Reducing the burden of hypoglycaemia in people with diabetes through increased understanding: design of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project.

BACKGROUND: Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all-cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of 'non-severe' hypoglycaemia and the glucose level below which hypoglycaemia causes harm. AIM: To increase understanding of hypoglycaemia by addressing the above issues over a 4-year period. METHODS: Hypo-RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor-detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. RESULTS: The outcomes of Hypo-RESOLVE will inform evidence-based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose-lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. CONCLUSION: Hypo-RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes.

Sweet dreams or bitter nightmare: a narrative review of 25 years of research on the role of sleep in diabetes and the contributions of behavioural science.

The aim of this review was to provide an overview of developments, clinical implications and gaps in knowledge regarding the relationship between diabetes and sleep over the past 25 years, with special focus on contributions from the behavioural sciences. Multiple prospective observational and experimental studies have shown a link between suboptimal sleep and impaired glucose tolerance, decreased insulin sensitivity and the development of type 2 diabetes. While prevalence rates of suboptimal sleep vary widely according to definition, assessment and sample, suboptimal subjective sleep quality appears to be a common reality for one-third of people with type 1 diabetes and over half of people with type 2 diabetes. Both physiological and psychosocial factors may impair sleep in these groups. In turn, suboptimal sleep can negatively affect glycaemic outcomes directly or indirectly via suboptimal daytime functioning (energy, mood, cognition) and self-care behaviours. Technological devices supporting diabetes self-care may have both negative and positive effects. Diabetes and its treatment also affect the sleep of significant others. Research on the merits of interventions aimed at improving sleep for people with diabetes is in its infancy. Diabetes and sleep appear to be reciprocally related. Discussion of sleep deserves a central place in regular diabetes care. Multi-day, multi-method studies may shed more light on the complex relationship between sleep and diabetes at an individual level. Intervention studies are warranted to examine the potential of sleep interventions in improving outcomes for people with diabetes.

Patients with type 1 diabetes mellitus have impaired IL-1ß production in response to Mycobacterium tuberculosis.

Patients with diabetes mellitus have an increased risk of developing tuberculosis. Although the underlying mechanism is unclear, evidence suggests a role for chronic hyperglycaemia. We examined the influence of hyperglycaemia on Mycobacterium tuberculosis-induced cytokine responses in patients with type 1 diabetes mellitus (T1D). Peripheral blood mononuclear cells (PBMCs) from 24 male T1D patients with sub-optimal glucose control [HbA1c > 7.0% (53 mmol/L)] and from 24 age-matched male healthy controls were stimulated with M. tuberculosis lysate. Cytokine analysis, assessment of aerobic glycolysis, receptor recognition and serum cross-over experiments were performed to explore the mechanistic differences. PBMCs from T1D patients produced less bioactive interleukin (IL)-1ß in response to M. tuberculosis. IL-6 and interferon (IFN)-γ production trended towards a decrease, whilst other cytokines such as tumour necrosis factor (TNF)-α, IL-17 and IL-1Ra were normal. The decrease in cytokine production was not correlated to HbA1c or plasma glucose levels. Cross-over serum experiments did not alter the cytokine profile of T1D or control patients, arguing for an intrinsic cellular defect. Cellular metabolism and the expression of M. tuberculosis-related pattern recognition receptors (PRRs) such as TLR2, TLR4 and NOD2 did not differ between T1D patients and healthy controls. Compared to matched controls, T1D patients have a reduced capacity to produce pro-inflammatory cytokines in response to M. tuberculosis. The impaired IL-1ß production in T1D patients may contribute to the increased susceptibility to tuberculosis. This effect appears not to be related to prevailing glucose levels but to an intrinsic cellular deficit.

A cost-controlling treatment strategy of adding liraglutide to insulin in type 2 diabetes.

