0.0001) with liraglutide and placebo, respectively. The bolus insulin dose decreased in liraglutide-treated patients and did not change with placebo treatment (4.0 ± 1.3 vs. 0.0 ± 1.0 IU, P = 0.02). Heart rate increased within the liraglutide group (P = 0.04) but not compared with placebo, whereas mean systolic blood pressure decreased compared with placebo (between-group difference 3.21 mmHg [95% CI -8.31 to 1.90], P = 0.04). Liraglutide was more frequently associated with gastrointestinal adverse effects. The incidence of hypoglycemia did not differ between groups.Liraglutide significantly reduces body weight and insulin requirements but has no additional effect on HbA1c in normal-weight patients with type 1 diabetes inadequately controlled on insulin alone.

Lanng S, Thorsteinsson B, Lund‐Andersen C, Nerup J, Schiatz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications. Acta Pzdiatr 1994;83: 72–7. Stockholm. ISSN 0803–5253. The prevalences of impaired glucose tolerance (IGT), diabetes mellitus and late diabetic complications were studied in all Danish cystic fibrosis (CF) patients. A total of 311 CF patients were identified with an estimated ascertainment rate above 98%. Glucose tolerdnce was classified in 278 (89%) patients: the prevalences of IGT and diabetes mellitus were 13.7% (38 patients) and 14.7% (41 patients), respectively, with no sex differences. The prevalence of diabetes mellitus increased with age but not with the severity of CF as compared with age‐ and sex‐matched non‐diabetic CF patients. Diabetes was diagnosed at a median age of 20 years (range 3–40 years) and the duration of diabetes was 1.7 years (0.1–17 years). Twenty‐eight of the diabetic patients (70%) were trcated with insulin, on average 20 (4–90) IU per day. Late diabetic complications were identified in 4 patients (10%) with a duration of diabetes mellitus of 1–17 years: background retinopathy (2 patients), diabetic nephropathy (1 patient), microalbuminuria (1 patient) and neuropathy (2 patients). Thus diabetic CF patients are probably not less prone to develop late diabetic complications than patients with other types of diabetes of equally long duration and comparable glycemic control.

Background The insertion (I) allele of the angiotensin-converting-enzyme (ACE) gene occurs at increased frequency in endurance athletes. This association suggests that low ACE activity is favourable for performance in conditions with limited substrate availability. Such conditions occur in endurance athletes during competition and in diabetic patients during insulin-induced hypoglycaemia. Patients rely on preserved functional capacity to recognise hypoglycaemic episodes and avoid progression by self-treatment. We studied whether ACE activity is related to the risk of severe hypoglycaemia in type 1 diabetes. Methods Consecutive adult outpatients with type 1 diabetes, untreated with ACE inhibitors or angiotensin-II-receptor antagonists (n=207) reported their experience of mild and severe hypoglycaemia during the previous 1 year and 2 years. The patients were further characterised by diabetes history, degree of hypoglycaemia awareness, measurement of C-peptide, haemoglobin A1c, and serum ACE concentrations, and determination of ACE genotype. Findings Patients with the DD genotype had a relative risk of severe hypoglycaemia in the preceding 2 years of 3·2 (95% CI 1·4-7·4) compared with those who had the II genotype. There was a significant relation between serum ACE activity and the rate of severe hypoglycaemia (relative risk per 10 U/L increment 1·4 [1·2-1·6]), corresponding to a 3·5 times higher risk for patients in the highest quartile than for those in the lowest quartile. Multiple regression analysis showed that the effect of the ACE genotype was explained by its influence on serum ACE activity and that the only other significant determinants of the risk of severe hypoglycaemia were the degree of hypoglycaemia awareness, β-cell function, and duration of diabetes of more than 20 years. Interpretation ACE activity is a clinically significant marker of the risk of severe hypoglycaemia in patients with type 1 diabetes, especially in those with impaired defence against hypoglycaemia. These findings need to be confirmed in prospective studies.

The reported risk of severe hypoglycaemia in insulin-treated Type 2 diabetes is highly variable and few studies have evaluated the influence of risk factors. We assessed the incidence and the influence of potential risk factors for severe hypoglycaemia in a questionnaire survey in subjects with insulin-treated Type 2 diabetes receiving currently recommended multifactorial intervention.Consecutive patients with insulin-treated Type 2 diabetes (n = 401) completed a questionnaire about occurrence of hypoglycaemia in the past, hypoglycaemia awareness and socio-demographic factors. A zero-inflated negative binomial model was used to assess the influence of potential risk factors on the rate of severe hypoglycaemia.The overall incidence of severe hypoglycaemia in the preceding year was 0.44 episodes/person year. Sixty-six (16.5%) patients had experienced at least one event. The risk of any episode of severe hypoglycaemia positively correlated with impaired hypoglycaemia awareness, being married and long duration of diabetes. The risk of repeated episodes of severe hypoglycaemia positively correlated with the presence of peripheral neuropathy, while long duration of diabetes prior to insulin treatment and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs) were associated with reduced risk. C-peptide concentration and HbA1c were not associated with the risk of severe hypoglycaemia.In this cohort of insulin-treated Type 2 diabetic patients, the incidence of severe hypoglycaemia is higher than reported in most studies, corresponding to about one-third of that in Type 1 diabetes. Impaired hypoglycaemia awareness is the most important risk factor for severe hypoglycaemia.

The prevalence of nocturnal biochemical hypoglycaemia -that is, blood glucose concentrations below 3 mmol/l (55 mg/100 ml)-was evaluated in a random sample of 58 insulin dependent diabetics receiving twice daily insulin.Seventeen patients had at least one blood glucose value below 3 mmol/l (55 mg/100 ml) and five a value below 2 mmol/l (36 mg/100 ml) during the night.Both bedtime (2300) and fasting morning (0700) blood glucose concentrations were significantly lower in the group

The relation between blood glucose concentration, the symptoms and signs of hypoglycaemia, and electroencephalographic changes in diabetic patients is not known.The effect of hypoglycaemia on brain function was studied in 13 patients with insulin dependent diabetes.During a gradual fall in blood glucose concentration induced by a bolus injection of insulin followed by an intravenous infusion of insulin, during 60 minutes of biochemical hypoglycaemia, and after restoration of normoglycaemia with intravenous glucose electroencephalograms were evaluated continuously by period-amplitude analysis; blood samples were taken every 10 minutes throughout.No changes were seen in electroencephalograms when the blood glucose concentration was above 3 mmol/l.At a median blood glucose concentration of 2-0 (95% confidence interval 1*7 to 2.3) mmol/l alpha activity decreased abruptly in the electroencephalograms concomitant with an increase in theta activity, reflecting neuronal dysfunction in the cortex.When the blood glucose concentration was further lowered changes were observed in the electroencephalograms indicating that deeper brain structures were affected.A normal electroencephalogram was re-established at a blood glucose concentration of 2*0 (1-8 to 2.1) mmol/l.There was no significant correlation between the blood glucose concentration at the onset of changes in the electroencephalograms and age, duration of diabetes, insulin dose, haemoglobin Alc con- centration, initial blood glucose concentration, rate of fall in blood glucose concentration, and appearance of symptoms and signs of hypoglycaemia.Changes in electroencephalograms during hypoglycaemia

Diabet. Med. 29, 558–566 (2012) Abstract Aims To explore incidence, risk factors, possible pathophysiological factors and clinical management of hypoglycaemia during pregnancy in women with Type 1 diabetes. Methods Literature review. Results In women with Type 1 diabetes, severe hypoglycaemia occurs three to five times more frequently in early pregnancy than in the period prior to pregnancy, whereas in the third trimester the incidence of severe hypoglycaemia is lower than in the year preceding pregnancy. The frequency distribution of severe hypoglycaemia is much skewed, as 10% of the pregnant women account for 60% of all recorded events. Risk factors for severe hypoglycaemia during pregnancy include a history with severe hypoglycaemia in the year preceding pregnancy, impaired hypoglycaemia awareness, long duration of diabetes, low HbA 1c in early pregnancy, fluctuating plasma glucose values (≤ 3.9 mmol/l or ≥ 10.0 mmol/l) and excessive use of supplementary insulin injections between meals. Pregnancy‐induced nausea and vomiting seem not to be contributing factors. Conclusions Striving for near‐normoglycaemia with focus on reduction of plasma glucose fluctuations during pregnancy should have high priority among clinicians with the persistent aim of improving pregnancy outcome among women with Type 1 diabetes. Pre‐conception counselling, carbohydrate counting, use of insulin analogues, continuous subcutaneous insulin infusion (insulin pump) therapy and real‐time continuous glucose monitoring with alarms for low glucose values might be relevant tools to obtain near‐normoglycaemia without episodes of severe hypoglycaemia.

Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N = 14), impaired (N = 4), and diabetic (N = 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.

The study aimed to identify risk markers (present at the start of the study in 1989) for the occurrence and progression of microvascular complications 6 years later (in 1995) in a Danish nationwide cohort of children and adolescents with Type 1 diabetes (average age at entry 13.7 years). Probabilities for the development of elevated albumin excretion rate (AER), retinopathy, and increased vibration perception threshold (VPT) could then be estimated from a stepwise logistic regression model. A total of 339 patients (47% of the original cohort) were studied. Sex, age, diabetes duration, insulin regimen and dose, height, weight, HbA(1c), blood pressure, and AER were recorded. In addition, information on retinopathy, neuropathy (VPT), and anti-hypertensive treatment was obtained at the end of the study. HbA(1c) (normal range 4.3-5.8, mean 5.3%) and AER (upper normal limit <20 microg min(-1)) in two, timed overnight urine collections were analysed centrally. Eye examination was performed by two-field fundus photography. Determination of VPT was assessed by biothesiometry. Increased AER (> or =20 microg min(-1)) was found in 12.8% of the patients in 1995, and risk markers for this were increased AER and high HbA(1c), in 1989 (both p<0.001). Retinopathy was present in 57.8% of patients in 1995, for which the risk markers were long duration of diabetes (p<0.0001), age (p<0.01), and high HbA(1c) (p<0.0001) in 1989. Elevated VPT (>6.5 V) was found in 62.5% of patients in 1995, for which the risk markers were male sex (p<0.05), age (p<0.0001), and increased AER (p<0.05) in 1989. This study confirms that hyperglycaemia plays a major role for the development of microvascular complications in kidneys and eyes, and emphasises the need for optimal glycaemic control in children and adolescents with Type 1 diabetes.

Glucose tolerance was evaluated in 356 living and dead patients with cystic fibrosis who were recorded at the Danish Cystic Fibrosis Centre. Twenty two patients (6%) were treated elsewhere, 25 (7%) were unable, unwilling or too young (age less than 2 years) to participate; 309 patients (87%) were therefore eligible for the study of whom 99 (32%) were dead and 210 (68%) were alive. Of the dead patients, 13 also had diabetes mellitus (13%). Of the living patients (median age 14 years, range 2-40), nine (4%) were known to have diabetes and all were being treated with insulin. In the remaining 201 patients an oral glucose tolerance test (1.75 g/kg body weight, maximum 75 g) was carried out. A total of 155 patients (74%) had normal glucose tolerance, 31 (15%) had impaired glucose tolerance, and 15 (7%) had diabetes mellitus according to the WHO criteria. The percentage of glycated haemoglobin (HbA1c) (reference range 4.1-6.4%) increased significantly as glucose tolerance decreased: when glucose tolerance was normal the median was 5.2%; when it was impaired the figure was 5.5%; in patients whose diabetes was diagnosed by the oral glucose tolerance test it was 5.9%; and in patients already known to have diabetes mellitus it was 8.6%. The incidence and prevalence of impaired glucose tolerance and diabetes mellitus increased with age. From the age of 15 to 30 years the decrease in the prevalence of normal glucose tolerance was almost linear. Within this age span the proportion of patients with cystic fibrosis with normal glucose tolerance was reduced by roughly 5%/year. Only 35% (95% confidence interval (CI) 22 to 48%) of the patients with cystic fibrosis who were alive at the age of 25 years had normal glucose tolerance; 32% (95% CI 14 to 49%) were diabetic. The prevalence of glucose intolerance in cystic fibrosis is rapidly increasing with age; its potentially harmful effect on the prognosis of cystic fibrosis is of increasing importance as the length of survival of these patients increases.

