Intraduodenal milk protein concentrate augments the glycemic and food intake suppressive effects of DPP-IV inhibition

Abstract

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 may hold promise for obesity treatment, as GLP-1 drugs reduce food intake and body weight in humans and animals. In an effort to improve GLP-1 pharmacotherapies, we focused our attention on macronutrients that, when present in the gastrointestinal tract, may enhance GLP-1 secretion and improve glycemic regulation and food intake suppression when combined with systemic administration of sitagliptin, a pharmacological inhibitor of DPP-IV (enzyme responsible for GLP-1 degradation). In particular, previous data suggest that specific macronutrient constituents found in dairy foods may act as potent secretagogues for GLP-1 and therefore may potentially serve as an adjunct dietary therapy in combination with sitagliptin. To directly test this hypothesis, rats received intraperitoneal injections of sitagliptin (6 mg/kg) or saline vehicle followed by intraduodenal infusions of either milk protein concentrate (MPC; 80/20% casein/whey; 4 kcal), soy protein (nondairy control infusate; 4 kcal), or 0.9% NaCl. Food intake was assessed 30 min postinfusion. In separate studies, regulation of blood glucose was examined via a 2-h oral glucose tolerance test (2 g/kg) following identical sitagliptin treatment and intraduodenal nutrient infusions. Collectively, results show that intraduodenal MPC, but not soy protein, significantly enhances both the food intake suppression and improved control of blood glucose produced by sitagliptin. These data support the hypothesis that dietary intake of dairy protein may be beneficial as an adjunct behavioral therapy to enhance the glycemic and food intake suppressive effects of GLP-1-based pharmacotherapies.

Keywords: GLP-1; dairy; diabetes; insulin; obesity.

Fig. 1.

A: administration of the DPP-IV inhibitor sitagliptin (6 mg/kg, ip) in combination with intraduodenal infusion of 4 kcal of milk protein concentrate (MPC) suppressed 30 min chow intake. *P < 0.008 from vehicle-saline. B: there were no differences among treatments when the same dose of sitagliptin was delivered in combination with intraduodenal infusions of 4 kcal of soy protein. Data are means ± SE.

Fig. 2.

Blood glucose concentrations (mg/dl) after intraperitoneal injection of vehicle or sitagliptin (6 mg/kg; time −20 min) in combination with intraduodenal infusions of 4 kcal of MPC or 0.9% NaCl in an oral glucose-tolerance test (2 g/kg of 25% glucose delivered via gavage at time 0). Sitagliptin alone significantly suppressed blood glucose levels compared with vehicle-saline at 20, 40, and 60 min postglucose load. MPC alone significantly suppressed blood glucose levels compared with vehicle-saline at 20 and 40 min postglucose load. When combined, MPC enhanced the glycemic suppressive effects of sitagliptin at 40 min postglucose load. Within a time point, data points with different letters are significantly different from each other (P < 0.05). Data are means ± SE.

Fig. 3.

Blood glucose concentrations (mg/dl) following intraperitoneal injection of vehicle or sitagliptin (6 mg/kg; time −20 min) in combination with intraduodenal infusions of 4 kcal of soy protein or 0.9% NaCl in an oral glucos-tolerance test (2 g/kg of 25% glucose delivered via gavage at time 0). Sitagliptin alone significantly suppressed blood glucose levels compared with vehicle-saline at 20, 40, and 60 min postglucose load. Soy protein alone significantly suppressed blood glucose levels compared with vehicle-saline at 20 and 40 min postglucose load. The combination of sitagliptin and soy protein did not produce any significant enhancement in the glycemic suppressive effects from either treatment alone. Within a time point, data points with different letters are significantly different from each other (P < 0.05). Data are means ± SE.

Fig. 4.

Within-subject percent suppression in blood glucose concentrations compared with vehicle-0.9% NaCl treatment after intraduodenal infusions of MPC or soy protein with (B) and without (A) sitagliptin administration. Between-subject analyses of this percent suppression shows that the combination of MPC with sitagliptin produced a significantly increased percent suppression in blood glucose compared with soy protein and sitagliptin administration at 40 min (P < 0.05).