GLP‐1 receptor agonist attenuates endoplasmic reticulum stress‐mediated β‐cell damage in Akita mice

Aims/Introduction: Endoplasmic reticulum (ER) stress is one of the contributing factors in the development of type 2 diabetes. To investigate the cytoprotective effect of glucagon‐like peptide 1 receptor (GLP‐1R) signaling in vivo, we examined the action of exendin‐4 (Ex‐4), a potent GLP‐1R agonist, on β‐cell apoptosis in Akita mice, an animal model of ER stress‐mediated diabetes. Materials and Methods: Ex‐4, phosphate‐buffered saline (PBS) or phlorizin were injected intraperitoneally twice a day from 3 to 5 weeks‐of‐age. We evaluated the changes in blood glucose levels, bodyweights, and pancreatic insulin‐positive area and number of islets. The effect of Ex‐4 on the numbers of C/EBP‐homologous protein (CHOP)‐, TdT‐mediated dUTP‐biotin nick‐end labeling (TUNEL)‐ or proliferating cell nuclear antigen‐positive β‐cells were also evaluated. Results: Ex‐4 significantly reduced blood glucose levels and increased both the insulin‐positive area and the number of islets compared with PBS‐treated mice. In contrast, there was no significant difference in the insulin‐positive area between PBS‐treated mice and phlorizin‐treated mice, in which blood glucose levels were controlled similarly to those in Ex‐4‐treated mice. Furthermore, treatment of Akita mice with Ex‐4 resulted in a significant decrease in the number of CHOP‐positive β‐cells and TUNEL‐positive β‐cells, and in CHOP mRNA levels in β‐cells, but there was no significant difference between the PBS‐treated group and the phlorizin‐treated group. Proliferating cell nuclear antigen staining showed no significant difference among the three groups in proliferation of β‐cells. Conclusions: These data suggest that Ex‐4 treatment can attenuate ER stress‐mediated β‐cell damage, mainly through a reduction of apoptotic cell death that is independent of lowered blood glucose levels. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00075.x , 2010)     

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self‐regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β‐cells by glucagon‐like peptide 1 receptor (GLP‐1R) agonists is known to be glucose‐dependent. GLP‐1R agonists potentiate glucose‐stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose‐regulated’ activity of GLP‐1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non‐regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP‐1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP‐1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP‐1R signalling promotes insulin secretion from pancreatic β‐cells via a glucose‐dependent process.     

Gastrointestinal actions of glucagon‐like peptide‐1‐based therapies: glycaemic control beyond the pancreas

The gastrointestinal hormone glucagon‐like peptide‐1 (GLP‐1) lowers postprandial glucose concentrations by regulating pancreatic islet‐cell function, with stimulation of glucose‐dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP‐1 are at least as important for glucose‐lowering. GLP‐1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP‐1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP‐1 receptor agonists, which mimic the effects of GLP‐1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP‐1 receptor agonists can be broadly categorized as short‐ or long‐acting, with each having unique islet‐cell and gastrointestinal effects that lower glucose levels. Short‐acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long‐acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β‐cell function.     

GLP‐1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes

Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine‐tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin‐mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon‐like peptide 1 (GLP‐1) receptors. GLP‐1, in addition to its well‐characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP‐1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP‐1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP‐1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP‐1 in cardiac as well as skeletal muscle function.     

Comparison of insulin degludec with insulin detemir in type 1 diabetes: a 1‐year treat‐to‐target trial

The long‐term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26‐week core + 26‐week extension, controlled, open‐label, parallel‐group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal‐time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg ? IDet) ?1.11 (95% CI ?1.83; ?0.40) mmol/l; p < 0.05. The present study confirmed the long‐term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet.     

Effects of DPP‐4 inhibitor linagliptin and GLP‐1 receptor agonist liraglutide on physiological response to hypoglycaemia in Japanese subjects with type 2 diabetes: A randomized,open‐label, 2‐arm parallel comparative,exploratory trial

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose‐dependent insulinotropic polypeptide (GIP) action, but not that of glucagon‐like peptide‐1 (GLP‐1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP‐4 inhibitor linagliptin on glucagon and other counter‐regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP‐1 receptor agonist liraglutide in a multi‐centre, randomized, open‐label, 2‐arm parallel comparative, exploratory trial. Three‐step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2‐week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2‐week treatment. Changes in other counter‐regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2‐week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.     

Insulin analogues in children with Type 1 diabetes: a 52‐week randomized clinical trial

Aims

This 52‐week, randomized, multinational, open‐label, parallel‐group, non‐inferiority trial investigated the efficacy and safety of basal–bolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in combination with insulin aspart, in subjects aged 2–16 years with Type 1 diabetes mellitus.

Methods

Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight were followed over 52 weeks.

Results

After 52 weeks, insulin detemir was shown to be non‐inferior to NPH insulin with regard to HbA_1c [mean difference insulin detemir–NPH: 1.30 mmol/mol, 95% CI –1.32 to 3.92 (0.12%, 95% CI –0.12 to 0.36) in the full analysis set and 1.41 mmol/mol, 95% CI –1.26 to 4.08 (0.13%, 95% CI –0.12 to 0.37) in the per protocol analysis set]. Hypoglycaemic events per subject‐year of exposure of 24‐h and nocturnal hypoglycaemia were significantly lower with insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.60–0.97, P = 0.028 and 0.62, 95% CI 0.47–0.84, P = 0.002, respectively). Weight standard deviation (sd ) scores (body weight standardized by age and gender) decreased with insulin detemir, but increased slightly with NPH insulin (change: –0.12 vs. 0.04, P < 0.001). At end of the trial, median insulin doses were similar in both treatment groups.

Conclusions

Insulin detemir was non‐inferior to NPH insulin after 52 weeks' treatment of children and adolescents aged 2–16 years, and was associated with a significantly lower risk of hypoglycaemia, together with significantly lower weight sd score when compared with NPH insulin.