BACKGROUND: Addition of the GLP-1 receptor agonist liraglutide to insulin can reverse insulin-associated weight gain, improve HbA1c and decrease the need for insulin, but is expensive. From a cost perspective, such treatment should be discontinued when it is clear that treatment targets will not be achieved. Our aim was to find the best cost-controlling treatment strategy: the shortest possible trial period needed to discriminate successfully treated patients from those failing to achieve predefined targets of treatment success. METHODS: We used data from the 'Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) trial, comparing additional liraglutide (n = 47) and standard insulin therapy (n = 24) during 26 weeks, to calculate the costs associated with different trial periods. Treatment success after 26 weeks was defined by having achieved ≥ 2 of the following: ≥ 4% weight loss, HbA1c ≤ 53 mmol/mol (7%), and/or discontinuation of insulin. RESULTS: The additional direct costs of adding liraglutide for 26 weeks were € 699 per patient, or € 137 per 1 kg weight loss, compared with standard therapy. The best cost-controlling treatment strategy (identifying 21 of 23 responders, treating four non-responders) was to continue treatment in patients showing ≥ 3% weight loss or ≥ 60% decrease in insulin dose at 8 weeks, with a total cost of € 246 for this t rial period, saving € 453 in case of early discontinuation. CONCLUSION: An 8-week trial period of adding liraglutide to insulin in patients with insulin-associated weight gain is an effective cost-controlling treatment strategy if the liraglutide is discontinued in patients not showing an early response regarding weight loss or insulin reduction.

A comparison of the pharmacodynamic profiles of jet-injected regular human insulin versus conventionally administered insulin aspart in healthy volunteers.

AIMS: Rapid-acting insulin analogues are generally preferred over regular human insulin because of their more immediate onset of action and shorter time-action profile. However, these analogues may not always be tolerated by or universally available for people with insulin-requiring diabetes. Jet injection has been demonstrated to facilitate faster insulin absorption. We determined whether administration of regular human insulin by jet injection achieves the same pharmacological properties as that of a rapid-acting insulin analogue. METHODS: Twenty healthy volunteers received regular human insulin (0.2units/kg) by jet injection. Glucose 20% was infused intravenously to maintain euglycaemia over six hours. The glucose infusion rates (GIR) were determined to compare pharmacological profiles. These profiles were compared with data from two other studies in which a similar dose of insulin aspart was administered by conventional pen. RESULTS: Regular human insulin by jet injection had a faster onset of glucose-lowering effect compared to aspart by conventional pen (T-GIR50%, 30.8±2.9 versus 43.1±3.2min, P<0.01). There were no differences in time to maximal GIR (106.1±11.9 versus 95.8±9.2min, P=0.50), maximal GIR (8.6±0.7 versus 7.7±0.7mg/kg/min, P=0.0.33), total glucose-lowering effect (101.0±9.8 versus 87.6±7.0g, P=0.28), and time until 50% of glucose disposal (144.8±5.6 versus 151.3±5.1min, P=0.39). CONCLUSIONS: Jet-injected regular human insulin had a pharmacological profile that was essentially not dissimilar from that of aspart insulin administered by conventional pen, and can therefore be used as an alternative for conventionally administered rapid-acting insulin analogues.

Durable efficacy of liraglutide in patients with type 2 diabetes and pronounced insulin-associated weight gain: 52-week results from the Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) randomized controlled trial.

BACKGROUND: Pronounced weight gain frequently complicates insulin therapy in patients with type 2 diabetes (T2DM). We have previously reported that addition of liraglutide for 26 weeks can reverse insulin-associated weight gain, decrease insulin dose and improve glycaemic control, as compared with continuation of standard insulin treatment. OBJECTIVES: To investigate whether the beneficial effects of liraglutide are sustained up to 52 weeks and whether similar effects could be obtained when liraglutide is added 6 months later. METHODS: Adult T2DM patients with ≥ 4% weight gain within 16 months of insulin therapy completing the first 26-week trial period of open-label addition of liraglutide 1.8 mg day(-1) (n = 26) versus continuation of standard insulin therapy (n = 24) were all treated with liraglutide for another 26 weeks. Results were analysed according to the intention-to-treat principle. RESULTS: Overall, 24 (92%) and 18 (75%) patients originally assigned to liraglutide and standard therapy, respectively, completed the study. Addition of liraglutide decreased body weight to a similar extend when given in the first 26 weeks (liraglutide group) or second 26 weeks (original standard therapy group): -4.4 vs. -4.3 kg (difference -0.32 kg, 95% confidence interval -2.2 to 1.6 kg; P = 0.74). Similar results were also seen in the two groups with regard to decrease in haemoglobin A1c (HbA1c ) (-0.77 vs. -0.66%; P = 0.23) and insulin dose (-28 vs. -26 U day(-1) ; P = 0.32). In both groups, 22% of patients could discontinue insulin. Continuation of liraglutide until 52 weeks led to sustained effects on body weight, HbA1c and insulin-dose requirements. CONCLUSION: In T2DM patients with pronounced insulin-associated weight gain, addition of liraglutide within 2 years leads to sustained reversal of body weight, improved glycaemic control and decrease in insulin dose. Thus, liraglutide offers a valuable therapeutic option.

Association between hypoglycaemia and impaired hypoglycaemia awareness and mortality in people with Type 1 diabetes mellitus.

AIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Severe hypoglycaemia and hypoglycaemia unawareness are not associated with increased risk of all-cause or cardiovascular mortality in people with Type 1 diabetes mellitus.

Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes.

AIMS: To test whether jet injection of insulin resulted in faster correction of marked hyperglycaemia than when insulin is injected by a conventional pen in patients with diabetes. METHODS: Adult, overweight or obese (BMI ≥25 and ≤40 kg/m(2)) patients with type 1 diabetes (n = 10) or insulin-treated type 2 diabetes (n = 10) were enrolled in a randomized, controlled, crossover study. On two separate occasions, patients were instructed to reduce insulin dose(s) to achieve marked hyperglycaemia (18-23 mmol/l). Subsequently, insulin aspart was administered either by jet injection or by conventional pen, in a dose based on estimated individual insulin sensitivity. Pharmacodynamic and pharmacokinetic profiles were derived from plasma glucose and insulin levels, measured for 6 h after injection. RESULTS: After conventional injection, plasma glucose concentration dropped by ≥10 mmol/l after 192.5 ± 13.6 min. The jet injector advanced this time to 147.9 ± 14.4 min [difference 44.6 (95% confidence interval 4.3, 84.8); P = 0.03], except in 3 patients who failed to reach this endpoint. The time advantage exceeded 1.5 h in patients with a BMI above the median. Jet injection also reduced the hyperglycaemic burden during the first 2 h (2042 ± 37.2 vs 2168 ± 26.1 mmol/min; P = 0.01) and the time to peak insulin levels (40.5 ± 3.2 vs 76.8 ± 7.7 min; P < 0.001), but did not increase the risk for hypoglycaemia. CONCLUSIONS: Administration of rapid-acting insulin by jet injection results in faster correction of marked hyperglycaemia in overweight or obese patients with insulin-requiring diabetes.

Diabetes in patients with HIV: patient characteristics, management and screening.

