Lawrence J. D'Souza

Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet‐induced obese and leptin‐deficient rodents

To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon‐like peptide‐1 receptor (GLP‐1R) agonist on metabolic variables in diet‐induced obese (DIO) rodents.

A novel long‐acting glucose‐dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents

Glucose‐dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N‐ and C‐terminally modified GIP analogue AC163794.

Effects of amylin and bupropion/naltrexone on food intake and body weight are interactive in rodent models.

Antagonism of opioid systems (e.g., with naltrexone) has been explored as an anti-obesity strategy, and is particularly effective when co-administered with dual inhibitors of dopamine and norepinephrine reuptake (e.g., bupropion). Previously, we demonstrated that amylin enhances the food intake lowering and weight loss effects of neurohormonal (e.g., leptin, cholecystokinin, melanocortins) and small molecule (e.g., phentermine, sibutramine) agents. Here, we sought to characterize the interaction of amylin with naltrexone/bupropion on energy balance. Wild-type and amylin knockout mice were similarly responsive to the food intake lowering effects of either naltrexone (1mg/kg, subcutaneous) or bupropion (50mg/kg, subcutaneous) suggesting that they act independently of amylinergic systems and could interact additively when given in combination with amylin. To test this, diet-induced obese rats were treated (for 11 days) with vehicle, rat amylin (50 μg/kg/d, infused subcutaneously), naltrexone/bupropion (1 and 20mg/kg, respectively by twice daily subcutaneous injection) or their combination. We found that amylin+naltrexone/bupropion combination therapy exerted additive effects to reduce cumulative food intake, body weight and fat mass. In a separate study, the effects of amylin and naltrexone/bupropion administered at the same doses (for 14 days) were compared to a pair-fed group. Although the combination and pair-fed groups lost a similar amount of body weight, rats treated with the combination lost 68% more fat and better maintained their lean mass. These findings support the strategy of combined amylin agonism with opioid and catecholaminergic signaling systems for the treatment of obesity.

Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents

Aims: Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches.

Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice

The combined glucose‐lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single‐dose or 4‐week dosing) in diabetic ob/ob mice. Vehicle‐corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post‐dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.

Synthesis & biological evaluation of PYY(3-36) analogs substituted with alanine.

Introduction PYY is a 36-residue peptide first isolated from porcine intestine (Figure 1) [1,2]. Two endogenous forms of PYY, PYY(1-36) and the post-DPPIV [3,4] activated PYY(3-36), are released into the circulation following a meal [1,5]. PYY(3-36) appears to be the predominant secreted form. PYY has been known to inhibit gastric, [6] pancreatic and intestinal secretions [7]. PYY binds and activates at least four receptor subtypes (Y1, Y2, Y4 and Y5) [8-10] in rats and humans. These Y receptor subtypes display different patterns of affinity and activation for PYY, PYY(3-36) and synthetically modified PYY analogs. PYY(3-36) is a selective ligand for Y2 and Y5 receptors, implicated in food intake and feeding behavior, respectively [11]. In this study, PYY(3-36) analogs, where each residue of the natural sequence is replaced by L-alanine, and analogs with multiple alanine substitutions were synthesized. The three alanines at positions 7, 12 and 22 were replaced by a D-alanine. The affinity of each analog to the Y family of receptors and the ability of the analogs to decrease acute food intake in mouse are presented. Additionally, the efficacy of a single equimolar dose of PYY(3-36) and a subset of the analogs to reduce body weight in the chronic weight loss assay in the mouse is summarized.