[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
Highlights
► Oral delivery of exenatide and pramlintide acetate in Intravail® is feasible. ► Oral exenatide and pramlintide in Intravail® is biologically active. ► [d-Leu-4]-OB3 enhances the effects of exenatide and pramlintide acetate.
Introduction
The World Health Organization has estimated that the number of children and adults with diabetes mellitus type 2 will rise to 366 million by 2030, and in 2035, approximately 300 million persons will be obese [1], [2]. The link between obesity and type 2 diabetes is strong; obesity has been found to contribute to approximately 55% of all cases of type 2 diabetes [3]. Additional factors which contribute to increasing the risk of type 2 diabetes include age-related impairment of pancreatic beta cells [4], high-fat diet [5] low levels of physical activity [6], and environmental toxins [7]. This combination of lifestyle and genetic factors, as well as an association of type 2 diabetes mellitus with a number of medical conditions such as hypertension [8], hyperlipidemia [9], and cancer [10], [11] has made the clinical management of type 2 diabetes a changing and challenging task.
Not unexpectedly, therapies for the management of diabetes and obesity that have been based on behavioral and nutritional modification have had only partial and temporary benefits. At the same time, a large number of existing pharmacotherapeutics have shown only limited efficacy, generated serious health risks, or have been withdrawn from clinical use [12], [13], [14], [15]. These events have catalyzed an intensified search for new approaches for the management of diabetes and obesity. One such approach is combination therapy utilizing existing FDA-approved drugs, currently used as the standard of care to treat diabetes mellitus in the clinic, with new anti-obesity/anti-diabetes drug candidates [16]. We have incorporated this strategy into the present study. In the following report, we describe the effects of oral delivery of two commonly used anti-diabetes medications normally given by injection, exenatide and pramlintide acetate, either alone or in combination with [d-Leu-4]-OB3 [17], an orally bioavailable anti-diabetes/anti-obesity peptide drug candidate, on energy balance and glycemic control in genetically obese C57BLK/6-m male db/db mice.
Section snippets
Housing
Six-week-old (+/− 3 days) male C57BLK/6-m db/db mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA). The animals were housed three per cage in polycarbonate cages fitted with stainless steel wire lids and air filters, and supported on ventilated racks (Thoren Caging Systems, Hazelton, PA, USA) in the Albany Medical College Animal Resources Facility. The mice were maintained at a constant temperature (24 °C) with lights on from 07:00 to 19:00 h, and allowed food and water ad libitum.
Effects on body weight gain
The effects of oral delivery (by gavage) of exenatide in DDM, either alone or in combination with [d-Leu-4]-OB3, on body weight gain in male db/db mice are described in Fig. 1A and Table 1. Mice given DDM alone for 14 days were 19.7% heavier than they were at the beginning of the study, while mice receiving exenatide alone were only 13.9% heavier. Mice given [d-Leu-4]-OB3 gained only 11.5% of their initial body weight. When exenatide and [d-Leu-4]-OB3 were given together, the mice lost 4.2% of
Discussion
The therapeutic potential of naturally occurring peptide and protein drugs in the treatment of human disease has long been recognized. These drugs frequently offer high potency and selectivity, and are generally free of chemical toxicity [23]. Because they are metabolized to naturally occurring amino acids in the gastrointestinal tract, as are the proteins ingested as food, peptide and protein drugs do not evoke xenobiotic metabolic responses, a major source of small molecule drug toxicity [24].
Acknowledgments
The authors thank Zachary Novakovic and Xiaolan Ding for their expert technical assistance, and Aegis Therapeutics for providing the Intravail® reagent. This research was supported by a grant from the Willard B. Warring Memorial Fund.
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