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Hyperglycemia Acutely Lowers the Postprandial Excursions of Glucagon-Like Peptide-1 and Gastric Inhibitory Polypeptide in Humans

Department of Medicine I (K.V., H.G., B.A.M., O.G., W.E.S., J.J.M.), St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany; and Department of Biomedical Sciences (J.J.H., C.F.D.), The Panum-Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Juris J. Meier, M.D., Assistant Professor, Department of Medicine I, St. Josef-Hospital , Ruhr-University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany. E-mail: juris.meier{at}rub.de.

Introduction: Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes. It is unclear whether this is a primary defect or a consequence of the hyperglycemia in type 2 diabetes. We examined whether acute hyperglycemia reduces the postprandial excursions of gastric inhibitory polypeptide (GIP) and GLP-1, and if so, whether this can be attributed to changes in gastric emptying.

Patients and Methods: Fifteen nondiabetic individuals participated in a euglycemic clamp and a hyperglycemic clamp experiment, carried out over 285 min. A mixed meal was ingested after 45 min. Plasma concentrations of glucose, insulin, C-peptide, glucagon, triglycerides, GIP, and GLP-1 were determined, and gastric emptying was assessed using a ¹³C-octanoate breath test.

Results: Glucose levels were 160 ± 1 mg/dl during the hyperglycemic clamp experiments and 83 ± 3 mg/dl during the euglycemia (P < 0.0001). Glucose infusion rates were higher during hyperglycemia, but meal ingestion led to a decline in glucose requirements in both experiments (P < 0.0001). Insulin and C-peptide levels were higher during the hyperglycemic clamp experiments (P < 0.0001), whereas glucagon levels were higher during euglycemia (P < 0.0001). The postprandial increases in GIP and GLP-1 concentrations were 46 and 52% lower during the experiments with hyperglycemia (P = 0.0017 and P = 0.021). Hyperglycemia also elicited a significant delay in gastric emptying (P < 0.0001).

Conclusions: Hyperglycemia acutely reduces the postprandial levels of GIP and GLP-1, possibly through a deceleration of gastric emptying. This supports the concept that reduced incretin levels in some patients with type 2 diabetes are a consequence rather than a cause of type 2 diabetes.