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Predictors of Incretin Concentrations in Subjects With Normal, Impaired, and Diabetic Glucose Tolerance

¹ Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Germany
² Department of Medical Physiology, The Panum-Institute, University of Copenhagen, Denmark
³ Diabeteszentrum Bad Lauterberg, Germany

Address correspondence and reprint requests to Dr. Juris J. Meier, Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791 Bochum, Germany. E-mail: juris.meier{at}rub.de

Key Words: AUC, area under the curve • DPP-4, dipeptidyl peptidase IV • FFA, free fatty acid • GIP, gastric inhibitory polypeptide • GLP-1, glucagon-like peptide 1 • HOMA, homeostasis model assessment • IGT, impaired glucose tolerance

OBJECTIVE—Defects in glucagon-like peptide 1 (GLP-1) secretion have been reported in some patients with type 2 diabetes after meal ingestion. We addressed the following questions: 1) Is the quantitative impairment in GLP-1 levels different after mixed meal or isolated glucose ingestion? 2) Which endogenous factors are associated with the concentrations of GLP-1? In particular, do elevated fasting glucose or glucagon levels diminish GLP-1 responses?

RESEARCH DESIGN AND METHODS—Seventeen patients with mild type 2 diabetes, 17 subjects with impaired glucose tolerance, and 14 matched control subjects participated in an oral glucose tolerance test (75 g) and a mixed meal challenge (820 kcal), both carried out over 240 min on separate occasions. Plasma levels of glucose, insulin, C-peptide, glucagon, triglycerides, free fatty acids (FFAs), gastric inhibitory polypeptide (GIP), and GLP-1 were determined.

RESULTS—GIP and GLP-1 levels increased significantly in both experiments (P < 0.0001). In patients with type 2 diabetes, the initial GIP response was exaggerated compared with control subjects after mixed meal (P < 0.001) but not after oral glucose ingestion (P = 0.98). GLP-1 levels were similar in all three groups in both experiments. GIP responses were 186 ± 17% higher after mixed meal ingestion than after the oral glucose load (P < 0.0001), whereas GLP-1 levels were similar in both experiments. There was a strong negative association between fasting glucagon and integrated FFA levels and subsequent GLP-1 concentrations. In contrast, fasting FFA and integrated glucagon levels after glucose or meal ingestion and female sex were positively related to GLP-1 concentrations. Incretin levels were unrelated to measures of glucose control or insulin secretion.

CONCLUSIONS—Deteriorations in glucose homeostasis can develop in the absence of any impairment in GIP or GLP-1 levels. This suggests that the defects in GLP-1 concentrations previously described in patients with long-standing type 2 diabetes are likely secondary to other hormonal and metabolic alterations, such as hyperglucagonemia. GIP and GLP-1 concentrations appear to be regulated by different factors and are independent of each other.

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