GLP-1 agonists for people living with HIV and obesity, is there a potential?

BACKGROUND AND OBJECTIVES: Obesity trends and metabolic dysregulation are rising in people living with HIV using antiretrovirals (ARVs). Underlying causes and preventive strategies are being investigated. Two glucagon like-peptide 1 (GLP-1) agonists, liraglutide and semaglutide, were formerly approved as glucose-lowering drugs and have been recently approved for long-term weight loss in people with obesity. Due to the lack of therapeutic guidelines or clinical trials in people with HIV, we discuss the potential benefits, safety aspects and pharmacological considerations of prescribing liraglutide and semaglutide in people with HIV. RESULTS: Clinical experience is limited to two clinical cases of diabetic people with HIV using liraglutide after which a successful weight loss and glycaemic control were observed. None of the adverse events associated with liraglutide and semaglutide usage indicate an additional risk for people with HIV. Extra caution showed be warranted when initiating GLP-1 agonist therapy in people with HIV taking protease inhibitors who have pre-existing risk factors for heart rate variability to reduce the incidence of RP interval prolongation. GLP-1 agonists are metabolized by endopeptidases, and thus do not generate major drug-drug interactions with most drugs, including ARVs. GLP-s agonists are known to inhibit gastric acid secretion, which warrants caution and close monitoring when combined with atazanavir and oral rilpivirine, two ARVs that require low gastric pH for an optimal absorption. CONCLUSION: Theoretical considerations and a few available clinical observations support semaglutide and liraglutide prescription in people with HIV, with, thus far, no indications of concern regarding efficacy, safety or pharmacological interactions with ARVs.

The challenge of choosing in cardiovascular risk management.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options.

Characteristics associated with polypharmacy in people with type 2 diabetes: the Dutch Diabetes Pearl cohort.

AIM: To describe the prevalence and characteristics of polypharmacy in a Dutch cohort of individuals with type 2 diabetes. METHODS: We included people with type 2 diabetes from the Diabetes Pearl cohort, of whom 3886 were treated in primary care and 2873 in academic care (secondary/tertiary). With multivariable multinomial logistic regression analyses stratified for line of care, we assessed which sociodemographic, lifestyle and cardiometabolic characteristics were associated with moderate (5-9 medications) and severe polypharmacy (≥10 medications) compared with no polypharmacy (0-4 medications). RESULTS: Mean age was 63 ± 10 years, and 40% were women. The median number of daily medications was 5 (IQR 3-7) in primary care and 7 (IQR 5-10) in academic care. The prevalence of moderate and severe polypharmacy was 44% and 10% in primary care, and 53% and 29% in academic care respectively. Glucose-lowering and lipid-modifying medications were most prevalent. People with severe polypharmacy used a relatively large amount of other (i.e. non-cardiovascular and non-glucose-lowering) medication. Moderate and severe polypharmacy across all lines of care were associated with higher age, low educational level, more smoking, longer diabetes duration, higher BMI and more cardiovascular disease. CONCLUSIONS: Severe and moderate polypharmacy are prevalent in over half of people with type 2 diabetes in primary care, and even more in academic care. People with polypharmacy are characterized by poorer cardiometabolic status. These results highlight the significance of polypharmacy in type 2 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.

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.

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.

Impact of a multifaceted strategy to improve perioperative diabetes care.

AIMS: To assess the impact of a multifaceted strategy to improve perioperative diabetes care throughout the hospital care pathway. METHODS: We conducted a controlled before-and-after study in six hospitals. The purpose of the strategy was to target four predominant barriers that obstruct optimal care delivery. We provided feedback on baseline indicator performance, developed a multidisciplinary protocol and patient information, and provided professional education. After a 6-month intervention, we determined the performance changes against three outcome indicators and nine process indicators using data on 811 patients with diabetes who underwent major surgery. The progress of the interventions was monitored closely. RESULTS: Two process indicators improved significantly in the intervention hospitals: the proportion of patients for whom glycaemic control had been evaluated preoperatively increased by 9% (P < 0.002) and the proportion of patients with blood glucose measurements within 1 h after surgery increased by 29% (P < 0.0001). Four other process indicators and all three outcome indicators improved more in the intervention hospitals than in the control hospitals, but the differences were not statistically significant. These included the proportion of patients with all glucose values at 6-10 mmol/l (+3%) and the proportion of patients with hyperglycaemia (-8%). The implementation of the multidisciplinary protocol was still ongoing after the 6-month intervention period. CONCLUSIONS: The multifaceted improvement strategy had a limited impact on the quality of perioperative diabetes care. This study demonstrates the complexity of improving perioperative diabetes care throughout the multiprofessional hospital care pathway.

Individual and partner's level of occupation and the association with HbA1c levels in people with Type 2 diabetes mellitus: the Dutch Diabetes Pearl cohort.

AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

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.

Perioperative diabetes care: room for improving the person centredness.

