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Impaired Incretin Response After a Mixed Meal Is Associated With Insulin Resistance in Nondiabetic Men

¹ Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden
² Molecular Endocrinology Laboratory, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K.
³ Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark
⁴ Department of Medicine, Lund University, Lund, Sweden

OBJECTIVE—To investigate whether features of the insulin resistance syndrome are associated with altered incretin responses to food intake.

RESEARCH DESIGN AND METHODS—From a population-based study, 35 men were recruited, representing a wide spectrum of insulin sensitivity and body weight. Each subject underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. A mixed meal was given, and plasma levels of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), as well as insulin, glucagon, and glucose were measured.

RESULTS—Insulin resistance was associated with impaired GIP and GLP-1 responses to a mixed meal. The total area under the curve (AUC) of the GIP response after the mixed meal was associated with insulin sensitivity (r = 0.54, P < 0.01). There was a significant difference between the highest and the lowest tertile of insulin sensitivity (P < 0.05). GLP-1 levels 15 min after food intake were significantly lower in the most insulin-resistant tertile compared with the most insulin-sensitive tertile. During the first hour, the AUC of GLP-1 correlated significantly with insulin sensitivity (r = 0.47, P < 0.01). Multiple linear regression analysis showed that insulin resistance, but not obesity, was an independent predictor of these decreased incretin responses.

CONCLUSIONS—In insulin resistance, the GIP and GLP-1 responses to a mixed meal are impaired and are related to the degree of insulin resistance. Decreased incretin responsiveness may be of importance for the development of impaired glucose tolerance.

Abbreviations: ANOVA, analysis of variance • AUC, area under the curve • CV, coefficients of variation • DPP-IV, dipeptidyl-peptidase IV • HOMA, homeostasis model assessment • GIP, gastric inhibitory polypeptide • GLP-1, glucagon-like peptide 1 • IGT, impaired glucose tolerance • MONICA, Monitoring of Trends and Determinants in Cardiovascular Disease • NEFA, nonesterified fatty acid • RIA, radioimmunoassay

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