Small Intestinal Glucose Exposure Determines the Magnitude of the Incretin Effect in Health and Type 2 Diabetes

Abstract

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 ...

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

“…The implication of these observations is that DPP-4 inhibitors may be more effective in reducing postprandial glycemia in patients with type 2 diabetes, who have relatively more rapid gastric emptying. Consistent with our previous studies (3,22), an increase in the rate of ID glucose delivery from 2 to 4 kcal/ min was accompanied by a marked increment in plasma insulin secretion, so that the glycemic response to ID4 was proportionally less than might be expected when compared with ID2. We have recently shown in similarly well controlled type 2 patients that this enhanced insulin response is primarily driven by the incretin effect, which is markedly impaired in response to ID2, but less so in response to ID4, compared with healthy subjects (3).…”

“…We have recently shown in similarly well controlled type 2 patients that this enhanced insulin response is primarily driven by the incretin effect, which is markedly impaired in response to ID2, but less so in response to ID4, compared with healthy subjects (3). As previously (3,22,24), ID2 induced substantial GIP, but minimal GLP-1 release, whereas ID4 stimulated substantial secretion of both GIP and GLP-1, although, as noted previously, the GLP-1 response occurred relatively later compared with GIP. Due to the impaired insulinotropic response to GIP in type 2 diabetes, but relatively intact response to GLP-1 (4), GLP-1 would appear to be progressively more important than GIP in driving the incretin effect and regulating blood glucose as the rate of gastric emptying of carbohydrate increases.…”

“…GIP secretion increases approximately in proportion to the rate of intraduodenal (ID) glucose entry, whereas the GLP-1 response is minimal when ID glucose is administered at 1-2 kcal/min, but considerably greater at 3-4 kcal/min (22)(23)(24). Not surprisingly, the incretin effect is substantially greater during ID glucose infusion at 4 than 2 kcal/min (3). Therefore, it might be assumed that the glucose-lowering efficacy of DPP-4 inhibitors will be greater in type 2 diabetic patients with relatively more rapid gastric emptying, notwithstanding that more rapid emptying increases glycemia (25).…”

Managing hyperglycemia and diabetes in patients receiving enteral feedings: A health system approach

“…Delayed gastric emptying may exist in patients with critical illness and those with long-standing or poorly controlled diabetes whether diagnosed with gastroparesis or not [16-18]. The effects of enteral nutrition, by way of continuous intestinal glucose exposure, on secretion and action of incretin hormones (gastric inhibitory polypep-tide and glucagon-like peptide-1) are not entirely known and may contribute to hyperglycemia seen in patients with and without a history of diabetes [16,19,20]. …”

DPP-4 Inhibition and the Known Unknown

“…In health and type 2 diabetes, the incretin effect is greater when glucose is delivered intraduodenally at 4 kcal/min compared with 2 kcal/min (18). Hence, the effect of DPP-4 inhibition on gastric emptying is of interest.…”