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