Nadine Taleb

Glucagon in the artificial pancreas systems; potential benefits and safety profile of future chronic use.

The role of glucagon in the pathophysiology of diabetes has long been recognized, although its approved clinical use has so far been limited to the emergency treatment of severe hypoglycaemia. A novel use of glucagon as intermittent mini‐boluses is proposed in the dual‐hormone version (insulin and glucagon) of the external artificial pancreas. Short‐term studies suggest that the incorporation of glucagon into artificial pancreas systems has the potential to further decrease hypoglycaemic risk and improve overall glucose control; however, the potential long‐term safety and benefits also need to be investigated given the recognized systemic effects of glucagon. In the present report, we review the available animal and human data on the physiological functions of glucagon, as well as its pharmacological use, according to dosing and duration (acute and chronic). Along with its main role in hepatic glucose metabolism, glucagon affects the cardiovascular, renal, pulmonary and gastrointestinal systems. It has a potential role in weight reduction through its central satiety function and its role in increasing energy expenditure. Most of the pharmacological studies investigating the effects of glucagon have used doses exceeding 1 mg, in contrast to the mini‐boluses used in the artificial pancreas. The available data are reassuring but comprehensive human studies using small but chronic glucagon doses that are close to the physiological ranges are lacking. We propose a list of variables that could be monitored during long‐term trials of the artificial pancreas. Such trials should address the questions about the risk–benefit ratio of chronic glucagon use.

The challenges of Achieving Postprandial Glucose Control using Closed-Loop Systems in Patients with Type 1 Diabetes

For patients with type 1 diabetes, closed‐loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared with conventional therapy. Yet, reducing glucose excursion and simplification of prandial insulin doses remain a challenge. The objective of this literature review is to examine current meal‐time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post‐meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with carbohydrate‐matched bolus in the post‐meal period. The latter strategy has been efficient in controlling post‐meal glucose using different algorithms and in various settings, but at the cost of a meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal‐priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and dynamic profiles of available rapid insulins as well as sensor accuracy and lag‐time. New and upcoming faster acting insulins could provide important benefits. Multi‐hormone CLS (eg, dual‐hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (eg, GLP‐1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined.

Body Composition and Epicardial Fat in Type 2 Diabetes Patients Following Insulin Detemir Versus Insulin Glargine Initiation.

The aim of the study was to compare body composition and epicardial fat thickness changes in insulin-naïve inadequately controlled patients with type 2 diabetes following basal insulin initiation with detemir vs. glargine. Six-month, open-label, interventional randomized pilot study was conducted. Dual-energy X-ray absorptiometry and echocardiography were used to estimate the body composition and epicardial fat thickness respectively. Thirty-six patients in the detemir group and 20 in the glargine group completed the study. Study groups baseline characteristics were comparable. At 6 months, for similar glycemic control, those on detemir significantly gained less total weight (0.6±2.5 vs. 4.2±4.1 kg, p=0.004), total fat mass (0.9±2.2 vs. 2.9±2.4 kg, p=0.02), and truncal fat mass (0.8±1.5 vs. 2.1±1.7 kg, p=0.02), with a loss in truncal lean mass (- 0.8±1.9 kg vs. 0.3±1.7 kg; p=0.02). EFT significantly decreased from baseline in both group (detemir - 1.7±0.52-mm, glargine - 1.1±1.6-mm; p<0.05, without significant difference inter-groups). Within the detemir group, epicardial fat thickness change correlated with truncal fat and total fat mass changes (r=0.65, p=0.06 and r=0.60, p=0.07). In conclusion, detemir resulted in less fat mass gain, a trend for a more pronounced epicardial fat thickness reduction when compared with glargine.

Can somatostatin antagonism prevent hypoglycaemia during exercise in type 1 diabetes

The prevention and management of exercise-induced hypoglycaemia remains a challenge for patients with type 1 diabetes. Strategies involving changes to insulin dosing and/or carbohydrate consumption in anticipation of or during different types of exercise have proved to be helpful but not sufficient to fully prevent the hypoglycaemic risk. Meanwhile, the defect in glucagon secretion in response to hypoglycaemia in diabetes and the contributory role of somatostatin to this dysregulation constitute an important therapeutic target. In this issue of Diabetologia (DOI 10.1007/s00125-016-3953-0), Leclair et al show that selective somatostatin receptor 2 antagonists can enhance glucagon secretion in rats with streptozotocin-induced diabetes during exercise. The implications of their interesting findings are discussed, as well as limitations and potential for clinical applications, together with other glucagon-based options for tackling exercise-induced hypoglycaemia in diabetes.

