Effect of Endogenous GLP-1 on Insulin Secretion in Type 2 Diabetes

OBJECTIVE

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) account for up to 60% of postprandial insulin release in healthy people. Previous studies showed a reduced incretin effect in patients with type 2 diabetes but a robust response to exogenous GLP-1. The primary goal of this study was to determine whether endogenous GLP-1 regulates insulin secretion in type 2 diabetes.

METHODS

Twelve patients with well-controlled type 2 diabetes and eight matched nondiabetic subjects consumed a breakfast meal containing d-xylose during fixed hyperglycemia at 5 mmol/l above fasting levels. Studies were repeated, once with infusion of the GLP-1 receptor antagonist, exendin-(9–39) (Ex-9), and once with saline.

RESULTS

The relative increase in insulin secretion after meal ingestion was comparable in diabetic and nondiabetic groups (44 ± 4% vs. 47 ± 7%). Blocking the action of GLP-1 suppressed postprandial insulin secretion similarly in the diabetic and nondiabetic subjects (25 ± 4% vs. 27 ± 8%). However, Ex-9 also reduced the insulin response to intravenous glucose (25 ± 5% vs. 26 ± 7%; diabetic vs. nondiabetic subjects), when plasma GLP-1 levels were undetectable. The appearance of postprandial ingested d-xylose in the blood was not affected by Ex-9.

CONCLUSIONS

These findings indicate that in patients with well-controlled diabetes, the relative effects of enteral stimuli and endogenous GLP-1 to enhance insulin release are retained and comparable with those in nondiabetic subjects. Surprisingly, GLP-1 receptor signaling promotes glucose-stimulated insulin secretion independent of the mode of glucose entry. Based on rates of d-xylose absorption, GLP-1 receptor blockade did not affect gastric emptying of a solid meal.Glucagon-like peptide 1 (GLP-1) is a gut-brain peptide that is a major component of the incretin effect and is essential for normal glucose tolerance (1). Based on studies in which synthetic GLP-1, or GLP-1 receptor (GLP-1r) agonists, is administered to humans, GLP-1 has a broad range of actions that promote glucose homeostasis, including stimulating insulin secretion (2), suppressing glucagon release (3–4), delaying gastric emptying (5), and increasing hepatic glucose balance (6–7). Importantly, and unlike other insulinotropic gut peptides, the effects of GLP-1 on glucose metabolism are retained in people with diabetes (8–10). This has led to the development of novel therapeutic compounds for use in diabetic patients that are based on GLP-1r signaling (11).The physiologic role of GLP-1 in individuals with diabetes has not been determined. However, there are several reasons to question whether the GLP-1 system is fully functional in this patient group. First, there is some evidence that GLP-1 secretion in response to meal ingestion in type 2 diabetes is impaired (12–15), although this finding has not been uniform (16–17). Second, the sensitivity of insulin secretion to exogenous GLP-1 is reduced in diabetic individuals (18). Finally, it has long been believed that the augmentation of glucose-stimulated insulin secretion during enteral glucose absorption, the incretin effect, is severely attenuated in type 2 diabetes, implying that incretins such as GLP-1 are not normally active in this group of subjects.In this study, we tested the hypothesis that the effect of endogenous GLP-1 to promote insulin secretion after meal ingestion is reduced in people with diabetes. Diabetic subjects and age- and weight-matched nondiabetic subjects were studied with and without infusion of the specific GLP-1r antagonist, exendin-(9–39) (Ex-9), during fixed hyperglycemia before and after a breakfast meal.