BACKGROUND: As HIV management has become more successful during the past years, non-communicable diseases have become more prevalent among HIV-infected individuals. As a result, more HIV-infected patients die of cardiovascular diseases, with diabetes being one of the main risk factors. This study evaluates screening and management of diabetes among HIV-infected patients in a university hospital in the Netherlands. METHODS: We examined clinical characteristics, glycaemic control and cardiovascular risk management of HIV-infected patients with coexisting diabetes, and determined the frequency of diabetes screening in those without. RESULTS: Of 518 HIV-infected patients, 28 had been diagnosed with diabetes (5.4%), mostly (20÷28) after being diagnosed with HIV. Patients with coexisting diabetes were older, had a longer duration of HIV, lower CD4 cell counts and higher body mass index (BMI), and were more likely to use aspirin, statins and antihypertensive medication than those without diabetes (all p < 0.05). HbA1c values were below 7% (53 mmol÷mol) in 54% of patients. Targets for systolic blood pressure (< 140 mmHg), LDL cholesterol (< 2.5 mmol÷l) and BMI (< 25 kg÷m2) were achieved by 82%, 50% and 29% of patients, respectively. Annual ophthalmology examination, screening for microalbuminuria and foot control were rarely performed. Among the patients without known diabetes, diabetes screening during the past year had been performed using (non-fasting) plasma glucose in 56% and HbA1c in 10%, but 42% of patients had not been screened. CONCLUSION: For HIV-infected individuals with diabetes, glycaemic control and cardiovascular risk management were reasonable, but screening for microvascular complications was rarely performed. Annual diabetes screening of HIV-infected patients was not routine.

Body mass index and the efficacy of needle-free jet injection for the administration of rapid-acting insulin analogs, a post hoc analysis.

We recently showed in a euglycaemic glucose clamp study among 18 healthy volunteers that using jet injectors rather than conventional pens significantly improved the time-action profiles of rapid-acting insulin analogs. Here, we investigated whether such profiles were modified by body mass index (BMI) and related weight parameters by comparing insulin administration by jet injection to that by conventional pen in subgroups defined by BMI, waist-to-hip ratio, waist circumference and insulin dose. After conventional administration, times to peak insulin levels (T-INS(max)) occurred 31.1 [95% confidence interval (CI) 13.7-48.5] min later and time to maximum glucose requirement (T-GIR(max)) 56.9 (95%CI 26.6-87.3) min later in more obese (BMI > 23.6 kg/m(2)) than in lean subjects (BMI < 23.6 kg/m(2)). In contrast, T-INS(max) and T-GIR(max) were similar in subjects with high and low BMI, when insulin was administered by jet injection. We conclude that using jet injection for insulin administration may especially benefit subjects with higher body weight.

Weight changes and their predictors amongst 11 140 patients with type 2 diabetes in the ADVANCE trial.

AIMS: To determine the baseline characteristics and glucose-lowering therapies associated with weight change among patients with type 2 diabetes. METHODS: Eleven thousand one hundred and forty participants in the ADVANCE trial were randomly assigned to an intensive [aiming for a haemoglobin A1c (HbA1c) ≤6.5%] or a standard blood glucose-control strategy. Weight was measured at baseline and every 6 months over a median follow-up of 5 years. Multivariable linear regression and linear-mixed effect models were used to examine predictors of weight change. RESULTS: The mean difference in weight between the intensive and standard glucose-control arm during follow-up was 0.75 kg (95% CI: 0.56-0.94), p-value <0.001. The mean weight decreased by 0.70 kg (95% CI: 0.53-0.87), p < 0.001 by the end of follow-up in the standard arm but remained stable in the intensive arm, with a non-significant gain of 0.16 kg (95% CI: -0.02 to 0.34), p = 0.075. Baseline factors associated with weight gain were younger age, higher HbA1c, Caucasian ethnicity and number of glucose-lowering medications. Treatment combinations including insulin [3.22 kg (95% CI: 2.92-3.52)] and thiazolidinediones [3.06 kg (95% CI: 2.69-3.43)] were associated with the greatest weight gain while treatment combinations including sulphonylureas were associated with less weight gain [0.71 kg (95%CI: 0.39-1.03)]. CONCLUSIONS: Intensive glucose-control regimens are not necessarily associated with substantial weight gain. Patient characteristic associated with weight change were age, ethnicity, smoking and HbA1c. The main treatment strategies predicting weight gain were the use of insulin and thiazolidinediones.

Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds.