We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACEgene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively.We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACEgene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia.High ACE activity and the presence of the D allele of the ACE gene predict a high rate of severe hypoglycaemia in Type 1 diabetes.

We studied glucose metabolism and insulin kinetics in cystic fibrosis patients with diabetic and normal glucose tolerance.Measurements of blood glucose and serum free insulin concentrations during hyperinsulinaemic normoglycaemic clamp and post-clamp insulin decay, followed by the calculation of insulin sensitivity (M-value and M/I ratio), insulin clearance rate, serum half-life and apparent distribution space for insulin.Cystic fibrosis patients, age range 20-29 years, with diabetes mellitus (n = 10) and normal glucose tolerance (n = 10), and 10 age-matched control subjects.During the glucose clamp, diabetic cystic fibrosis patients needed less glucose than cystic fibrosis patients with normal glucose tolerance and control subjects (M-value), and steady-state serum insulin concentrations were lower in cystic fibrosis patients with diabetic and normal glucose tolerance than in control subjects. The quantity of glucose metabolized per unit of serum insulin concentration (M/I ratio) was similar in the three study groups (median approximately 145 (mumol/kg/min)/(nmol/l); range 70-252). Insulin clearance rates were higher in cystic fibrosis patients with diabetic (24.4 (19.3-29.9) ml/kg/min) and normal (22.6 (14.9-28.4) ml/kg/min) glucose tolerance than in control subjects (17.5 (15.9-24.2) ml/kg/min). Although insulin clearance rates were inversely related to body mass index (R(S) = -0.59, P < 0.001), the higher insulin clearance rates in CF patients cannot be accounted for solely by differences in body mass index since the insulin clearance rates were similarly increased in patients with body mass index above and below 20 kg/m2 (22.7 (14.9-28.4) and 24.4 (19.3-29.9) ml/kg/min, respectively). Serum half-lives for insulin were shorter in cystic fibrosis patients (approximately 4.3 (3.2-7.2) min) than in control subjects (5.9 (3.8-12.5) min), whereas the apparent distribution spaces for insulin were similar in the three study groups (approximately 150 (88-391) ml/kg).Insulin sensitivity, calculated as the quantity of glucose metabolized per kg body weight per unit of serum insulin concentration, is normal in cystic fibrosis patients with normal glucose tolerance and with well controlled diabetes mellitus. The insulin clearance rate is increased in cystic fibrosis patients with diabetic and normal glucose tolerance, owing to a shorter serum half-life of insulin, whereas the apparent distribution space for insulin is normal.

Aims Recommendations for self-monitoring of blood glucose (SMBG) from the DCCT have not been implemented with the same rigour as recommendations for intensifying insulin therapy. We assessed the frequency of and motives for SMBG and compared SMBG behaviour with clinical, behavioural and demographic characteristics. Methods Cross-sectional Danish-British multicentre survey of 1076 consecutive patients with type 1 diabetes, who completed a detailed questionnaire on SMBG and related issues. The key variables were test frequency and motive. Results SMBG was performed daily by 39% of the patients and less than weekly by 24%. Sixty-seven percent reported to perform routine testing, while the remaining 33% only tested when hypo- or hyperglycaemia was suspected. Age, gender, and level of diabetes-related concern were associated with test pattern. Reported frequencies of mild and severe hypoglycaemia and awareness of hypoglycaemia were independently associated with testing behaviour, whereas the presence of late diabetic complications was not. Lower HbA1c was associated with more frequent testing. Conclusion Patient compliance regarding SMBG is limited. Thus, almost two thirds of the patients do not perform daily SMBG and one third do not perform routine tests.

The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed regimens.A questionnaire was posted from six Danish diabetes clinics to 6112 unselected patients with type 1 diabetes and filled in by 3861 patients (63.2%). Primary endpoint was number of episodes of severe hypoglycaemia in the preceding year. Mild hypoglycaemia was also reported.The frequency of severe hypoglycaemic episodes per patient-year in patients receiving long-acting insulin analogues was 1.47±0.18 versus 1.09±0.10 in patients on long-acting human insulin (p=0.01). The frequency of severe hypoglycaemic episodes per patient-year was 1.09±0.11 in patients on short-acting insulin analogues versus 1.26±0.13 in patients on short-acting human insulin (p=0.15), which was statistically significant in an adjusted analysis.Severe hypoglycaemia is more frequent in patients with type 1 diabetes treated with long-acting insulin analogues. Confounding by indication may be involved. Clinical intervention trials using insulin analogues in patients prone to severe hypoglycaemia are highly needed.

Providing care for adolescents with type 1 diabetes is complex, demanding, and often unsuccessful. Guided self-determination (GSD) is a life skills approach that has been proven effective in caring for adults with type 1 diabetes. To improve care, GSD was revised for adolescents, their parents, and interdisciplinary healthcare providers (HCP) to create GSD-Youth (GSD-Y). We evaluated the impact of GSD-Y after it was integrated into pediatric outpatient visits versus treatment-as-usual, focusing on glycemic control and the development of life skills in adolescents with type 1 diabetes.Seventy-one adolescents (mean age: 15 years, mean duration of diabetes: 5.7 years, mean HbA1c: 77 mmol/mol (9.1%), upon entering the study) from two pediatric departments were randomized into a GSD-Y group (n = 37, GSD-Y was provided during individual outpatient sessions) versus a treatment-as-usual group (n = 34). The primary outcome was the HbA1c measurement. The secondary outcomes were life skills development (assessed by self-reported psychometric scales), self-monitored blood glucose levels, and hypo- and hyperglycemic episodes. The analysis followed an intention-to-treat basis.Fifty-seven adolescents (80%) completed the trial, and 53 (75%) completed a six-month post-treatment follow-up. No significant effect of GSD-Y on the HbA1c could be detected in a mixed-model analysis after adjusting for the baseline HbA1c levels and the identity of the HCP (P = 0.85). GSD-Y significantly reduced the amotivation for diabetes self-management after adjusting for the baseline value (P = 0.001). Compared with the control group, the trial completion was prolonged in the GSD-Y group (P <0.001), requiring more visits (P = 0.05) with a higher rate of non-attendance (P = 0.01). GSD-Y parents participated in fewer of the adolescents' visits (P = 0.05) compared with control parents.Compared with treatment-as-usual, GSD-Y did not improve HbA1c levels, but it did decrease adolescents' amotivation for diabetes self-management.ISRCTN 54243636, registered on 10 January 2010. Life skills for adolescents with type 1 diabetes and their parents.

OBJECTIVE We test the hypotheses that the implementation in Denmark of new, stricter European Union (EU) legislation on driver’s licensing, with the purpose to improve traffic safety in January 2012, has reduced the self-reported rate of severe hypoglycemia in a routine clinical setting and that anonymous reporting results in higher event rates. RESEARCH DESIGN AND METHODS A cohort of 309 patients with type 1 diabetes was recruited in the outpatient clinic at Nordsjællands University Hospital Hillerød, Denmark. Yearly numbers of severe hypoglycemic events defined by need for treatment assistance from another person were retrieved from medical records in the years 2010 to 2012 and retrospectively reported in an anonymous questionnaire. Data from medical records in 2012 were compared with those from 2010 and 2011 and with data from the questionnaire. RESULTS Reported rates of severe hypoglycemia in the medical records were reduced by 55% in 2012 compared with the prior years (P = 0.034). The proportion of subjects reporting recurrent episodes was grossly reduced from 5.6 to 1.5% (P = 0.014). Compared with anonymous reporting in the questionnaire, the rate of severe hypoglycemia in 2012 was 70% lower (P &amp;lt; 0.001). CONCLUSIONS Reporting of severe hypoglycemia by patients with type 1 diabetes is significantly reduced following implementation of EU driver’s licensing legislation that implies withdrawal of driver’s licensing in case of recurrent episodes within 1 year. The resulting burden of concealed severe hypoglycemia may impair the safety of affected patients and unintentionally paradoxically reduce the general traffic safety.

ContextRecurrent hypoglycemia promotes impaired awareness, resulting in an increased risk for asymptomatic hypoglycemia. However, there are no firm data on the frequency of hypoglycemia in daily life needed to initiate this vicious cycle or the role of asymptomatic hypoglycemia.

After Danish nationwide investigations (1987, 1989) demonstrated unacceptable blood glucose control in unselected young diabetic patients, we set out to estimate the present glycaemic control and the prevalence of microvascular complications in a cohort of children and adolescents participating in the two previous studies.This follow-up represents 339 patients (47% of the inception cohort), median age 21.1 years (range 12.0-26.9), median diabetes duration 13.2 years (range 8.9-24.5). A standardized questionnaire, fundus photographs (with central reading) and a physical examination were performed. HbA1c and overnight albumin excretion rate (AER) were analysed centrally.Although 88% (n= 309) of the young persons were treated with three or more daily insulin injections, HbA1c (nondiabetic range 4.3-5.8, mean 5.3%) was 9.7+/-1.7% (mean+/-SD). Males had higher HbA1c values than females (P < 0.015). Mean daily insulin dose was 0.92+/-0.25 IU.kg(-1).24h(-1). Microalbuminuria (AER > 20-150 microg/min) and macroalbuminuria (AER > 150 microg/min) were found in 9.0% and 3.7% of the patients, respectively, and was associated with increased diastolic blood pressure (P<0.01) and presence of retinopathy (P<0.01). Retinopathy was present in approximately 60% of the patients and was associated with age, diabetes duration, HbA1c, diastolic blood pressure and AER (all P<0.01). Subclinical neuropathy (vibration perception threshold by biothesiometry > 6.5 V) was found in 62% and showed a significant association with age, linear height, diastolic blood pressure (all P < 0.01) and diabetic retinopathy (P = 0.01).In spite of the majority of the patients being on multiple insulin injections, only 11% had HbA1c values below 8% and the prevalence of diabetic microvascular complications in kidneys, eyes and nerves was unacceptable high.

Intensive treatment regimens including early initiation of insulin treatment are important to prevent late complications in type 2 diabetes. The assumed risk of severe hypoglycemia (SH) is a major barrier to initiation of insulin treatment. To assess the relevance of this risk we evaluated the frequency of SH as reported in the literature. Using Medline and Embase search we identified 11 studies (5 retrospective and 6 prospective) including at least 50 patients with insulin-treated type 2 diabetes followed for at least 6 months in which frequency of SH was reported. The incidence of SH in the retrospective studies varied from 15 to 73 episodes per 100 patient-year with a proportion of the patients having one or more episodes between 1.4 to 15%. In the prospective studies, both incidence rate and proportion of the patients having one or more episodes of SH were lower than in the retrospective studies. Only few studies looked into the impact of risk factors on the rate of SH. Impaired hypoglycemia awareness, high age, long duration of diabetes and insulin therapy increased the risk, while no association was found with HbA1c and insulin dose. The present knowledge of SH in insulin-treated type 2 diabetes is characterized by the paucity of data and the heterogeneity of the few studies available. Large and long-lasting studies with SH as primary endpoint are warranted in order to further clarify the occurrence of SH and influence of the risk factors in unselected patients with insulin-treated type 2 diabetes.

In a 10-yr prospective population study 406 subjects who were 70 yr old received an oral glucose tolerance test. Of these subjects 169 were retested at 80. Three sets of diagnostic criteria were evaluated, of which the WHO criteria are recommended for screening studies in this age group. The prevalences of diabetes mellitus (DM) and impaired glucose tolerance (IGT) according to the latter criteria were 10% vand 26% at 70 and 12% and 35% at 80 in men and women. Excess 10-yr mortality was seen in both sexes when DM existed at 70, and in men also when IGT existed at this age. The excess mortality in men could solely—and in women partly—be explained by cardiovascular diseases. The 10-yr incidence of DM was 20% if IGT existed at 70, but only 4% when normal glucose tolerance was present at 70.