AIMS: Person centredness is an important principle for delivering high-quality diabetes care. In this study, we assess the level of person centredness of current perioperative diabetes care. METHODS: We conducted a survey in six Dutch hospitals, among 690 participants with diabetes who underwent major abdominal, cardiac or large-joint orthopaedic surgery. The survey included questions regarding seven dimensions of person-centred perioperative diabetes care. RESULTS: Complete data were obtained from 298 participants. The survey scores were low for many of the dimensions of person centredness. The dimensions 'information', 'patient involvement' and 'coordination and integration of care' had the lowest scores. Only half the participants had received information about perioperative diabetes treatment, and approximately one-third had received information about the effect of surgery on blood glucose values, target glucose values and glucose measurement times. Similarly, half the participants had an opportunity to ask questions preoperatively, and only one-third of the participants felt involved in the decision-making regarding diabetes treatment. Most participants knew neither the caregiver in charge of perioperative diabetes treatment nor whom to contact in case of diabetes-related problems during their hospital stay. CONCLUSIONS: Current perioperative diabetes care is characterized by a lack of patient information and limited patient involvement. These results indicate that there is ample room for improving the person centredness of perioperative diabetes care.

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-specific emotional distress in people with Type 2 diabetes: a comparison between primary and secondary care.

AIMS: To compare levels of diabetes distress in people with Type 2 diabetes treated in primary and secondary care and to examine demographic and clinical correlates that may explain potential differences in levels of distress between care settings. METHODS: People with Type 2 diabetes from 24 primary care practices (n = 774) and three secondary care clinics (n = 526) completed the Problem Areas In Diabetes questionnaire. Data on HbA1c levels and diabetes complications were derived from medical charts. Hierarchical ordinal regression analysis was used to investigate which correlates could explain the potential differences in level of diabetes distress between care settings. RESULTS: Diabetes distress levels and the prevalence of elevated diabetes distress were considerably lower in the participants treated in primary care (mean (SD) total diabetes distress score 8 (11); 4% of participants with a Problem Areas In Diabetes score ≥ 40) than in secondary care (mean (SD) total diabetes distress score 23 (21); 19% of participants with a Problem Areas In Diabetes score ≥ 40, P < 0.001). In addition to care setting, the following variables were also independently related to diabetes distress: younger age, ethnic minority status, using insulin, having a higher HbA1c level, having a higher BMI and the presence of neuropathy. Other diabetes complications were not independently associated with diabetes distress. CONCLUSIONS: In primary care, lower levels of diabetes distress were reported than in secondary care. The difference in diabetes distress between care settings can be largely, but not fully, explained by specific demographic and clinical characteristics. These results need to be interpreted with caution as they are based on two separate studies, but do call into question the need to screen for diabetes distress in people with Type 2 diabetes in primary care.

The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance.

Inflammation at the level of the ß cell appears to be involved in progressive ß-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on ß-cell function. Sixteen participants with impaired glucose tolerance were treated with 150 mg anakinra daily for 4 weeks in a double blind, randomized, placebo-controlled cross-over study with a wash-out period of 4 weeks. At the end of each treatment period, oral glucose tolerance tests (OGTTs) and hyperglycaemic clamps were performed. First-phase insulin secretion improved after anakinra treatment compared with placebo, 148 ± 20 versus 123 ± 14 mU/l, respectively (p = 0.03), and the insulinogenic index was higher after anakinra treatment. These results support the concept of involvement of IL-1ß in the (progressive) decrease of insulin secretion capacity associated with type 2 diabetes.

Beta2-adrenoceptor stimulation has no effect on skeletal muscle glucose uptake.

INTRODUCTION: Blockade of the ß-adrenergic receptor induces insulin resistance and chronic ß-adrenoceptor stimulation improves insulin sensitivity in animals. We tested whether acute ß2-adrenoceptor stimulation increased insulin-induced glucose uptake in human forearm skeletal muscle. MATERIALS AND METHODS: During a hyperinsulinemic euglycemic clamp procedure, forearm glucose uptake was calculated by multiplying the arteriovenous glucose gradient and forearm blood flow before and during local infusion of the ß2-adrenoceptor salbutamol into the brachial artery. CONCLUSIONS: ß2-Adrenergic stimulation had no effect on insulin-stimulated glucose uptake in human forearm skeletal muscle.

Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue.

AIMS/HYPOTHESIS: Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. METHODS: We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. RESULTS: As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-α and IL-1ß after 6 months of insulin therapy compared with those who had not gained weight. CONCLUSIONS/INTERPRETATION: We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00781495. FUNDING: The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.

Differential associations between depressive symptoms and glycaemic control in outpatients with diabetes.

