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The Pathophysiology of Diabetes Involves a Defective Amplification of the Late-Phase Insulin Response to Glucose by Glucose-Dependent Insulinotropic Polypeptide—Regardless of Etiology and Phenotype

Department of Internal Medicine F (T.V., F.K.K., T.K.), Gentofte Hospital, DK-2900 Hellerup, Denmark; Department of Medical Physiology (T.V., J.J.H.), The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Steno Diabetes Center (A.J., T.H., O.P.), DK 2820 Gentofte, Copenhagen, Denmark; Department of Endocrinology (S.M.), Hvidovre Hospital, DK-2650 Hvidovre, Denmark; and Department of Gastroenterology (S.L.), Glostrup Hospital, DK-2600 Glostrup, Denmark

Address all correspondence and requests for reprints to: Tina Vilsbøll, M.D., Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: tivi{at}gentoftehosp.kbhamt.dk.

The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20–120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m²); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1 gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7–36)amide/kg body weight·min or 4 pmol GIP pmol/kg body weight·min. The early-phase (0–20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20–120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.

This work was supported by the Danish Diabetes Association and the Novo Nordisk Foundation.

Abbreviations: AUC, Area under the curve; CP, chronic pancreatitis; FPG, fasting plasma glucose; GAD₆₅, glutamic acid decarboxylase; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; ICA, islet cell autoantibodies; LADA, latent autoimmune diabetes in adults; MODY, maturity-onset diabetes of the young; NS, not statistically significant; PG, plasma glucose.

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