No consensus exists on classification of hypoglycemia awareness. We compared three methods for assessment of hypoglycemia awareness in a clinical setting.A questionnaire including the three methods was filled in by 372 outpatients with Type 1 diabetes [43% women, age 51 ± 14 years (mean ± S.D.)], duration of diabetes 24 ± 13 years, and hemoglobin A1c 8.2 ± 1.0%). Method A (Diabetes Care, 17, 697-703) and B (Diabetes Care, 18, 517-522) classify into two degrees of awareness, while Method C (Diabetes/Metabolism Research and Reviews, 19, 232-240) includes three classes.Normal awareness was reported in 75%, 51%, and 41% (A, B, C); 25% and 28% had impaired awareness (A, B); and 13% were unaware (C); 46% belonged to the intermediate class of impaired awareness (C), while 21% were not classifiable (B). Higher rates of severe hypoglycemic events were reported by patients with impaired awareness (A, B) and unawareness (C) compared to aware patients. Patients with impaired awareness (C) had more severe hypoglycemia than aware patients and less severe hypoglycemia than unaware patients. A lower rate of severe hypoglycemia was reported by aware patients classified by Method C than A. Fractions of patients with normal awareness without an event of severe hypoglycemia were 0.81, 0.86, and 0.91 (A, B, C).All three methods for assessment of hypoglycemia awareness are feasible in clinical practice since the degree of awareness is associated with risk of severe hypoglycemia. The trisected method (C) identifies an intermediate group with impaired awareness and with a risk of severe hypoglycemia that is significantly different from those of aware and unaware patients.

Background: A reliable method to detect biochemical nocturnal hypoglycemia is highly needed, especially in patients with recurrent severe hypoglycemia. We evaluated reliability of nocturnal continuous glucose monitoring (CGM) in patients with type 1 diabetes at high risk of severe hypoglycemia. Patients and Methods: Seventy-two type 1 diabetes patients with recurrent severe hypoglycemia (two or more events within the last year) participated for 4 nights in blinded CGM recordings (Guardian® REAL-Time CGMS and Sof-Sensor®; Medtronic MiniMed, Northridge, CA). Blood was drawn hourly from 23:00 to 07:00 h for plasma glucose (PG) measurements (gold standard). Results: Valid data were obtained in 217 nights. The sensitivity of CGM was 65% (95% confidence interval, 53–77%) below 4 mmol/L, 40% (24–56%) below 3 mmol/L, and 17% (0–47%) below 2.2 mmol/L. PG and CGM readings correlated in the total measurement range (Spearman's ρ=0.82; P<0.001). In the normo- and hyperglycemic ranges CGM underestimated PG by 1.1 mmol/L (0.9–1.2 mmol/L) (P<0.001); in contrast, in the hypoglycemic range (PG<4 mmol/L) CGM overestimated PG levels by 1.0 mmol/L (P<0.001). The mean absolute relative differences in the hypo- (≤3.9 mmol/L), normo- (4–9.9 mmol/L), and hyperglycemic (≥10 mmol/L) ranges were 45% (37–53%), 23% (22–25%), and 20% (19–21%), respectively. Continuous glucose error grid analysis indicated a clinical accuracy of 56%, 99%, and 93% in the hypo-, normo-, and hyperglycemic ranges, respectively. Conclusions: The accuracy in the hypoglycemic range of nocturnal CGM data using Sof-Sensor is suboptimal in type 1 diabetes patients at high risk of severe hypoglycemia. To ensure clinical useful sensitivity in detection of nocturnal hypoglycemic episodes, an alarm threshold should not be lower than 4 mmol/L.

Hypoglycemia and fear of hypoglycemia threaten individuals' ability to work and drive. We studied the effect of hypoglycemia on the individual and society, with a focus on possible implications of new European union legislation on patients' continued ability to drive.A cross-sectional survey of Danish Diabetes Association members was conducted to investigate individual and societal consequences of hypoglycemia.A total of 3117/9951 individuals with type 1 diabetes (T1DM) (32.2%) or type 2 diabetes (T2DM) (67.8%) completed the survey. The calculated incidence rates of self-reported severe and mild hypoglycemia were 2.9, 0.6 and 0.1 events per patient year (ppy) in patients with T1DM, insulin using T2DM and non-insulin using T2DM, respectively; and incidence rates of self-reported mild hypoglycemia were 99.0, 23.2 and 10.9 events ppy, respectively. Self-care strategies to avoid hypoglycemia include maintaining higher blood glucose levels (45.7%) and reducing physical activity (15.7%). Few people take sick leave as a result of hypoglycemia, but prolonged mental recovery ≥4 h following an episode of mild or severe hypoglycemia was reported by 8.7 and 31.0%, respectively. 26.5% of patients holding a valid driving license reported having ever had at least one episode of severe hypoglycemia. Patients considering underreporting of hypoglycemia to maintain their driving license were more likely to have experienced severe hypoglycemia (odds ratio [OR]: 3.03; 95% CI: 2.42-3.79; p < 0.0001).A high proportion of insulin-treated patients experience hypoglycemia resulting in fear of hypoglycemia and changes in self-care behavior that may compromise glycemic control. Many patients with a history of severe hypoglycemia consider underreporting hypoglycemic events through concern over retaining their driving license.

Hypoglycemia is associated with increased activity in the low-frequency bands in the electroencephalogram (EEG). We investigated whether hypoglycemia awareness and unawareness are associated with different hypoglycemia-associated EEG changes in patients with type 1 diabetes. Twenty-four patients participated in the study: 10 with normal hypoglycemia awareness and 14 with hypoglycemia unawareness. The patients were studied at normoglycemia (5-6 mmol/L) and hypoglycemia (2.0-2.5 mmol/L), and during recovery (5-6 mmol/L) by hyperinsulinemic glucose clamp. During each 1-h period, EEG, cognitive function, and hypoglycemia symptom scores were recorded, and the counterregulatory hormonal response was measured. Quantitative EEG analysis showed that the absolute amplitude of the θ band and α-θ band up to doubled during hypoglycemia with no difference between the two groups. In the recovery period, the θ amplitude remained increased. Cognitive function declined equally during hypoglycemia in both groups and during recovery reaction time was still prolonged in a subset of tests. The aware group reported higher hypoglycemia symptom scores and had higher epinephrine and cortisol responses compared with the unaware group. In patients with type 1 diabetes, EEG changes and cognitive performance during hypoglycemia are not affected by awareness status during a single insulin-induced episode with hypoglycemia.

<h3>Objective</h3> To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. <h3>Design and setting</h3> Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design conducted at eight hospitals in Denmark. <h3>Participants and interventions</h3> 412 participants with type 2 diabetes (glycated haemoglobin (HbA_1c) ≥7.5% (≥58 mmol/mol); body mass index &gt;25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA_1c ≤7.0% (≤53 mmol/mol). <h3>Outcomes</h3> The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA_1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. <h3>Results</h3> Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI −0.003 to 0.026), p=0.11). HbA_1c was more reduced in the metformin group (between-group difference −0.42% (95% CI −0.62% to −0.23%), p&lt;0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p&lt;0.001). The metformin group gained less weight (between-group difference −2.6 kg (95% CI −3.3 to −1.8), p&lt;0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p&lt;0.001). <h3>Conclusions</h3> Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA_1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. <h3>Trial registration number</h3> NCT00657943; Results.

To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]).Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

Family history, as well as genetic and immunological markers of diabetes mellitus, were studied in cystic fibrosis (CF) patients with and without diabetes mellitus. Positive family history of diabetes mellitus in first‐degree relatives was found in only 6 of 210 (3%) CF patients, with no difference between non‐diabetic and diabetic patients. The frequency distributions of the HLA types DR3, DR4 and DR3/4, which normally confer susceptibility to insulin‐dependent diabetes mellitus and of HLA‐DR2, which normally confers resistance to insulin‐dependent diabetcs mellitus, were not different in non‐diabetic CF patients, diabetic CF patients and normal subjects. The genotypic frequencies of tumor necrosis factor‐β and of heat shock protein 70, located within the HLA region on chromosome 6, in CF patients with diabetes were not different from those in patients with insulin‐dependent diabetes mellitus, while non‐diabetic CF patients and normal subjects shared other patterns. The frequencies of the interleukin‐1β alleles, located on chromosome 2, were not different in non‐diabetic and diabetic CF patients, insulin‐dependent diabetic patients and normal subjects. Islet cell cytoplasmic antibodies. measured before, at and after the diagnosis of diabetes in 33 diabetic CF patients and in 32 matched non‐diabetic CF patients, were detected in only 2 of 236 (0.8%) serum samples; m a pre‐diabetic patient and in a non‐diabetic control patient. Birth weights were not different in diabetic and non‐diabetic CF patients, arguing against the importance of the intrauterine environment as a determinant in the transmission of diabetes mellitus in CF patients. We conclude that diabetes mellitus in CF is without family history of diabetes mellitus, HLA‐DR association, and serological evidence for autoimmune destruction of the β‐cells. The significance of similar frequcncies of tumor necrosis factor‐β and heal shock protein 70 alleles in insulin‐dependent diabetic patients and diabetic CF patients remains to bc determined.

Objective Nocturnal hypoglycemia is a feared complication to insulin treated diabetes. Impaired awareness of hypoglycemia (IAH) increases the risk of severe hypoglycemia. EEG changes are demonstrated during daytime hypoglycemia. In this explorative study, we test the hypothesis that specific hypoglycemia-associated EEG-changes occur during sleep and are detectable in time for the patient to take action. Research design and methods Ten patients with type 1 diabetes (duration 23.7 years) with IAH were exposed to insulin-induced hypoglycemia during the daytime and during sleep. EEG was recorded and analyzed real-time by an automated multi-parameter algorithm. Participants received an auditory alarm when EEG changes met a predefined threshold, and were instructed to consume a meal. Results Seven out of eight participants developed hypoglycemia-associated EEG changes during daytime. During sleep, nine out of ten developed EEG changes (mean BG 2.0 mmol/l). Eight were awakened by the alarm. Four corrected hypoglycemia (mean BG 2.2 mmol/l), while four (mean BG 1.9 mmol/l) received glucose infusion. Two had false alarms. EEG-changes occurred irrespective of sleep stage. Post hoc improvement indicates the possibility of earlier detection of hypoglycemia. Conclusions Continuous EEG monitoring and automated real-time analysis may constitute a novel technique for a hypoglycemia alarm in patients with IAH.

Abstract Aim To explore and illustrate how the Guided Self‐Determination‐Youth method influences the development of life skills in adolescents with type 1 diabetes supported by their parents and healthcare providers. Background Evidence‐based methods that accomplish constructive cooperation between adolescents with poorly controlled type 1 diabetes, their parents and healthcare providers are needed. We adjusted an adult life skills intervention comprising reflection sheets and advanced communication for use by adolescent‐parent‐professional triads in outpatient visits. Design A qualitative realistic evaluation design comprising eight context‐mechanism‐outcome configurations directed the analysis of the Guided Self‐Determination‐Youth's influence on adolescent‐parent‐professional triads to evaluate what worked for whom, how and in what circumstances. Thirteen adolescents aged 13–18 years diagnosed with type 1 diabetes for ≥1 year and having poor glycaemic control participated together with 17 parents and eight healthcare providers. Data were collected from December 2009–March 2012 and consisted of digitally recorded outpatient Guide Self‐Determination‐Youth visits collected during the intervention period (11·5–24·5 months) and semi‐structured interviews at 6‐month follow‐up. Findings Emerging life skills in adolescents were identified as: (1) developing new relatedness with healthcare providers and parents; (2) becoming decision makers in their own lives with diabetes; and (3) growing personally. Reflection sheets combined with healthcare providers' advanced communication were central to promoting mutual problem‐solving. Conclusion A life skills approach turned outpatient visits into person‐specific visits with improved cooperation patterns in the triads. Combining reflection sheets and advanced communication skills supported adolescents in beginning a process of developing life skills.

