D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, augments the effects of orally delivered exenatide and pramlintide acetate on energy balance and glycemic control in insulin-resistant male C57BLK/6-m db/db mice

Abstract

The escalation predicted for the incidence of both type 2 diabetes mellitus and obesity has prompted investigators to search for additional pharmacotherapeutic approaches to their treatment. Two of these approaches, combination pharmacotherapy and utilization of leptin-related bioactive synthetic peptides as anti-diabetes/anti-obesity agents, were used in the present study. Exenatide or pramlintide acetate was reconstituted in dodecyl maltoside (DDM) in the absence or presence of [d-Leu-4]-OB3, and delivered orally by gavage to insulin-resistant male C57BLK/6-m db/db mice twice daily for 14days. Body weight gain, food and water intake, blood glucose, and serum insulin levels were measured. Mice given DDM alone for 14days were 19.7% heavier than they were at the beginning of the study, while oral delivery of exenatide or [d-Leu-4]-OB3 in DDM reduced body weight gain to only 13.9% and 11.5%, respectively, of initial body weight. Mice receiving exenatide and [d-Leu-4]-OB3 were 4.2% lighter than they were at the beginning of the study. In another study, Intravail® treated control mice gained 38.2% of their initial body weight, while mice receiving pramlintide acetate or [d-Leu-4]-OB3 were only 26.8% and 25.4% heavier, respectively, at the end of the study, Co-administration of pramlintide acetate and [d-Leu-4]-OB3 did not further enhance the effect of pramlintide acetate on body weight gain. Food intake was reduced by exenatide, pramlintide acetate, and [d-Leu-4]-OB3 alone, and co-delivery with [d-Leu-4]-OB3 did not induce a further decrease. Water intake was not affected by exenatide, pramlintide acetate, or [d-Leu-4]-OB3 alone, but co-delivery of exenatide or pramlintide acetate with [d-Leu-4]-OB3 resulted in a significant reduction in water intake. Oral delivery of exenatide or pramlintide acetate in DDM significantly lowered blood glucose levels by 20.4% and 30.2%, respectively. Co-delivery with [d-Leu-4]-OB3 further reduced blood glucose by 38.3% and 50.5%, respectively. A concentration-dependent increase in serum insulin was observed in response to increasing concentrations of exenatide, and [d-Leu-4]-OB3 slightly reduced the insulin response to exenatide at all concentrations tested. Increasing concentrations of pramlintide acetate alone did not elevate serum insulin, and when given in combination with [d-Leu-4]-OB3, serum insulin levels fell below those of DDM-treated control mice. Our data indicate that (1) exenatide and pramlintide acetate, currently administered by subcutaneous injection, can be given orally in DDM; (2) the bioactivity of exenatide and pramlintide acetate is retained following oral delivery in DDM; and (3) the effects of exenatide and pramlintide acetate on energy balance and glycemic control can be enhanced by co-administration with [d-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity.