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Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients

¹ Department of Internal Medicine and Consiglio Nazionale delle Ricerche (CNR) Institute of Clinical Physiology, University of Pisa, Italy
² CNR Institute of Biochemical Engineering, Padova, Italy
³ Division of Internal Medicine, Spedali Riuniti, Pistoia, Italy
⁴ Department of Medical Physiology, Panum Institute, Copenhagen, Denmark

Corresponding author: Ele Ferrannini, MD, Department of Internal Medicine, Via Roma, 67, 56122 Pisa, Italy. E-mail: ferranni{at}ifc.pi.cnr.it

Abbreviations: AUC, area under the time concentration curve; FFM, fat-free mass; GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; TTR, tracer-to-tracee ratio

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 versus intravenous glucose).

RESEARCH DESIGN AND METHODS—Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20–61 kg/m²). 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-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, 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 diabetes compared with NGT or IGT (P 0.05). The results were similar when subjects were stratified by BMI tertile (P 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27–0.59, P 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients.

CONCLUSIONS—Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.

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