Relative contribution of muscle and liver insulin resistance to dysglycemia in postmenopausal overweight and obese women: A MONET group study

OBJECTIVES The relative contribution of muscle and liver insulin resistance (IR) in the development of dysglycemia and metabolic abnormalities is difficult to establish. The present study aimed to investigate the relative contribution of muscle IR vs. liver IR to dysglycemia in non-diabetic overweight or obese postmenopausal women and to determine differences in body composition and cardiometabolic indicators associated with hepatic or muscle IR. MATERIAL AND METHODS Secondary analysis of 156 non-diabetic overweight or obese postmenopausal women. Glucose tolerance was measured using an oral glucose tolerance test. Whole-body insulin sensitivity (IS) was determined as glucose disposal rate during a euglycemic-hyperinsulinemic clamp. Muscle and liver IR have been calculated using Abdul-Ghani et al. OGTT-derived formulas. Participants body compositions as well as cardiometabolic risk indicators were also determined. RESULTS Overall, 57 (36.5%) of patients had dysglycemia, among them 25 (16.0%); 21 (13.5%); 11 (7.1%) had impaired fasting glycemia, impaired glucose tolerance and combined glucose intolerance respectively. Fifty-three (34.0%) participants were classified as combined IS while on the opposite 51 participants (32.7%) were classified as combined IR and 26 (16.7%) participants had either muscle IR or liver IR. For similar body mass index and total fat mass, participants with liver IR were more likely to have lower whole-body IS, dysglycemia and higher visceral fat, liver fat index, triglycerides and alanine aminotransferase than participants with muscle IR. CONCLUSION In the present study, the presence of liver IR is associated with a higher prevalence of dysglycemia, ectopic fat accumulation and metabolic abnormalities than muscle IR.

Timing of insulin basal rate reduction to reduce hypoglycemia during late post-prandial exercise in adults with type 1 diabetes using insulin pump therapy: A randomized crossover trial

AIMS To compare the efficacy of three timings to decrease basal insulin infusion rate to reduce exercise-induced hypoglycaemia in patients with type 1 diabetes (T1D) using pump therapy. METHODS A single-blinded, randomized, 3-way crossover study in 22 adults that had T1D > 1 year and using insulin pump > 3 months (age, 40 ± 15 years; HbA1c, 56.3 ± 10.2 mmol/mol). Participants practiced three 45-min exercise sessions (ergocyle) at 60% VO2peak 3 hours after lunch comparing an 80% reduction of basal insulin applied 40 minutes before (T-40), 20 minutes before (T-20) or at exercise onset (T0). RESULTS No significant difference was observed for percentage of time spent < 4.0 mmol/L (T-40: 16 ± 25%; T-20: 26 ± 27%; T0: 24 ± 29%) (main outcome) and time spent in target range 4.0-10.0 mmol/L (T-40: 63 ± 37%; T-20: 66 ± 25%; T0: 65 ± 31%). With T-40 strategy, although not significant, starting blood glucose (BG) was higher (T-40: 8.6 ± 3.6 mmol/L; T-20: 7.4 ± 2.5 mmol/L ; T0: 7.4 ± 2.7 mmol/L), fewer patients needed extra carbohydrates consumption prior to exercise for BG < 5.0 mmol/L (T-40: n = 3; T-20: n = 5; T0: n = 6) as well as during exercise for BG < 3.3 mmol/L [T-40: n = 6 (27%); T-20: n = 12 (55%); T0: n = 11 (50%)] while time to first hypoglycaemic episode was delayed (T-40: 28 ± 14 min; T-20: 24 ± 10 min; T0: 22 ± 11 min). CONCLUSION Decreasing basal insulin infusion rate by 80% up to 40 minutes before exercise onset is insufficient to reduce exercise-induced hypoglycaemia.

Contrôle glycémique durant l’exercice pour patients diabétiques de type 1 traités par pompe à insuline : stratégies actuelles et aperçu de l’impact des nouvelles technologies

Resume L’effet de l’exercice sur le controle de la glycemie pose un grand defi pour les patients atteints de diabete de type 1, et depend de plusieurs facteurs, tels que le type d’exercice, son intensite, sa duree, sa distance des repas, etc. Pour les utilisateurs des pompes a insuline, des ajustements des debits et bolus d’insuline sont suggeres en se basant sur des etudes qui ont teste certains de ces facteurs. Des nouvelles technologies, comme le pancreas artificiel externe, ont le potentiel de faciliter la gestion du diabete avec l’activite physique.

Insulin Pumps and Artificial Pancreas

Several technologies have recently been implemented to advance the management of insulin replacement in diabetes. The aim of these technologies is to provide the patients with better tools to meet the glycemic targets and to improve treatment flexibility and quality of life. Continuous subcutaneous insulin infusion using insulin pumps allowed a more flexible insulin delivery and continuous glucose monitoring by subcutaneous sensors improved glucose profiling to guide, in real-time, diabetes management. Different combinations of insulin pumps and glucose sensors have been made available over the years with the most advanced and promising being their integration in the external artificial pancreas. Better glucose control with a reduced risk of hypoglycemia has marked the clinical studies testing the artificial pancreas across different ages and conditions. This article sheds the light on these various technologies displaying their mode of action, clinical efficacy and limitations and discusses the challenges that still need to be overcome in the future of diabetes management.