Daily Supplementation of Dietary Protein Improves the Metabolic Effects of GLP-1-based Pharmacotherapy in Lean and Obese Rats

Glucagon-like peptide-1 (GLP-1) is an incretin hormone released from intestinal L-cells in response to food entering into the gastrointestinal tract. GLP-1-based pharmaceuticals improve blood glucose regulation and reduce feeding. Specific macronutrients, when ingested, may trigger GLP-1 secretion and enhance the effects of systemic sitagliptin, a pharmacological inhibitor of DPP-IV (an enzyme that rapidly degrades GLP-1). In particular, macronutrient constituents found in dairy foods may act as potent secretagogues for GLP-1, and acute preclinical trials show that ingestion of dairy protein may represent a promising adjunct behavioral therapy in combination with sitagliptin. To test this hypothesis further, chow-maintained or high-fat diet (HFD)-induced obese rats received daily IP injections of sitagliptin (6mg/kg) or saline in combination with a twice-daily 8ml oral gavage of milk protein concentrate (MPC; 80/20% casein/whey; 0.5kcal/ml), soy protein (non-dairy control; 0.5kcal/ml) or 0.9% NaCl for two months. Food intake and body weight were recorded every 24-48h; blood glucose regulation was examined at baseline and at 3 and 6.5weeks via a 2h oral glucose tolerance test (OGTT; 25% glucose; 2g/kg). MPC and soy protein significantly suppressed cumulative caloric intake in HFD but not chow-maintained rats. AUC analyses for OGTT show suppression in glycemia by sitagliptin with MPC or soy in chow- and HFD-maintained rats, suggesting that chronic ingestion of dairy or soy proteins may augment endogenous GLP-1 signaling and the glycemic- and food intake-suppressive effects of DPP-IV inhibition.