Antidiabetogenic Effect of Glucagon-like Peptide-1 (7–36)amide in Normal Subjects and Patients with Diabetes Mellitus

TLDR

Glucagon‑like peptide‑1 (GLIP) is a gastrointestinal peptide that potentiates insulin release at physiologic concentrations. The study compared the effects of a two‑fold increase in plasma GLIP versus saline infusion on meal‑related insulin, glucagon, and somatostatin release in normal subjects, NIDDM, and IDDM patients. During closed‑loop insulin‑infusion control of blood glucose, GLIP infusion allowed measurement of meal‑related exogenous insulin requirements and insulin sensitivity in normoglycemic clamps. GLIP infusion increased the insulinogenic index by ~10‑fold, reduced meal‑related insulin requirements by >80 % in NIDDM and IDDM, lowered glucagon and somatostatin release, and raised glucose utilization in normoglycemic clamps, indicating an antidiabetogenic effect.

Abstract

Glucagon-like peptide-1 (7-36) amide (glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations. Its effects in patients with diabetes mellitus are not known.We compared the effect of an infusion of GLIP that raised plasma concentrations of GLIP twofold with the effect of an infusion of saline, on the meal-related release of insulin, glucagon, and somatostatin in eight normal subjects, nine obese patients with non-insulin-dependent diabetes mellitus (NIDDM), and eight patients with insulin-dependent diabetes mellitus (IDDM). The blood glucose concentrations in the patients with diabetes were controlled by a closed-loop insulin-infusion system (artificial pancreas) during the infusion of each agent, allowing measurement of the meal-related requirement for exogenous insulin. In the patients with IDDM, normoglycemic-clamp studies were performed during the infusions of GLIP and saline to determine the effect of GLIP on insulin sensitivity.In the normal subjects, the infusion of GLIP significantly lowered the meal-related increases in the blood glucose concentration (P less than 0.01) and the plasma concentrations of insulin and glucagon (P less than 0.05 for both comparisons). The insulinogenic index (the ratio of insulin to glucose) increased almost 10-fold, indicating that GLIP had an insulinotropic effect. In the patients with NIDDM, the infusion of GLIP reduced the mean (+/- SE) calculated isoglycemic meal-related requirement for insulin from 17.4 +/- 2.8 to 2.0 +/- 0.5 U (P less than 0.001), so that the integrated area under the curve for plasma free insulin was decreased (P less than 0.05) in spite of the stimulation of insulin release. In the patients with IDDM, the GLIP infusion decreased the calculated isoglycemic meal-related insulin requirement from 9.4 +/- 1.5 to 4.7 +/- 1.4 U. The peptide decreased glucagon and somatostatin release in both groups of patients. In the normoglycemic-clamp studies in the patients with IDDM, the GLIP infusion significantly increased glucose utilization (saline vs. GLIP, 7.2 +/- 0.5 vs. 8.6 +/- 0.4 mg per kilogram of body weight per minute; P less than 0.01).GLIP has an antidiabetogenic effect, and it may therefore be useful in the treatment of patients with NIDDM: