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Departments of Internal Medicine F (T.V., T.K.), Gentofte Hospital; Medical Physiology (T.V., J.J.H.), The Panum Institute; Clinical Pharmacology (J.S.), Gentofte Hospital; Endocrinology (S.M.), Hvidovre Hospital, DK-2650 Copenhagen; Biostatistics (A.V.), Novo Nordisk A/S; and Assay and Cell Technology (A.G.J.), Novo Nordisk A/S, DK-2880 Bagsværd, Denmark
Address all correspondence and requests for reprints to: Tina Vilsbøll, M.D., Department of Internal Medicine F, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: tivi{at}gentoftehosp.kbhamt.dk.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. ß-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the ß-cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal.
This work was supported by the Danish Diabetes Association and the Novo Nordisk A/S Foundation.
Abbreviations: AUC, Area under the curve; BMI, body mass index; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide; ISR, insulin secretion rate.
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