A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

Abstract

OBJECTIVENutrient "preloads" given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODSTwenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a 13 C-octanoate-labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated. RESULTSCompared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P < 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P < 0.05 each). CONCLUSIONSIn metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.The "incretin" hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia (1). The latter is an important target in patients with type 2 diabetes, particularly those with modestly elevated HbA 1c (2). In health, both incretins stimulate insulin secretion in a glucose-dependent manner (1). However, the effect of GIP is substantially diminished in type 2 diabetes (3), whereas GLP-1

Small Intestinal Glucose Delivery Affects the Lowering of Blood Glucose by Acute Vildagliptin in Type 2 Diabetes

“…Unfortunately, GIP receptor antagonists suitable for human use are not currently available. Although stimulation of endogenous GLP-1 secretion has been shown to potentiate glucose-lowering by DPP-4 inhibitors (18,19), recent studies employing the GLP-1 receptor antagonist, exendin (9 -39), suggest that GLP-1 accounts for only ϳ50% of the insulinotropic and glucose-lowering effects associated with DPP-4 inhibition in patients with type 2 diabetes (16,17). Several other DPP-4 substrates (eg, oxyntomodulin, PACAP and SDF-1␣ (38)) may, like the incretin hormones, contribute to the lowering of glucose by VILD.…”

“…GLP-1 appears to mediate about 50% of the insulinotropic and glucose-lowering effects associated with DPP-4 inhibition (16,17). Furthermore, stimulation of GLP-1 secretion (eg, by small macronutrient preloads ingested before the main meal) potentiates the lowering of blood glucose by DPP-4 inhibitors (18,19).…”

Insulinotropic Effects of Whey: Mechanisms of Action, Recent Clinical Trials, and Clinical Applications

“…The same study also found WPH independently inhibited DPP-IV activity, though the effect was less potent than the combined therapy. A combined therapy that included a preload of 25 g WPI 60 min post administration of another gliptin - vildagliptin - in patients with T2DM on metformin resulted in significant increases in the levels of GIP, GLP-1 and decreases in postprandial glycemia and slower gastric emptying [52]. The study also tested WPI preloads again in the same patients on metformin without vildagliptin and found significant reductions in the glycemic peak, increased insulin and total and intact GLP-1 and GIP compared to control.…”

DPP-4 Inhibition and the Known Unknown

“…Hence, the effect of DPP-4 inhibition on gastric emptying is of interest. Although Nauck et al (9) found no effect measured by a breath test (9), there is probably a modest slowing (10,19), albeit much less than that induced by short-acting GLP-1 agonists (16). Gastric emptying is also a determinant of the glycemic response to DPP-4 inhibition (19,20), and strategies that slow gastric emptying and stimulate GLP-1 secretion, such as whey preloads (19), potentiate glucose lowering.…”