The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and glucagon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes.It was established in 1964 that the insulin response to oral and enteral glucose is much greater than that to an isoglycemic intravenous glucose infusion (1,2). This "incretin effect," mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and calculated by comparing the plasma insulin, or C-peptide, responses to isoglycemic oral and intravenous glucose loads, ranges between 40 and 70% in health (3), independent of glycemia (4), and may be diminished in type 2 diabetes (5).Gastric emptying, which exhibits substantial interindividual variation in health (1-4 kcal/min) (6) and particularly in type 2 diabetes because of the high prevalence of delayed, and sometimes accelerated, emptying, modulates postprandial glycemic excursions (7). The relationships of the rate of small intestinal glucose delivery, a surrogate of gastric emptying, with glycemic and GLP-1, but not GIP, responses are nonlinear in health and type 2 diabetes (8,9). It has been suggested that both the incretin effect and gastrointestinal glucose disposal (GIGD; which takes into account the actions of the incretin hormones but also changes in glucagon and hepatic glucose uptake [10]) increase with higher glucose loads and are reduced in type 2 diabetes (5,11). However, a fundamental limitation in interpreting these studies has been their failure to account for gastric emptying.We have now evaluated the effects of different rates of duodenal glucose delivery on the incretin effect and GIGD in health and type 2 diabetes.
RESEARCH DESIGN AND METHODS
SubjectsWe studied 10 male BMI-matched controls (age 47 6 3 years; BMI 29.3 6 1 kg/m 2 ) and 11 male type 2 patients (age 64 6 2 years; BMI 31 6 1.3 kg/m 2 ; HbA 1c 6.9 6 0.2% [52 6 2.2 mmol/mol]; duration of known diabetes 4.9 6 1.3 years) managed by diet or metformin only. Subjects with known gastrointestinal disease, with medical illness(es) apart ...