Beneficial long‐term antidiabetic actions of N‐ and C‐terminally modified analogues of apelin‐13 in diet‐induced obese diabetic mice

Aims To investigate the chronic effects of twice‐daily administration of stable apelin analogues, apelin‐13 amide and pyroglutamyl (pGlu) apelin‐13 amide, on metabolic variables in glucose‐intolerant and insulin‐resistant diet‐induced obese mice fed a high‐fat diet for 150 days. Methods Groups of mice received twice‐daily (9 am and 5 pm ) injections of saline vehicle, apelin‐13 amide, (pGlu)apelin‐13 amide or exendin‐4(1‐39) for 28 days (all at 25 nmol/kg). Energy intake, body weight, non‐fasting blood glucose, plasma insulin, glucose tolerance, metabolic response to feeding and insulin sensitivity, together with pancreatic hormone content and biochemical variables such as lipids and total GLP‐1 were monitored. Dual‐energy X‐ray absorptiometry analysis and indirect calorimetry were also performed. Results Administration of apelin‐13 amide, (pGlu)apelin‐13 amide or exendin‐4 significantly decreased body weight, food intake and blood glucose and increased plasma insulin compared with high‐fat‐fed saline‐treated controls ( P < .05 and P < .001), Additionally, all peptide‐treated groups exhibited improved glucose tolerance (oral and intraperitoneal), metabolic responses to feeding and associated insulin secretion. (pGlu)apelin‐13 amide also significantly improved glycated haemoglobin and insulin sensitivity after 28 days. Both (pGlu)apelin‐13 amide and exendin‐4 increased bone mineral content and decreased respiratory exchange ratio, whereas only (pGlu)apelin‐13 amide increased energy expenditure. All treatment groups displayed reduced circulating triglycerides and increased glucagon‐like peptide‐1 concentrations, although only (pGlu)apelin‐13 amide significantly reduced LDL cholesterol and total body fat, and increased pancreatic insulin content. Conclusion These data indicate the therapeutic potential of stable apelin‐13 analogues, with effects equivalent to or better than those of exendin‐4.