AIMS/HYPOTHESIS: There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA(1c) and the risks of vascular complications and death in such patients. METHODS: Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA(1c) measurements during follow-up and prior to the first event. Adjusted risks for each HbA(1c) decile were estimated using Cox models. Possible differences in the association between HbA(1c) and risks at different levels of HbA(1c) were explored using linear spline models. RESULTS: There was a non-linear relationship between mean HbA(1c) during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA(1c) studied (5.5-10.5%), there was evidence of 'thresholds', such that below HbA(1c) levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA(1c) level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001). CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, HbA(1c) levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.

The effect of antecedent hypoglycaemia on ß2-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the ß2-adrenergic receptor.

AIMS/HYPOTHESIS: Homozygosity for glycine at codon 16 (GlyGly) of the ß(2)-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on ß(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the ß(2)-adrenergic receptor. METHODS: We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the ß(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)). RESULTS: The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased ß(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in ß(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047). CONCLUSION/INTERPRETATION: Antecedent hypoglycaemia did not affect ß(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in ß(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00160056.

Contribution of change in glycosylated haemoglobin to insulin-associated weight gain: results of a longitudinal study in type 2 diabetic patients.

To investigate the contribution of glycosylated haemoglobin change (HbA1c) on body weight in patients with type 2 diabetes after start of insulin therapy. We analysed 122 individual weight-profiles in relation to the change in HbA1c per se in these patients up to 36 months after the start of insulin therapy. Data were analysed separately for the first 9 months after commencement of insulin therapy and for the period thereafter. Within the first 9 months of insulin therapy mean body weight increased by 0.52 kg per month. HbA1c decreased from 9.9 ± 1.8 to 7.9 ± 1.3%. Only 12% of the initial weight gain could be attributed to the change in HbA1c. Furthermore, the mean monthly increase in body weight gain was reduced by 0.006 kg for every 1 kg higher body weight at baseline. From 9 to 36 months after start of insulin therapy, body weight increased by 0.1 kg/month, which was independent of change in HbA1c. Improvement of glycaemic control per se contributes little to initial weight gain after start of insulin therapy in patients with T2DM. After 9 months of insulin treatment, weight gain is unrelated to change in glycosylated haemoglobin. Other factors have to be responsible for weight gain after start of insulin therapy.

Successful treatment of severe subcutaneous insulin resistance with inhaled insulin therapy.

The potential of inhaled insulin therapy for severe resistance to subcutaneous insulin was tested in a 7-yr old boy with type 1 diabetes mellitus. The efficiency of 1 mg inhaled insulin (Exubera) was examined by a 4-h euglycemic clamp study. During the clamp, the glucose infusion rate started to increase 25 min after inhalation and peaked 120 min after inhalation. Subsequently, a trial of inhaled insulin monotherapy was initiated consisting of pre-meal inhalations and one inhalation during the night. Since glycemic control remained fair (HbA1c approximately 8.5%), this therapy was continued. Over the ensuing 18 months, mild keto-acidosis occurred twice during gastro-enteritis. Inhaled insulin was well tolerated and pulmonary function did not deteriorate. We conclude that severe resistance to subcutaneous insulin does not preclude sufficient absorption of insulin delivered by pulmonary.

Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

AIMS/HYPOTHESIS: The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial. METHODS: Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 ('normal', n = 8,689), 24-27 ('mild dysfunction', n = 2,231) and <24 ('severe dysfunction', n = 212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis. RESULTS: Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p < 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p

Efficacy and safety of inhaled insulin in the treatment of diabetes mellitus.

Many patients with diabetes mellitus view subcutaneous injections of insulin as a daily burden. Pulmonary delivery of insulin offers an alternative route of administration and may as such improve diabetes treatment. Inhaled insulin provides a rapid absorption of insulin, but with low bioavailability. Phase III clinical trials in type 1 and type 2 diabetes have disclosed clinical equivalence between three inhaled insulin products (Exubera, AErx idMs, and hIIp) and regular human insulin, both in terms of glycaemic control and hypoglycaemic risk. Inhaled insulin cannot be used to replace basal insulin requirements. The most commonly reported adverse effects of inhaled insulin are cough and insulin antibody formation, the clinical significance of which is uncertain. No or minimal deterioration in pulmonary function parameters have been recorded, although studies were typically of short duration. Patients participating in inhaled insulin trials generally expressed satisfaction with the product and chose to remain on it. The availability of inhaled insulin may increase willingness in type 2 diabetic patients to consider insulin therapy. More studies of longer duration are required to determine (pulmonary) safety and cost-effectiveness of inhaled insulin, and to disclose which patients may benefit the most.

Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.

Iatrogenic hypoglycaemia is a well-known complication of insulin therapy in patients with diabetes mellitus and a limiting factor for glycaemic control. In a setting of endogenous insulin deficiency (type 1 and advanced type 2 diabetes), one episode of hypoglycaemia reduces both counterregulatory hormone responses to and subjective awareness of subsequent hypoglycaemia, thus impairing physiological defences against hypoglycaemia. This phenomenon may lead to a vicious cycle of recurrent hypoglycaemia and glucose counterregulatory failure, of which hypoglycaemia unawareness (i.e. the inability to perceive symptoms of hypoglycaemia) is the clinical representative. The underlying mechanism of hypoglycaemia-induced counterregulatory failure has not yet been disclosed. Patients with clinical hypoglycaemia unawareness are at high risk of severe hypoglycaemia that requires third-party assistance. Management options include avoidance of hypoglycaemic events and optimisation of insulin therapy to limit deterioration of glycaemic control associated with hypoglycaemia avoidance. Several counterregulatory-stimulating agents have been found to improve hypoglycaemic awareness in small clinical trials, but none have been tested in sufficiently large randomised studies to justify their use in daily practice. More research is required to elucidate the pathogenesis of counterregulatory failure and to develop adequate treatment strategies.

[Treatment of patients with diabetes mellitus by means of inhaled insulin]. / Behandeling van patiënten met diabetes mellitus door middel van inhalatie-insuline.

Good glycaemic control of diabetes mellitus is still hampered by the fear of insulin injections. Particularly in patients with type 2 diabetes, inhaled insulin as a novel therapeutic option for glycaemic control could be an alternative to subcutaneous insulin. Phase III clinical studies have shown glycaemic equivalence between inhaled insulin and conventional subcutaneous insulin. However, no study comparing inhaled insulin with short-acting insulin analogues has yet been published. Thus, methodological problems preclude conclusive remarks concerning quality-of-life issues. Inhaled insulin should be reserved for selected patient groups only. Lengthier studies to evaluate the long-term (pulmonary) safety of inhaled insulin and a cost-effectiveness study are needed.

Sensitivity-enhanced 13C MR spectroscopy of the human brain at 3 Tesla.

A new coil design for sensitivity-enhanced 13C MR spectroscopy (MRS) of the human brain is presented. The design includes a quadrature transmit/receive head coil optimized for 13C MR sensitivity. Loss-less blocking circuits inside the coil conductors allow this coil to be used inside a homogeneous circularly polarized 1H B1 field for 1H decoupled 13C MRS. A quadrature 1H birdcage coil optimized for minimal local RF heating makes broadband 1H decoupling in the entire human brain possible at 3 Tesla while remaining well within international safety guidelines for RF absorption. Apart from a substantial increase in sensitivity compared to conventional small linear coils, the quadrature 13C coil combined with the quadrature 1H birdcage coil allows efficient cross polarization (CP) in the brain, resulting in an additional 3.5-fold sensitivity improvement compared to direct 13C measurements without nuclear Overhauser enhancement (NOE) or polarization transfer. Combined with the gain in power efficiency, this setup allows broadband 1H to 13C CP over large areas of the brain. Clear 13C resonances from glutamate (Glu), glutamine (Gln), aspartate (Asp), lactate (Lac), and gamma-aminobutyrate (GABA) carbon spins in the human brain demonstrate the quality of 13C MR spectra obtained in vivo with this coil setup.