Obstructive Sleep Apnoea (OSA) is frequent in patients with type 2 diabetes. The aim of this study is to evaluate prevalence of OSA in patients with type 1 diabetes. In a cross-sectional design, all patients with type 1 diabetes attending the outpatient clinic were offered screening for OSA for one night with the ApneaLink + home-monitoring device. OSA was classified by the Apnoea–Hypopnea index (AHI; apnoeas/hypopneas per hour sleep). Symptoms of OSA were scored using the Epworth Sleepiness Score. Presence of autonomic neuropathy was evaluated by the Vagus® device. A total of 200 of 518 eligible patients with type 1 diabetes (39%) participated (68% men; age 52 ± 15 years (mean ± SD), diabetes duration 24 ± 14 years and BMI 25.3 ± 3.3 kg/m2). OSA was diagnosed in 92 patients (46% (95% CI: 40–53)). Five patients had known OSA, and OSA was newly diagnosed in 87 patients, predominantly mild OSA (60 patients (69%)). OSA was present in 32% of the patients with normal BMI, in 60% of overweight patients, and in 61% of obese patients. Patients with type 1 diabetes and OSA were largely asymptomatic and did not report more sleepiness than patients without OSA. At multivariate analysis, age, BMI and presence of nephropathy were positively associated with risk of OSA. The prevalence of asymptomatic OSA is high in a cohort of patients with type 1 diabetes. Older age, overweight, and presence of nephropathy are associated with OSA.

Aim Glucagon‐like peptide‐1 receptor agonist ( GLP‐1RA ) therapy is a potential treatment as adjunct to insulin in type 1 diabetes ( T1D ). However, GLP‐1RAs inhibit glucagon secretion and delay the gastric emptying ( GE ) rate and may impair recovery from hypoglycaemia. We evaluated the effect of the GLP‐1RA liraglutide on counterregulatory responses and GE rate during hypoglycaemia in persons with T1D . Materials and methods In a 12‐week, randomized, double‐blind, placebo‐controlled study, 20 patients aged &gt;18 years with T1D and HbA1c ≥8% (64 mmol/mol) were randomly assigned (1:1) to liraglutide 1.2 mg once daily or placebo as add‐on to insulin treatment. Before and at end of treatment a hypoglycaemic clamp (plasma glucose target 2.5 mmol/ L ) was carried out, followed by a liquid meal. Primary endpoint was change in GE rate (evaluated by area under the paracetamol curve and time to peak). Secondary endpoints included changes in glycaemic recovery, counter‐regulatory hormones, pancreatic polypeptide ( PP ), GLP ‐1, blood pressure and heart rate. Results During the period J une 2013 to O ctober 2014, 20 patients were enrolled. After 12 weeks of treatment, changes in GE rates did not differ significantly between groups ( P = .96), with no significant changes from baseline, whether evaluated from AUCs or time to peak. The secondary endpoints, glycaemic recovery, counter‐regulatory hormone responses, systolic blood pressure and GLP ‐1 and PP responses, were also similar. Heart rate increased with liraglutide from 69 ± 4 to 80 ± 5 beats/min ( P = .02). Conclusions Liraglutide does not compromise glycaemic recovery, GE rate or counter‐regulatory hormone responses in T1D patients during hypoglycaemia. No treatment‐related safety issues were identified.

The relationship between symptomatic (subjective feelings) and biochemical (blood glucose concentration less than 3 mmol l-1) hypoglycaemia was studied in 66 randomly selected insulin-dependent diabetic out-patients under normal conditions of daily life with conventional insulin injection regimens. The patients (a) collected 7-point diurnal blood glucose profiles at home on three consecutive days and then once weekly for 3 weeks, (b) indicated whether they felt hypoglycaemic at sampling times, and (c) collected extra samples if they felt hypoglycaemic at any time during the study period. The weekly frequencies of symptomatic and biochemical hypoglycaemia were 0.99 and 1.75 per patient, respectively. Biochemical hypoglycaemia was present in 29% of the symptomatic episodes, and symptomatic hypoglycaemia accompanied 16% of the biochemical episodes. Symptomatic hypoglycaemia was experienced at a median blood glucose concentration of 3.4 mmol l-1 (range 1.4-14.9 mmol l-1). Fifty per cent of both symptomatic and biochemical episodes occurred before lunch, while the remainder were evenly distributed throughout the day. The occurrence of biochemical hypoglycaemia, but not of symptomatic hypoglycaemia, was inversely correlated with HbA1c and median blood glucose concentration. Thus symptomatic hypoglycaemia is an unreliable indicator of biochemical hypoglycaemia and of the degree of glycaemic control. Blood glucose measurements are a prerequisite for the diagnosis of hypoglycaemia.

Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal–bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). Analogue-based treatment resulted in a 6% (2–10%; P = 0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32–46%; P < 0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36–57%]; P < 0.0001) and asymptomatic (28% [14–39%]; P = 0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.

Measurement of glycosuria is still widely used for home monitoring of glycaemic control in non-insulin-dependent diabetes (NIDDM). This method has been criticized because the renal threshold for glucose (RTglu) varies between subjects. In order to evaluate the validity of RTglu by measuring corresponding measurements of blood and urine glucose in NIDDM patients, we studied the blood/urine glucose relationship in 24 NIDDM patients. RTglu estimated from 75 contemporary blood and urine glucose concentrations measured at home by each patient (h-RTglu) was compared with RTglu measured by a hyperglycaemic glucose clamp (c-RTglu). H-RTglu and c-RTglu, being 7.6 mmol/1 (range 5.5–12.4) and 10.3 mmol/1 (6.2–12.3) respectively (P < 0.005), were weakly correlated (R(S) = 0.35, P = 0.15). In conclusion, c-RTglu varies two-fold between NIDDM patients. RTglu detected by home monitored urine and blood glucose determinations underestimates the true RTglu, probably due to the splay phenomenon. However, the method for detection of RTglu used by us seems of clinical relevance, since it reflects the individual blood glucose level at which glucose is detectable in the urine.

Abstract Aim Continuous glucose monitoring may reveal episodes of unrecognized hypoglycaemia. We evaluated reproducibility and reliability of hypoglycaemic episodes recorded in daily life by the Medtronic MiniMed Continuous Glucose Monitoring System (CGMS). Methods Twenty‐nine adult patients with Type 1 diabetes underwent 6 days of continuous subcutaneous glucose monitoring, applying one CGMS on each side of the abdomen. Blood glucose was measured by HemoCue B‐Glucose Analyzers six times daily and two different 4‐point calibration sets were generated (set A and B). Using these calibration sets, CGMS raw data were recalibrated generating four different CGMS data sets [left‐A (left side of abdomen, calibration set A), left‐B, right‐A and right‐B]. Agreement between CGMS data sets was evaluated during hypoglycaemic events, comparing CGMS readings = 2.2 mmol/l with nadir values from corresponding CGMS data sets. CGMS readings were also compared with independent self‐monitored blood glucose (SMBG) values. Results With hypoglycaemia (CGMS readings = 2.2 mmol/l) in calibration set left‐A, values below 3.5 mmol/l were present in 99% (95% CI: 95–100%) of samples in left‐B, 91% (95% CI: 84–96%) of samples in right‐A, and 90% (95% CI: 83–95%) of samples in right B. In 84% of these episodes (95% CI: 59–96%) independent SMBG values were below 3.5 mmol/l. Difference in duration was observed with a median difference of 20 min; (left‐A vs. right‐B). Conclusion Hypoglycaemic episodes recorded by CGMS are reproducible and agreement with independent SMBG values is acceptable for retrospective recording of hypoglycaemic events with CGMS.

Alcohol consumption is a well-known risk factor for severe hypoglycemia in insulin-treated diabetes. 1 Kerr D. Drugs and alcohol. in: Frier B.M. Fisher B.M. Hypoglycaemia and Diabetes. Edward Arnold, London, United Kingdom1993: 328-336 Google Scholar Studies based on interviews have implicated alcohol use in up to 19% of severe hypoglycemic episodes. 2 Potter J. Clarke P. Gale E.A. et al. Insulin-induced hypoglycaemia in an accident and emergency department The tip of an iceberg?. BMJ. 1982; 285: 1180-1182 Crossref PubMed Scopus (114) Google Scholar , 3 Moses R.G. Hubert P.A. Lewis-Driver D.J. Severe hypoglycaemia. A one-year prospective study in Wollongong. Med J Aust. 1985; 142: 294-296 PubMed Google Scholar , 4 Feher M.D. Grout P. Kennedy A. et al. Hypoglycaemia in an inner-city accident and emergency department A 12-month survey. Arch Emerg Med. 1989; 6: 183-188 Crossref PubMed Scopus (29) Google Scholar , 5 Hart S.P. Frier B.M. Causes, management and morbidity of acute hypoglycaemia in adults requiring hospital admission. QJM. 1998; 91: 505-510 Crossref PubMed Scopus (73) Google Scholar Alcohol may promote the risk of severe hypoglycemia by interfering with cognitive function and self-care, compromising awareness of hypoglycemic symptoms, 6 Kerr D. Macdonald I.A. Heller S.R. Tattersall R.B. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia. 1990; 33: 216-221 Crossref PubMed Scopus (117) Google Scholar and reducing the mobilization of carbohydrates during hypoglycemia. 7 Avogaro A. Beltramello P. Gnudi L. et al. Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients. Evidence for a critical role of free fatty acids. Diabetes. 1993; 42: 1626-1634 Crossref PubMed Google Scholar , 8 Turner B.C. Jenkins E. Kerr D. et al. The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes. Diabetes Care. 2001; 24: 1888-1893 Crossref PubMed Scopus (145) Google Scholar

The aim of this study was to investigate whether components of the renin-angiotensin system and semicarbazide-sensitive amine oxidase (SSAO) are associated with the development of pre-eclampsia in women with type 1 diabetes.This was an observational study of 107 consecutive pregnant women with type 1 diabetes (median duration 16 years [range 1-36 years], HbA(1c) 6.6% [range 4.9-10.5%]) in early pregnancy. At 8, 14, 21, 27 and 33 weeks and once within 5 days postpartum, blood was sampled for measurements of prorenin, renin, angiotensinogen, ACE and SSAO. HbA(1c), blood pressure and urinary albumin excretion were recorded. Pre-eclampsia was defined as blood pressure >140/90 mmHg and proteinuria ≥300 mg/24 h after 20 weeks.Pre-eclampsia developed in nine women (8%) with longer diabetes duration (median 20 [range 10-32] vs 16 [range 1-36] years, p = 0.04), higher SSAO concentrations (592 [range 372-914] vs 522 [range 264-872] mU/l, p = 0.04) and a tendency towards higher prorenin levels (136 [range 50-296] vs 101 [range 21-316] ng angiotensin I ml(-1) h(-1), p = 0.06) at 8 weeks compared with women without pre-eclampsia. Levels of renin, angiotensinogen and ACE did not differ in the two groups. Throughout pregnancy, prorenin and SSAO levels were 30% (p = 0.004) and 16% (p = 0.04) higher, respectively, in women developing pre-eclampsia. Using multivariate logistic regression analysis, prorenin concentration at 8 weeks was associated with pre-eclampsia (OR 4.4 [95% CI 1.5-13.0], p = 0.007), i.e. an increase of prorenin of 100 ng angiotensin I ml(-1) h(-1) implies a 4.4 times higher risk of subsequent pre-eclampsia.In type 1 diabetic women with pre-eclampsia, a higher concentration of prorenin in early pregnancy and higher levels of prorenin and SSAO throughout pregnancy were seen.

Introduction The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO) enhances cognitive function during hypoglycemia. Materials and Methods Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint), hypoglycemic symptoms, and counter-regulatory hormonal response were recorded. Results Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (−4.7 (−8.1 to −1.3), p = 0.01) and a less reaction time prolongation (−66 (−117 to −16) msec, p = 0.02). EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment. Conclusion In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment. Trial Registration ClinicalTrials.gov NCT00615368

To investigate whether the incidence of severe hypoglycaemia in pregnant women with type 1 diabetes can be reduced without deteriorating HbA1c levels or pregnancy outcomes in a routine care setting.Two cohorts (2004-2006; n=108 and 2009-2011; n=104) were compared. In between the cohorts a focused intervention including education of caregivers and patients in preventing hypoglycaemia was implemented. Women were included at median 8 (range 5-13) weeks. Severe hypoglycaemia (requiring assistance from others) was prospectively reported in structured interviews.In the first vs. second cohort, severe hypoglycaemia during pregnancy occurred in 45% vs. 23%, p=0.0006, corresponding to incidences of 2.5 vs. 1.6 events/patient-year, p=0.04. Unconsciousness and/or convulsions occurred at 24% vs. 8% of events. Glucagon and/or glucose injections were given at 15% vs. 5% of events. At inclusion HbA1c was comparable between the cohorts while in the second cohort fewer women reported impaired hypoglycaemia awareness (56% vs. 36%, p=0.0006), insulin dose in women on multiple daily injections was lower (0.77 IU/kg (0.4-1.7) vs. 0.65 (0.2-1.4), p=0.0006) and more women were on insulin analogues (rapid-acting 44% vs. 97%, p<0.0001; long-acting 6% vs. 76%, p<0.0001) and insulin pumps (5% vs. 23%, p<0.0001). Pregnancy outcomes were similar in the two cohorts.A 36% reduction in the incidence of severe hypoglycaemia in pregnancy with unchanged HbA1c levels and pregnancy outcomes was observed after implementation of focused intervention against severe hypoglycaemia in a routine care setting. Improved insulin treatment, increased health professional education and fewer women with impaired hypoglycaemia awareness may contribute.

Background: Hypoglycemia is an increasingly important endpoint in clinical diabetes trials. The assessment of hypoglycemia should therefore be as complete as possible. Blinded continuous glucose monitoring (CGM) provides an improved opportunity to capture asymptomatic and nocturnal events. Here we report results from the HypoAna trial comparing all-analog-insulin therapy (aspart/detemir) with all-human-insulin therapy (neutral protamine Hagedorn/regular) on non–severe hypoglycemia (symptomatic and asymptomatic hypoglycemia) as assessed by blinded CGM and compared with data obtained by self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes and recurrent severe hypoglycemia. Methods: Fifty-three patients completed a substudy of 4 × 3 days of blinded CGM. CGM traces were reviewed for hypoglycemic events lasting 15 min or longer. Results: At the threshold ≤3.9 mmol/L, the per-protocol analysis demonstrated a 40% rate reduction (95% confidence interval [CI] 20%–60%; P = 0.002) in nocturnal non–severe hypoglycemia during analog treatment, mainly due to a 40% rate reduction (95% CI 0%–70%; P = 0.03) of nocturnal asymptomatic hypoglycemia. Similar nonsignificant trends were seen at the glucose threshold ≤3.0 mmol/L. Overall CGM-detected that nocturnal asymptomatic hypoglycemia ≤3.9 mmol/L was ∼17 times more frequent than SMBG-detected episodes (52 vs. 3 events/patient-year). This translates into a time needed to treat one patient with insulin analogs to prevent one episode that is 34 times shorter using CGM data than SMBG data (1.4 vs. 47 weeks). Conclusions: Capturing hypoglycemic events by the conventional method of SMBG in patients with impaired awareness reveals only a limited number of events. Blinded CGM can provide more complete data, particularly in terms of asymptomatic and nocturnal events.

Abstract Aim The epidemiology of asymptomatic (silent) hypoglycaemia is not well‐described. We investigated incidence and risk factors for asymptomatic hypoglycaemia in Type 1 diabetes. Methods A cohort of 153 people with Type 1 diabetes participated in 6 days of blinded continuous glucose monitoring ( CGM ) and recording of hypoglycaemia symptoms. At entry, hypoglycaemia awareness was classified (by three different methods) and HbA 1c and C‐peptide were measured. Hypoglycaemic episodes were defined as interstitial glucose ≤ 3.9 mmol/l ( IG 3.9 ) or ≤ 3.0 mmol/l ( IG 3.0 ) for ≥ 15 min, and were considered asymptomatic if no hypoglycaemic symptoms were reported. Results At thresholds IG 3.9 and IG 3.0 , the incidence rates of hypoglycaemic episodes were 5.0 (7.9) [median ( IQR )] and 1.3 (3.4) episodes/person‐week, respectively. Three‐quarters of episodes were asymptomatic. In total, 77% and 52% of participants experienced one or more episode of asymptomatic hypoglycaemia at IG 3.9 and IG 3.0 [3.0 (6.2) and 1.0 (2.3) asymptomatic episodes/person‐week]. At multivariate analysis, reduced awareness was positively associated with asymptomatic hypoglycaemia, particularly nocturnal events, and negatively with symptomatic hypoglycaemia. High insulin dose was associated with increased risk of both asymptomatic and symptomatic hypoglycaemia, whereas low HbA 1c and long diabetes duration were risk factors only for symptomatic hypoglycaemia. Conclusions Asymptomatic hypoglycaemia constitutes the majority of hypoglycaemic events in Type 1 diabetes. Reduced hypoglycaemia awareness and high insulin dose are risk factors for asymptomatic hypoglycaemia but other conventional risk factors for severe hypoglycaemia do not correlate with risk of asymptomatic episodes.

Patients with type 2 diabetes (T2DM) have an increased mortality rate primarily because of macrovascular disease. Where T2DM patients cannot be managed sufficiently through diet, exercise and peroral antidiabetic drugs, that is when haemoglobin A1c (HbA1c) is above 7.0%, it is yet unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal.The primary objective of this trial is to evaluate the effect of an 18-month treatment with metformin vs. placebo in combination with one of three insulin analogue regimens, the primary outcome measure being carotid intima-media thickness (CIMT) in T2DM patients.A randomized, stratified, multicentre trial having a 2 x 3 factorial design. The metformin part is double masked and placebo controlled. The insulin treatment is open. The intervention period is 18 months.Nine hundred and fifty patients with T2DM and HbA1c > or = 7.5% on treatment with oral hypoglycaemic agents or on insulin treatment and deemed able, by the investigator, to manage once-daily insulin therapy with a long-acting insulin analogue.Central randomization stratified for age (above 65 years), previous insulin treatment and treatment centre.Metformin 1 g x two times daily vs. placebo (approximately 475 patients vs. 475 patients) in combination with insulin detemir before bedtime (approximately 315 patients) or biphasic insulin aspart 30 before dinner with the possibility to increase to two or three injections daily (approximately 315 patients) or insulin aspart before the main meals (three times daily) and insulin detemir before bedtime (approximately 315 patients). Intervention follows a treat-to-target principle in all six arms aiming for an HbA1c < or = 7.0%.Primary outcome measure is the change in CIMT from baseline to 18 months. Secondary outcome measures comprises the composite outcome of death, acute myocardial infarction, stroke or amputation assessed by an adjudication committee blinded to intervention, other cardiovascular clinical outcomes, average postprandial glucose increment from 0 to 18 months, hypoglycaemia and any inadvertent medical episodes. In addition, change in plaque formation in the carotids, HbA1c, cardiovascular biomarkers, body composition, progression of microvascular complications and quality of life will be assessed as tertiary outcome measures. TIME SCHEDULE: Patient enrolment started May 2008. Follow-up is expected to finish in March 2011.CIMT is designed to provide evidence as to whether metformin is advantageous even during insulin treatment and to provide evidence regarding which insulin analogue regimen is most advantageous with regard to cardiovascular disease.

Adolescents with type 1 diabetes face demanding challenges due to conflicting priorities between psychosocial needs and diabetes management. This conflict often results in poor glycaemic control and discord between adolescents and parents. Adolescent-parent conflicts are thus a barrier for health care providers (HCPs) to overcome in their attempts to involve both adolescents and parents in improvement of glycaemic control. Evidence-based interventions that involve all three parties (i.e., adolescents, parents and HCPs) and are integrated into routine outpatient clinic visits are lacking. The Guided Self-Determination method is proven effective in adult care and has been adapted to adolescents and parents (Guided Self-Determination-Young (GSD-Y)) for use in paediatric diabetes outpatient clinics. Our objective is to test whether GSD-Y used in routine paediatric outpatient clinic visits will reduce haemoglobin A1c (HbA1c) concentrations and improve adolescents' life skills compared with a control group. Using a mixed methods design comprising a randomised controlled trial and a nested qualitative evaluation, we will recruit 68 adolescents age 13 - 18 years with type 1 diabetes (HbA1c > 8.0%) and their parents from 2 Danish hospitals and randomise into GSD-Y or control groups. During an 8-12 month period, the GSD-Y group will complete 8 outpatient GSD-Y visits, and the control group will completes an equal number of standard visits. The primary outcome is HbA1c. Secondary outcomes include the following: number of self-monitored blood glucose values and levels of autonomous motivation, involvement and autonomy support from parents, autonomy support from HCPs, perceived competence in managing diabetes, well-being, and diabetes-related problems. Primary and secondary outcomes will be evaluated within and between groups by comparing data from baseline, after completion of the visits, and again after a 6-month follow-up. To illustrate how GSD-Y influences glycaemic control and the development of life skills, 10-12 GSD-Y visits will be recorded during the intervention and analysed qualitatively together with individual interviews carried out after follow-up. This study will provide evidence of the effectiveness of using a GSD-Y intervention with three parties on HbA1c and life skills and the feasibility of integrating the intervention into routine outpatient clinic visits. Danish Data Association ref nr. 2008-41-2322 ISRCTN54243636

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450).

The frequency and distribution of daytime biochemical hypoglycaemia (capillary blood glucose concentration below 3 mmol/l) was assessed in type 1 diabetic patients on conventional twice daily insulin therapy ( n = 79) and on continuous subcutaneous insulin infusion ( n = 20). Patients collected and mailed to the hospital blood for seven‐point blood glucose profiles. For both treatment regimens the frequency of biochemical hypoglycaemia on individual days was inversely related to the median blood glucose concentration in a curvilinear manner ( p &lt; 0.001). Hypoglycaemia was more frequent pre‐prandially than post‐prandially ( p &lt; 0.01), and was evenly distributed during the day in patients on continuous subcutaneous insulin infusion. In patients on conventional therapy, however, pre‐lunch hypoglycaemia was four times more frequent than pre‐breakfast or pre‐dinner hypoglycaemia ( p &lt; 0.0001).

Background The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. Methods Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. Results Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. Conclusions High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial.The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year.In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996.

To examine whether severe hypoglycaemia and impaired hypoglycaemic awareness, a principal predictor of severe hypoglycaemia, are associated with all-cause mortality or cardiovascular mortality in Type 1 diabetes mellitus.Mortality was recorded in two cohorts, one in Denmark (n = 269, follow-up 12 years) and one in the Netherlands (n = 482, follow-up 6.5 years). In both cohorts, awareness class was characterized and numbers of episodes of severe hypoglycaemia either during lifetime (Danish cohort) or during the preceding year (Dutch cohort) were recorded. In addition, episodes of severe hypoglycaemia were prospectively recorded every month for 1 year in the Danish cohort. Follow-up data regarding mortality were obtained through medical reports and registries (Danish cohort).All-cause mortality was 14% (n = 39) in the Danish and 4% (n = 20) in the Dutch cohort. In either cohort, neither presence of episodes with severe hypoglycaemia nor impaired hypoglycaemia awareness were associated with increased mortality in age-truncated Cox proportional hazard regression models. Variables associated with increased risk of all-cause mortality in both cohorts were evidence of macrovascular disease and reduced kidney function.Severe hypoglycaemia and hypoglycaemia unawareness are not associated with increased risk of all-cause or cardiovascular mortality in people with Type 1 diabetes mellitus.

Background: Recurrent hypoglycemia has been shown to blunt hypoglycemia symptom scores and counterregulatory hormonal responses during subsequent hypoglycemia. We therefore studied whether hypoglycemia-associated electroencephalogram (EEG) changes are affected by an antecedent episode of hypoglycemia. Methods: Twenty-four patients with type 1 diabetes mellitus (10 with normal hypoglycemia awareness, 14 with hypoglycemia unawareness) were studied on 2 consecutive days by hyperinsulinemic glucose clamp at hypoglycemia (2.0–2.5 mmol/L) during a 1-h period. EEG was recorded, cognitive function assessed, and hypoglycemia symptom scores and counterregulatory hormonal responses were obtained. Results: Twenty-one patients completed the study. Hypoglycemia-associated EEG changes were identified on both days with no differences in power or frequency distribution in the theta, alpha, or the combined theta–alpha band during hypoglycemia on the 2 days. Similar degree of cognitive dysfunction was also present during hypoglycemia on both days. When comparing the aware and unaware group, there were no differences in the hypoglycemia-associated EEG changes. There were very subtle differences in cognitive function between the two groups on day 2. The symptom response was higher in the aware group on both days, while only subtle differences were seen in the counterregulatory hormonal response. Conclusion: Antecedent hypoglycemia does not affect hypoglycemia-associated EEG changes in patients with type 1 diabetes mellitus.

