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Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients

Department of Endocrinology, Hvidovre Hospital, University of Copenhagen (M.-B.T.-N., M.B.D., S.M.), DK-2650 Hvidovre, Denmark; Department of Medical Physiology, Panum Institute, University of Copenhagen (M.-B.T.-N., J.J.H.), DK-2200 Copenhagen N, Denmark; Department of Clinical Chemistry, Rigshospitalet, University of Copenhagen (L.M.H.), DK-2100 Copenhagen Ø, Denmark; Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biochemical Research (T.E.H.), Summit, New Jersey 08901; and Department of Diabetes Autoimmunity, Hagedorn Research Institute (B.K.M.), DK-2820 Gentofte, Denmark

Address all correspondence and requests for reprints to: Jens Juul Holst, M.D., Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: holst{at}mfi.ku.dk

Abstract

To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucose- dependent insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0–240 min after the start of the meal was significantly decreased in the patients (2482 ± 145 compared with 3101 ± 198 pmol/liter·240 min; P = 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucose-dependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.

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