AIMS: Depression is common in people with diabetes, and related to higher HbA(1c) levels. Depression, however, is a heterogeneous construct that involves a variety of symptoms. As little is known about the associations of individual depressive symptoms with HbA(1c), we explored these associations in outpatients with diabetes. METHODS: The study was conducted in three tertiary diabetes clinics in the Netherlands. At baseline, the presence of the nine depressive symptoms that are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition was assessed with the nine-item Patient Health Questionnaire (PHQ-9). At baseline and after a 1-year follow-up, HbA(1c) was derived from the medical charts. RESULTS: A total of 288 out of 646 subjects with diabetes (45%) reported one or more depressive symptom(s). Depressed mood (ß = 0.11, P = 0.005), sleeping difficulties (ß = 0.16, P < 0.001), appetite problems (ß = 0.15, P < 0.001) and suicidal ideation (ß = 0.14, P = 0.001) were significantly related to higher baseline HbA(1c) values. Furthermore, depressed mood (ß = 0.09, P = 0.03) sleeping difficulties (ß = 0.12, P = 0.004), appetite problems (ß = 0.11, P = 0.01) and psychomotor agitation/retardation (ß = 0.09, P = 0.04) were significantly related to higher HbA(1c) values at 1-year follow-up. Associations were more pronounced in Type 1 diabetes than in Type 2 diabetes. None of the depressive symptoms were related to change in HbA(1c) over time, except suicidal ideation. CONCLUSION: In people with diabetes, several individual depressive symptoms were related to higher HbA(1c) levels. These associations persisted over time. More research is needed to investigate potential mechanistic pathways.

Psychometric and screening properties of the WHO-5 well-being index in adult outpatients with Type 1 or Type 2 diabetes mellitus.

OBJECTIVE: The 5-item World Health Organization well-being index is a commonly used measure of emotional well-being, but research on psychometric properties in outpatients with diabetes is scarce. We examined psychometric and screening properties for depression of this index in a large sample of Dutch outpatients with diabetes. METHODS: Patients with Type 1 (n = 384) and Type 2 (n = 549) diabetes from three outpatient clinics completed the WHO-5 index, the nine-item Patient Health Questionnaire, the Problem Areas in Diabetes survey and the Short Form-12 health survey. Internal consistency of the WHO-5 index was determined by Cronbach's alpha. The factor structure was tested by confirmatory factor analysis. Concurrent validity was assessed by correlations with the Patient Health Questionnaire, Problem Areas in Diabetes and the Short Form-12 mental component scores. Sensitivity and specificity of the WHO-5 index as depression screener were tested against two existing Patient Health Questionnaire cut-off scores for depression using receiver operating characteristic curves. RESULTS: A one-factor structure of the WHO-5 index was verified by confirmatory factor analysis for patients with Type 1 and Type 2 diabetes. Moderate to strong correlations were observed between the WHO-5 index and the Patient Health Questionnaire scores, the Problem Areas in Diabetes scores and the Short Form-12 mental component scores (r = 0.55-0.69, P < 0.001). Receiver operating characteristic curves showed that a WHO-5 index cut-off of < 50 performed best as an indication for likely depression, with sensitivity compared with a Patient Health Questionnaire score ≥ 10 and ≥ 12 of 79% and 88%, respectively, and specificity of 88% and 76%, respectively. CONCLUSIONS: The WHO-5 index is a short, psychometrically sound measure of emotional well-being that appears suitable for use as screening test for likely depression in outpatients with Type 1 and Type 2 diabetes.

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.

Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice.

Adipose triglyceride lipase (ATGL) is a lipolytic enzyme that is highly specific for triglyceride hydrolysis. The ATGL-knockout mouse (ATGL(-/-)) accumulates lipid droplets in various tissues, including skeletal muscle, and has poor maximal running velocity and endurance capacity. In this study, we tested whether abnormal lipid accumulation in skeletal muscle impairs mitochondrial oxidative phosphorylation, and hence, explains the poor muscle performance of ATGL(-/-) mice. In vivo ¹H magnetic resonance spectroscopy of the tibialis anterior of ATGL(-/-) mice revealed that its intramyocellular lipid pool is approximately sixfold higher than in WT controls (P = 0.0007). In skeletal muscle of ATGL(-/-) mice, glycogen content was decreased by 30% (P < 0.05). In vivo ³¹P magnetic resonance spectra of resting muscles showed that WT and ATGL(-/-) mice have a similar energy status: [PCr], [P(i)], PCr/ATP ratio, PCr/P(i) ratio, and intracellular pH. Electrostimulated muscles from WT and ATGL(-/-) mice showed the same PCr depletion and pH reduction. Moreover, the monoexponential fitting of the PCr recovery curve yielded similar PCr recovery times (τPCr; 54.1 ± 6.1 s for the ATGL(-/-) and 58.1 ± 5.8 s for the WT), which means that overall muscular mitochondrial oxidative capacity was comparable between the genotypes. Despite similar in vivo mitochondrial oxidative capacities, the electrostimulated muscles from ATGL(-/-) mice displayed significantly lower force production and increased muscle relaxation time than the WT. These findings suggest that mechanisms other than mitochondrial dysfunction cause the impaired muscle performance of ATGL(-/-) mice.

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.