The relationship between the cystic fibrosis (CF) genotype and endocrine and exocrine pancreatic function was studied in 215 CF patients. In the 211 patients with the Δ F508 mutation, endocrine pancreatic function (oral glucose tolerance; WHO criteria) was normal in 72.5%, impaired in 12.3%, and diabetic in 15.2% of the patients, with no difference between CF patients homozygous (N=163, median age 15 years, range 2–40) or heterozygous (N=48, 18 years, 3–40; age difference not significant) for the Δ F508 mutation. Exocrine pancreatic sufficiency (no need for pancreatic enzyme substitution) was found in 0.6% of the patients homozygous for the Δ F508 mutation and in 10.4% of the heterozygotes (p&lt;0.01). Homozygous patients with pancreatic insufficiency took more pancreatic enzyme capsules (median 42 per day, range 0–192) than the heterozygotes (29 per day, 0–300; p&lt;0.001). The four patients (1.9%) without the Δ F508 mutation had normal glucose tolerance but exocrine pancreatic insufficiency. In conclusion, the major mutation genotype in CF ( Δ F508) affects the severity of the exocrine pancreatic insufficiency, whereas endocrine pancreatic function is unrelated to this genotype.

The general use of first order kinetics to describe the disappearance of insulin from plasma in man contrasts the available evidence of saturation kinetics for insulin. In order to bridge this gap, we have put forward three alternative models of insulin kinetics. Model 1 considers the combined existence of first order and saturation (Michaëlis-Menten) kinetics. Model 2 considers saturation kinetics alone. Model 3 considers first order kinetics alone. The validity of the models was studied in normal and type I (insulin-dependent) diabetic subjects. Sequential constant intravenous infusions of insulin at different rates were used to achieve different levels of steady state plasma insulin concentrations, while the glycaemic level (usually normoglycaemia) was maintained by a glucose clamp. Appropriate validation procedures demonstrated that the model of saturation kinetics alone (model 2) was superior to the other models in normal subjects at physiological and supraphysiological plasma insulin concentrations, and in diabetic patients at supraphysiological concentrations. The minimal model at physiological insulin concentrations in type I diabetic patients was that of first order kinetics (model 3). The kinetics of insulin was independent of the species of insulin (human or porcine) in both study groups. The actual glycaemic clamp level (normoglycaemia and moderate hyperglycaemia) did not influence the insulin disappearance rate. Binding of insulin to its receptor is considered to be the initial step in insulin degradation. Saturation kinetics of insulin may therefore be influenced by the saturation of binding of insulin molecules to their receptors. We found values of Km (i.e. the concentration of plasma insulin at which the insulin disappearance rate is half maximal) in normal subjects comparable to values of Kd (i.e. the dissociation constant for insulin-receptor binding) from receptor studies in isolated cells. Changes in regional (hepatic and/or renal) blood flow at hyperinsulinaemia represent an alternative explanation to a model of saturation kinetics. Increases in Vmax (i.e. the maximal insulin disappearance rate) and Km with increasing insulin dose were observed in normal subjects. This finding suggests that insulin may disappear from plasma by more than one saturable pathway. Additional studies are needed to confirm this observation. The clearance rate of insulin at infinitesimal plasma insulin concentrations (Vmax/Km) was 28 +/- 8 ml.kg-1.min-1 in normal subjects. This value is higher than most clearance rates previously reported in studies using first order kinetics. The clearance rate of insulin in type I diabetic patients was 20 +/- 4 ml.kg-1.min-1, corresponding to a reduction in clearance of 30% compared to normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma semicarbazide-sensitive amine oxidase (SSAO) is elevated in patients with type 1 and type 2 diabetes and has been implicated in the pathophysiology of diabetic late complications. The regulation of SSAO production remains unknown. We studied correlations between plasma SSAO activity and parameters associated with diabetic late complications.Plasma SSAO was measured in a well-characterised group of 287 patients with type 1 diabetes. Standard statistical methods were used to investigate correlations with clinical parameters and components of the renin-angiotensin system.Overall, plasma SSAO was elevated, at 693+/-196 mU/l (mean+/-SD; normal controls 352+/-102 mU/l). Plasma SSAO was higher in the group with late complications or hypertension, and in patients treated with ACE-inhibitors. In univariate analysis a significant positive correlation (p<0.001, r=0.27) was found between plasma SSAO and serum ACE activity in patients untreated with ACE inhibitors or angiotensin II receptor antagonists (n=221), but plasma SSAO did not differ by ACE I/D genotype. Plasma SSAO correlated positively with duration of diabetes, HbA(1)c and plasma renin, and negatively with plasma angiotensinogen and body mass index. A multiple regression analysis including these variables resulted in serum ACE activity (p<0.001), ACE genotype (negatively, p<0.001) and HbA(1)c (p=0.023) as explaining variables.Results suggest that a common factor is involved in the regulation of both plasma SSAO and serum ACE, which is different from the genetic determination of ACE activity.

Brain-derived natriuretic peptide (BNP) is a cardioprotective peptide released, together with the inactive NH(2)-terminal part of its prohormone (NT-pro-BNP), in response to different kinds of myocardial stress. Hypoglycemia and hypoxemia are conditions that threaten cellular function and hence potentially stimulate BNP release. BNP interacts with the renin-angiotensin system (RAS). The aim of this study was, therefore, to explore if basal RAS activity has an impact on NT-pro-BNP concentrations during myocardial stress induced by hypoglycemia and hypoxemia. From a cohort of 303 healthy young men, 10 subjects with high-RAS activity and 10 subjects with low-RAS activity (age 26 +/- 1 yr; mean +/- SE) were studied in a single-blinded, randomized, counterbalanced, crossover study on three occasions separated by at least 3 wk: 1) hypoglycemia (mean nadir plasma glucose 2.7 +/- 0.5 mmol/l), 2) hypoxemia (mean nadir Po(2) 5.8 +/- 0.5 kPa), and 3) normoglycemic normoxia (control). NT-pro-BNP was measured at baseline, during the stimuli, and in the recovery phase. Hypoxemia was associated with a 9% increase in NT-pro-BNP from 2.2 +/- 1.5 pmol/l at baseline to 2.4 +/- 1.5 pmol/l during hypoxemia (P < 0.001). Hypoglycemia did not affect the NT-pro-BNP level. RAS activity had no impact on NT-pro-BNP levels during hypoglycemia and hypoxemia. Hypoxemia, but not hypoglycemia, stimulates NT-pro-BNP. This indicates that cardiac defense mechanisms against hypoglycemia, if any, are probably different from those against hypoxemia. Basal RAS activity had no impact on NT-pro-BNP levels.

Abstract Aims Severe hypoglycaemia is a significant problem in pregnant women with Type 1 diabetes. We explored whether frequent severe hypoglycaemia during pregnancy in women with Type 1 diabetes is related to placental growth hormone (GH) and insulin‐like growth factor I (IGF‐I) levels. Methods A prospective, observational study of 107 consecutive pregnant women with Type 1 diabetes. Blood samples were drawn for IGF‐I and placental GH analyses at 8, 14, 21, 27 and 33 weeks. Severe hypoglycaemic events were reported within 24 h. Results Eleven women (10%) experienced frequent severe hypoglycaemia (≥ 5 events), accounting for 60% of all events. Throughout pregnancy, IGF‐I levels were 25% lower in these women ( P &lt; 0.005) compared with the remaining women, despite similar placental GH levels. Eighty per cent of the severe hypoglycaemic events occurred before 20 weeks when IGF‐I levels were at their lowest. This finding was not explained by differences in insulin dose, median plasma glucose levels or glycated haemoglobin. History of severe hypoglycaemia the year preceding pregnancy and impaired hypoglycaemia awareness—being the only predictors of frequent severe hypoglycaemia in a logistic regression analysis—were not associated with IGF‐I or placental GH levels at 8 weeks. Conclusions In women with Type 1 diabetes experiencing frequent severe hypoglycaemia during pregnancy, IGF‐I levels are significantly lower compared with the remaining women despite similar placental GH levels. IGF‐I levels are lowest in early pregnancy where the incidence of severe hypoglycaemia is highest. IGF‐I may be a novel factor of interest in the investigation of severe hypoglycaemia in patients with Type 1 diabetes.

Abstract Blurred vision and cognitive difficulties are prominent symptoms during acute insulin‐induced hypoglycemia. Our hypothesis was that changes in cerebral activity reflect these symptoms. Positron emission tomography (PET) with oxygen‐15‐labelled water was used to measure relative changes in regional cerebral blood flow (rCBF) as a marker of cerebral activity. Hypoglycemia was induced by intravenous insulin infusion in 19 healthy men performing two different cognitive tasks of varying complexity. The hypoglycemic stimulus [plasma glucose 2.2 mmol/liter (0.4)] produced a significant hormonal counterregulatory response. During the low cognitive load, rCBF decreased in response to hypoglycemia in a large bilateral area in the posterior part of the temporal lobe, and rCBF increased bilaterally in the anterior cingulate gyrus, the right frontal gyrus, the fusiform gyrus, thalamus, and the left inferior part of the frontal gyrus. During the high cognitive load, rCBF decreased bilaterally in a large region in the posterior part of the temporal gyrus and increased in the left and right anterior cingulate gyrus, left and right frontal gyrus, right parahippocampal and lingual gyrus, and left superior temporal gyrus. Visual impairment during hypoglycemia was associated with deactivation in the ventral visual stream. The anterior cingulate gyrus was activated during hypoglycemia in a load‐dependent manner. Areas on the frontal convexity were differentially activated in response to the cognitive load during hypoglycemia. Our findings suggest that hypoglycemia induces changes in sensory processing in a cognition‐independent manner, whereas activation of areas of higher order functions is influenced by cognitive load as well as hypoglycemia. © 2009 Wiley‐Liss, Inc.

Diabetic MedicineVolume 26, Issue 12 p. 1306-1308 Prospective and retrospective recording of severe hypoglycaemia, and assessment of hypoglycaemia awareness in insulin-treated Type 2 diabetes K. Akram, K. Akram Steno Diabetes Center, GentofteSearch for more papers by this authorU. Pedersen-Bjergaard, U. Pedersen-Bjergaard Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, DenmarkSearch for more papers by this authorB. Carstensen, B. Carstensen Steno Diabetes Center, GentofteSearch for more papers by this authorK. Borch-Johnsen, K. Borch-Johnsen Steno Diabetes Center, GentofteSearch for more papers by this authorB. Thorsteinsson, B. Thorsteinsson Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, DenmarkSearch for more papers by this author K. Akram, K. Akram Steno Diabetes Center, GentofteSearch for more papers by this authorU. Pedersen-Bjergaard, U. Pedersen-Bjergaard Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, DenmarkSearch for more papers by this authorB. Carstensen, B. Carstensen Steno Diabetes Center, GentofteSearch for more papers by this authorK. Borch-Johnsen, K. Borch-Johnsen Steno Diabetes Center, GentofteSearch for more papers by this authorB. Thorsteinsson, B. Thorsteinsson Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, DenmarkSearch for more papers by this author First published: 24 November 2009 https://doi.org/10.1111/j.1464-5491.2009.02834.xCitations: 17Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume26, Issue12December 2009Pages 1306-1308 RelatedInformation

Abstract Aims To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. Methods A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA 1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2‐year randomized, crossover trial of basal‐bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). Results During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P &lt; 0.0001) with insulin analogue. Conclusions Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia.

