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Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients.

¹Department of Internal Medicine and C.N.R. Institute of Clinical Physiology, University of Pisa, Italy
^a C.N.R. Institute of Biochemical Engineering, Padova, Italy
^b Division of Internal Medicine, Spedali Riuniti, Pistoia, Italy
^c Department of Medical Physiology, Panum Institute, Copenhagen, Denmark

Objective: To quantitate the separate impact of obesity and hyperlycemia on the incretin effect, i.e. the gain in β-cell function after oral glucose vs intravenous glucose.

Research Design and Methods: Isoglycemic oral (75 g) and IV glucose administration was performed in 51 subjects (24 NGT, 17 IGT and 10 type 2 DM), with a wide range of BMI (20-61 kg^.m^–2). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (=slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral/IV ratio of responses. In 8 NGT and 10 DM, oral glucose appearance was measured by the double-tracer technique.

Results: The incretin effect on total insulin secretion and β-cell glucose sensitivity, and the GLP-1 response to oral glucose were significantly reduced in DM compared to NGT or IGT (p0.05). The results were similar when subjects were stratified by BMI tertile (p0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (=2-hour plasma glucose levels) and BMI (partial r =0.27-0.59, p0.05) in an independent, additive manner. Oral glucose appearance did not differ between DM and NGT, and was positively related to the GLP-1 response (r=0.53, p<0.01). Glucagon suppression during the OGTT was blunted in DM patients.

Conclusions: Potentiation of insulin secretion, glucose sensing, GLP-1 release, and glucagon suppression are physiological manifestations of the incretin effect. The incretin effect is impaired as an independent function of both glucose tolerance and obesity.

Key Words: Incretin effect • GLP-1 • GIP • glucose tolerance • obesity • insulin secretion • β-cell function.

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