<h3>Objective</h3> To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes. <h3>Design and setting</h3> Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design, conducted at 8 hospitals in Denmark. <h3>Participants and interventions</h3> Participants with type 2 diabetes (glycated haemoglobin (HbA_1c)≥7.5% (≥58 mmol/mol), body mass index &gt;25 kg/m²) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1–3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA_1c≤7.0% (≤53 mmol/mol). <h3>Outcomes</h3> Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA_1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes. <h3>Results</h3> Carotid IMT change did not differ between groups (biphasic −0.009 mm (95% CI −0.022 to 0.004), aspart+detemir 0.000 mm (95% CI −0.013 to 0.013), detemir −0.012 mm (95% CI −0.025 to 0.000)). HbA_1c was more reduced with biphasic (−1.0% (95% CI −1.2 to −0.8)) compared with the aspart+detemir (−0.4% (95% CI −0.6 to −0.3)) and detemir (−0.3% (95% CI −0.4 to −0.1)) groups (p&lt;0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p&lt;0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ. <h3>Conclusions</h3> Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA_1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results. <h3>Trial registration number</h3> NCT00657943.

Abstract Aim Obstructive sleep apnoea (OSA) is frequent in type 2 diabetes (T2D). The aim was to investigate the effect of a 12‐week treatment with continuous positive airway pressure (CPAP) on glycaemic control assessed by continuous glucose monitoring (CGM), HbA1c and fasting blood glucose in patients with T2D and newly detected OSA. Methods In a randomized controlled multicentre study, 72 participants with T2D and moderate to severe OSA (78% male, age 62 ± 7, AHI 35 ± 15) were recruited from outpatient clinics in three Danish hospitals and were randomized to CPAP intervention or control. The main outcome was glycaemic control assessed by 6 days CGM at baseline and after 12‐week therapy, as well as by HbA1c and fasting blood glucose. Results No significant changes were found in average glucose levels, time in glucose range, time with hypoglycaemia, time with hyperglycaemia or coefficient of variability. HbA1c decreased 0.7 mmol/mol (0.07%; P = .8) in the CPAP group and increased 0.8 mmol/mol (0.08%; P = .6) in the control group (intergroup difference, P = .6). Fasting blood glucose increased by 0.2 mmol/L ( P = .02) in the CPAP group and by 0.4 mmol/L ( P = .01) in the control group (intergroup difference, P = .7). In a prespecified subgroup analysis comparing participants with high adherence (minimum usage of four hours/night for 70% of all nights) to CPAP to the control group, no significant changes were observed either, although these participants had a tendency towards better glycaemic indices. Conclusions CPAP treatment for 12 weeks does not significantly change glycaemic control in patients with type 2 diabetes and OSA.

Abstract Background Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM). Methods The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed. Results After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI − 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference − 0.33 V (95% CI − 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA 1c did not confound the associations. Conclusions Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA 1c . Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H–D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

The aim of this work was to assess the effect of spontaneous nocturnal hypoglycaemia on quality of life and mood during subsequent days in type 1 diabetes.A total of 153 people with type 1 diabetes participated in 6 days of blinded continuous glucose monitoring while documenting hypoglycaemic symptoms, quality of life and mood, daily. Hypoglycaemia was defined by interstitial glucose ≤3.9 mmol/l (IG3.9) and ≤ 3.0 mmol/l (IG3.0) for ≥15 min and was classified as asymptomatic if no hypoglycaemic symptoms were reported.Self-estimated quality of life assessed by the EQ-5D VAS (but not by the WHO Well-Being Index) was higher the day after asymptomatic (but not after symptomatic) hypoglycaemic nights, as compared with non-hypoglycaemic nights (IG3.9, p = 0.021; IG3.0, p = 0.048). The effect increased with lower glucose nadir and longer duration of nocturnal hypoglycaemia (IG3.9, p = 0.03). The finding was confined to participants with impaired hypoglycaemia awareness. There was no effect of nocturnal hypoglycaemia on mood or self-estimated effectiveness at work the following day.Individuals with type 1 diabetes and impaired hypoglycaemia awareness reported higher quality of life on days preceded by nights with asymptomatic (but not symptomatic) hypoglycaemia. The effect was amplified by lower glucose nadir and longer duration of the episodes and may help explain resistance to implementation of interventions to reduce hypoglycaemia in many people with impaired hypoglycaemia awareness.

AimsHypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the ‘dead-in-bed syndrome’ in patients with type 1 diabetes. Evidence suggests that the renin–angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS activity affects cardiac repolarization during hypoglycaemia, thereby potentially carrying prognostic information on risk of the ‘dead-in-bed syndrome’.

To estimate short-term cost-effectiveness of insulin detemir vs. NPH insulin based on the incidence of mild hypoglycaemia in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands.A model was developed to evaluate cost-effectiveness based on mild (self-treated) hypoglycaemia and pharmacy costs over 1 year. Published rates of mild hypoglycaemia were used for NPH insulin and insulin detemir. Effectiveness was calculated in terms of quality-adjusted life expectancy. Pharmacy costs were accounted using published prices and defined daily doses for both insulins. Costs were expressed in 2010 euros (€).Treatment with insulin detemir was associated with fewer mild hypoglycaemic events than NPH insulin (mean rates of 26.3 vs. 35.5 events per person-year), leading to an improvement in mean quality-adjusted life expectancy of approximately 0.019 (0.030) quality-adjusted life years (standard deviation). Annual costs were € 573.55 (110.42) vs. € 332.76 (62.18) in Denmark for insulin detemir and NPH insulin, respectively. These values were € 545.79 (106.54) vs. € 306.12 (57.78) in Sweden, € 720.10 (140.74) vs. € 408.73 (78.61) in Finland and € 584.01 (109.47) vs. € 359.60 (64.84) in the Netherlands. Incremental cost-effectiveness ratios were approximately € 12,644 (Denmark), € 12,612 (Sweden), € 16,568 (Finland) and € 12,216 (the Netherlands) per quality-adjusted life year gained for insulin detemir vs. NPH insulin.Insulin detemir is likely to be cost-effective vs. NPH insulin in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. Increased pharmacy costs with insulin detemir should not be a barrier to therapy based on these findings.

The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting that preeclampsia is associated with cardiovascular changes in early pregnancy.

Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial.A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms.In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.

Objectives. Acute STEMI is routinely treated by acute PCI. This treatment may itself damage the tissue (reperfusion injury). Conditioning with GLP-1 analogs has been shown to reduce reperfusion injury. Likewise, ischemic postconditioning provides cardioprotection following STEMI. We tested if combined conditioning with the GLP-1 analog liraglutide and ischemic postconditioning offered additive cardioprotective effect after reperfusion of 45 min coronary occlusion of left anterior descending artery (LAD). Design. Fifty-eight non-diabetic female Danish Landrace pigs (60 ± 10kg) were randomly assigned to four groups. Myocardial infarction (MI) was induced by occluding the LAD for 45 min. Group 1 (n = 14) was treated with i.v. liraglutide after 15 min of ischemia. Group 2 (n = 17) received liraglutide treatment concomitant with ischemic postconditioning, after 45 min of ischemia. Group 3 (n = 15) recieved ischemic postconditioning and group 4 (n = 12) was kept as controls. Results. No intergroup differences in relative infarct size were detected (overall mean 57 ± 3%; p = 0.68). Overall mortality was 34% (CI 25–41%) including 26% post-intervention, with no intergroup differences (p = 0.99). Occurrence of ventricular fibrillation (VF) was 59% (CI 25–80%) including 39% postintervention with no intergroup differences (p = 0.65). Conclusions. In our closed-chest pig-model, we were unable to detect any cardioprotective effect of liraglutide or ischemic postconditioning either alone or combined.

Prediction of risk of severe hypoglycemia (SH) in patients with type 1 diabetes is important to prevent future episodes, but it is unknown if it is possible to predict the long-term risk of SH. The aim of the study is to assess if long-term prediction of SH is possible in type 1 diabetes.A follow-up study was performed with 98 patients with type 1 diabetes. At baseline and at follow-up, the patients filled in a questionnaire about diabetes history and complications, number of SH in the preceding year and state of awareness, and HbA1c and C-peptide levels were measured.During the 12 years of follow-up, there was a decrease in HbA1c, C-peptide levels, and incidence of SH (1.1 to 0.4 episodes per patient-year; P < .001). At baseline, the relative rate of SH was 3.6 (P = .001) and 10.9 (P < .0001) in patients with impaired awareness and unawareness of hypoglycemia, respectively, as compared to patients with normal awareness. At follow-up, patients with unawareness at baseline tended to have maintained an increased rate of SH (RR = 3.1; P = .07). Impaired awareness, HbA1c and C-peptide determined at baseline did not correspond with an increased rate of SH at follow-up.Long-term prediction of severe hypoglycemia in type 1 diabetes was not possible, although baseline hypoglycemia unawareness tended to remain a predictor for risk of SH at follow-up. Therefore, it is important repeatedly to assess the different risk factors of SH to determine the actual risk.

To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D).Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat.Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100.Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Diabetic patients treated with insulin injected subcutaneously are characterized by peripheral hyperinsulinaemia and an increased mass of total body exchangeable sodium. We hypothesized that this may cause, at least in part, the glomerular hyperfiltration seen in the diabetic state. Six normal subjects were studied on 2 days in random order. Day A: Basal state for 40 min, hyperinsulinaemic euglycaemic clamp for 1 h (insulin infusion rate 2 mU kg-1 min-1 and 50% glucose infusion) and hyperinsulinaemic euglycaemic clamp combined with volume expansion (2 1 isotonic sodium chloride) for 2 h. Day B: as day A, but without insulin and glucose infusion. During combined volume expansion and hyperinsulinaemia an increase in glomerular filtration rate (GFR) (128 +/- 6 vs 117 +/- 8 ml min-1 1.73 m-2, p less than 0.01) and lithium clearance (CLi) (50 +/- 4 vs 33 +/- 5 ml min-1 1.73 m-2, p less than 0.01) was observed compared with basal conditions. GFR and CLi were unchanged during day B. Insulin infusion reduced renal sodium excretion. Absolute proximal tubular reabsorption was unchanged on both days. Insulin infusion without volume expansion caused a decrease of 24% in the fractional distal sodium excretion. Superimposed volume expansion and the concomitant increase in GFR and CLi was accompanied by a subsequent enhanced fractional distal sodium excretion of 27%. The changes in plasma concentrations of aldosterone, renin, angiotensin II, atrial natriuretic peptide and catecholamines did not explain the differences in GFR. An increase in GFR of 10%, comparable with that observed in diabetic patients, was induced by combined hyperinsulinaemia and volume expansion in euglycaemic normal subjects. The enhanced GFR is probably a compensatory response to the sodium retention induced by the action of insulin on the distal tubules.

Background: Diabetes-related anxiety influences the quality-of-life of people with diabetes.Aim: To compare diabetes-related concerns in insulin-treated patients with type 1 and type 2 diabetes.Method: A cross-sectional questionnaire survey was carried out in two cohorts of adult outpatients with type 1 diabetes (n=223) and insulin-treated type 2 diabetes (n=104). Assessment of concerns about mild and severe hypoglycaemia, blindness and kidney failure was carried out using the seven-point Likert scale.Results: Insulin-treated patients with type 1 or 2 diabetes worry mostly about late diabetic complications, less about severe hypoglycaemia and little about mild hypoglycaemia. Patients with type 1 diabetes worry more about severe hypoglycaemia than those with type 2 diabetes; no differences in levels of anxiety about mild hypoglycaemia, blindness and kidney failure exist. Severe hypoglycaemia in the preceding year is associated with more worry about severe hypoglycaemia in patients with type 1 or 2 diabetes. Those with type 1 or 2 diabetes who have impaired awareness of hypoglycaemia tend to worry more about severe hypoglycaemia than those with normal awareness of hypoglycaemia. The presence of eye or kidney complications does not influence the level of anxiety in people with type 1 diabetes. Patients with type 2 diabetes without complications tend to worry more about mild and severe hypoglycaemia than those with complications.Conclusion: Patients with insulin-treated diabetes worry considerably about microvascular complications and severe hypoglycaemia risk. Recent experience of severe hypoglycaemia and presence of impaired hypoglycaemia awareness are associated with increased worry scores for severe hypoglycaemia in patients with type 1 or 2 diabetes. Screening for diabetes-related concerns should be integrated into diabetes care.

Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function.We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1 diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion.Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia.Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia.

Introduction: In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal cognitive function during hypoglycaemia. Methods: Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests. Results: Despite a similar hypoglycaemic stimulus in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group. The total hypoglycaemic symptom response was greater in the high ACE group than in the low ACE group (p=0.031).There were no differences in responses of counterregulatory hormones or in concentrations of substrates between the groups. Conclusion: Healthy humans with high ACE activity are more susceptible to cognitive dysfunction and report higher symptom scores during mild hypoglycaemia than subjects with low ACE activity.

Aims/hypothesis. High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. Methods. A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. Results. ACE activity is reproducible over 40 months (p < 0.00001). Patients with SH during the baseline study also had SH during follow-up (p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up (p = 0.0003) with a 3.2-fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles (p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. Conclusion. In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders.

Hypoglycaemia is associated with reduced skin temperature (Ts). We studied whether infrared thermography can detect Ts changes during hypoglycaemia in patients with type 1 diabetes and how the Ts response differs between patients with normal hypoglycaemia awareness and hypoglycaemia unawareness.Twenty-four patients with type 1 diabetes (ten aware, 14 unaware) were studied during normoglycaemia (5.0-6.0 mmol/l), hypoglycaemia (2.0-2.5 mmol/l) and during recovery from hypoglycaemia (5.0-6.0 mmol/l) using hyperinsulinaemic glucose clamping. During each 1 h phase, Ts was measured twice by infrared thermography imaging in pre-defined areas (nose, glabella and the five left fingertips), symptoms of hypoglycaemia were scored and blood was sampled.Ts decreased during hypoglycaemia on the nose and glabella. The highest decrements were recorded on the nose (aware: -2.6 °C, unaware: -1.1 °C). In aware patients, the differences in temperature were statistically significant on both nose and glabella, whereas there was only a trend in the unaware group. There was a significant difference in hypoglycaemia-induced temperature changes between the groups. Patients in the aware group had higher hypoglycaemia symptom scores and higher adrenaline (epinephrine) levels during hypoglycaemia.The hypoglycaemia-associated decrement in Ts can be assessed by infrared thermography and is larger in patients with normal hypoglycaemia awareness compared with unaware patients.

Aim: Continuous glucose monitoring (CGM) is widely used in clinical practice and research to detect hypoglycemia. A consensus definition of CGM-recorded hypoglycemia is made by a group of international experts under the auspice of the Advanced Technologies and Treatments for Diabetes (ATTD). The purpose of this study is to compare the definition with patient-reported hypoglycemia. Methods: In a prospective, observational study of 186 patients with type 1 diabetes using blinded Medtronic iPro 2 CGM for 6 days, every patient-reported symptomatic hypoglycemic event and interstitial glucose (IG) values at the registration time were classified according to the ATTD definition of CGM-recorded hypoglycemia. For comparison between CGM and self-monitored blood glucose (SMBG) values, the International Hypoglycemia Study Group (IHSG) classification of hypoglycemia and chi-square test were used. Results: A total of 321 events of symptomatic hypoglycemia were reported by 68% of the patients, corresponding to 2.0 ± 2.3 events (mean ± standard deviation) per patient-week. A total of 206 (64%) events met the CGM consensus definition. In the remaining 115 (36%) not-confirmed events, 5 events had an IG <3.9 mmol/L, which lasted <15 min. The overall mean IG value was 3.6 ± 1.1 mmol/L (median 3.1, range 2.2-10.4). In symptomatic hypoglycemic events with both CGM and SMBG data, SMBG confirmed significantly more symptomatic hypoglycemic events than CGM (P < 0.001). Conclusion: CGM-recorded hypoglycemia according to the consensus definition is present at two thirds of all patient-reported events when recorded by the Medtronic iPro 2 system. The recommended minimum duration of a hypoglycemic event of 15 min is supported by the study. SMBG measurements detect significantly more symptomatic hypoglycemic events than Medtronic iPro 2 CGM.

A double-blind cross-over study of the sc absorption of radiolabelled semi-synthetic human (SHI) and purified porcine (PPI) insulin was made. Absorption of both isophane (n = 10) and soluble insulin (n = 8) was studied. There was no significant difference between the disappearance from the injection site, the plasma free insulin concentrations, or blood glucose levels after sc injection of the isophane preparations. A faster disappearance of the soluble SHI (as judged from T/50 and AUC) was found (both P-values less than 0.01). However, no difference was observed between the plasma insulin concentrations at any time point (P less than 0.05). Blood glucose levels showed no statistical differences between the two soluble preparations. The data indicate minor differences between the pharmacokinetics of SHI and PPI, but these seem of no clinical importance.

To investigate the mechanism of insulin degradation in normal subjects, a kinetic model of insulin disappearance was constructed: insulin was assumed to be extracted from plasma by two independent processes, one saturable and one non-saturable. On the basis of these assumptions, a linear (non-proportional) relationship between steady-state plasma insulin concentration and steady-state plasma disappearance rate was predicted over the concentration range studied. Constant infusion experiments were performed on eight healthy normal subjects, normoglycaemia and fasting plasma C-peptide concentrations being maintained during the experiments. Agreement was found between the predictions of the model and the experimental results, and it is concluded that insulin degradation in normal subjects may be described in terms of two processes: one that is saturated at physiological plasma insulin concentrations and one that is apparently non-saturable over a wide concentration range.

The distribution spaces at equilibrium for 3H2O, [14C]urea and 3-O-[14C]-methylglucose were measured in white fat cells using centrifugation through silicone oil at 2500 × g; no significant differences were observed. l-[14C] Glucose added immediately before the centrifugation was used as a marker for the extracellular water space. The calculated intracellular water content of the cells after the centrifugation through oil (e.g. 3H2O space minus l-[14C] glucose space) is an unbiased measure of the water content of the cells in suspension as judged by the following criteria: (1) The intracellular distribution space for 3-O-[14C]methylglucose at equilibrium (methylglucose space minus l-glucose space) was not different from that calculated from a methylglucose wash-out curve. (2) The intracellular content of l-[14C]glucose (half time of efflux about 60 min) in cells preloaded during incubation of the tissue with collagenase was not different in cells recovered by (a) centrifugation through oil at 2500 × g, (b) centrifugation through oil at 600 × g, (c) centrifugation at 600 × g in the absence of oil and (d) filtration on Millipore filters. The intracellular content of water determined on cells from single rats weighing 120–150 g was 2.75 ± 0.55 μl/100 μl fat cells (± S.D., n = 30). The intracellular content of potassium, determined on cells from the same rats, was 252 ± 62 nmols/100 μl fat cells (± S.D., n = 30). The concentration of potassium in the intracellular water was calculated as 104 ± 15 mM (± S.D., n = 30).

Abstract Background Varenicline is a new drug indicated for smoking cessation. It has primarily been investigated in healthy adults. The commonest side‐effects are nausea, headache, sleep disturbance, constipation, flatulence and vomiting. Hypoglycaemia has not been reported. As smoking cessation is important to reduce risk of cardiovascular morbidity, especially in diabetes, use of effective drugs indicated for smoking cessation is rational. Case report We report multiple episodes of severe hypoglycaemia after starting varenicline in a 53‐year‐old woman with Type 1 diabetes. Since onset of diabetes at age 25 years and until start of varenicline therapy, she had only experienced one episode of severe hypoglycaemia and hypoglycaemia awareness was not impaired. The severe hypoglycaemic episodes disappeared after withdrawal of varenicline. Conclusions We recommend cautious prescription of varenicline, intensified blood glucose monitoring and careful education of patients with diabetes treated with varenicline. Further investigation of the use of varenicline in patients with diabetes is warranted.

In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus—9 with high and 9 with low RAS activity—underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group (P = .004) and from 76 to 109 pg/L in the low-RAS group (P = .01), with no difference between RAS groups (P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.

Objective GH is implicated in the counter-regulatory response to hypoglycemia. We tested whether IGF1 levels are associated with occurrence of severe hypoglycemic events in patients with type 1 diabetes and whether the IGF1 concentration is influenced by glycemic control. Methods A total of 228 outpatients with type 1 diabetes were included in a post hoc analysis of a 1-year observational study on severe hypoglycemia. Serum total IGF1 was measured at entry into the study. The occurrence of severe episodes of hypoglycemia, mild symptomatic, and biochemical as well as hypoglycemia awareness status was assessed. Also patients were included in a multiple regression analysis to investigate the role of HbA1c in the IGF1 concentration. Results IGF1 levels were associated with neither severe hypoglycemia in the entire cohort ( P =0.30) nor in any gender nor when confining the analysis to those with long-standing diabetes (&gt;20 years) ( n =112, P =0.68) and those with both long-standing diabetes and undetectable C-peptide ( n =51, P =0.067). Levels of IGF1 were associated with neither mild symptomatic hypoglycemia ( P =0.24) nor biochemical hypoglycemia (0.089) nor hypoglycemia awareness ( P =0.16). At a multiple regression analysis, HbA1c was negatively associated with IGF1 ( P =0.001). Conclusion In type 1 diabetes, circulating IGF1 levels are negatively associated with glycemic control. However, IGF1 levels were not associated with occurrence of hypoglycemia or hypoglycemia awareness in these patients.

Aims Sulphonylureas (SU) are currently recommended as a well-established second line treatment in guidelines for type 2 diabetes (T2DM). In the Capital Region of Denmark 16,865 patients were given SU as part of their treatment of T2DM in 2010–2011. To what extent SU are associated with hospitalizations due to severe hypoglycaemic episodes, defined as episodes with a need for external assistance, was investigated. The prevalence and characteristics of these patients and potential risk factors were studied. Methods ICD-10 diagnosis codes were used to identify patients hospitalized due to hypoglycaemia and T2DM for a period of 2 years (2010–2011). Inclusion criteria were T2DM, hospitalization due to hypoglycaemia and treatment with SU as monotherapy or in combination with other glucose-lowering drugs except insulin treatment. Results We identified 161 patients fulfilling the inclusion criteria. Their mean age was 76 (53–97) years and 54% were males. Sixty percent of the patients had diabetic complications, including 19% with diabetic nephropathy. The major reason for severe hypoglycaemia was an unchanged dose of SU despite of a significant decline in food intake (45%). In 22% of the patients more than one reason was listed, most commonly a concomitant infection associated with decreased food intake and unchanged dose of SU. Conclusion The incidence of hospital admission-requiring severe hypoglycaemia in patients treated with SU was 0.48 episodes per 100 patient-years of SU-treated patients. It was mainly older patients with diminished food intake, excessive alcohol use or other medications, concomitant infection, and with diabetic complications.

To evaluate whether levels of placental growth hormone (GH) and Insulin-like Growth Factor-I (IGF-I) are associated with development of LGA infants in pregnant women with type 1 diabetes.Observational study of 103 consecutive pregnant women with long-term type 1 diabetes and median HbA1c 6.6% (range 4.9-10.5) (49 mmol/mol (30-91)) in early pregnancy. At 8, 14, 21, 27 and 33 weeks weight was recorded and blood was sampled for measurements of placental GH, IGF-I and HbA1c. LGA was defined as birth weight >90th percentile after adjustment for gender and gestational age.Throughout pregnancy placental GH levels were similar in 51 (50%) women delivering LGA infants compared with the remaining women except at 8 weeks where placental GH levels were lower in women with LGA infants (1.1 ng/ml (0.1-4.3) vs. 1.7 (0.3-11.7), p = 0.04). IGF-I levels were similar in women with and without LGA infants (p=0.97). Gestational age at first blood sampling was similar in women with and without LGA infants (60 days (37-89) vs. 61.5 (42-94), p = 0.42). Placental GH levels at 14 weeks correlated negatively with weight gain in early pregnancy (r=-0.32, p=0.002). As predictors of LGA infants,multivariate logistic regression analysis identified placental GH levels at 8 weeks (OR 0.4 (95% CI: 0.2-0.9), p = 0.02), HbA1c at 33 weeks (3.6 (1.3-9.9), p = 0.01) and parity ≥1 (3.1 (1.3-7.5), p = 0.01) after adjustment for pre-pregnancy BMI.Women delivering LGA infants had lower placental GH levels in early pregnancy. Growth factors and maternal weight gain in early pregnancy may be important for healthy fetal growth.