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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2078-2084
Copyright © 2004 by The Endocrine Society

Inhibition of Dipeptidyl Peptidase-4 Reduces Glycemia, Sustains Insulin Levels, and Reduces Glucagon Levels in Type 2 Diabetes

Bo Ahrén, Mona Landin-Olsson, Per-Anders Jansson, Maria Svensson, David Holmes and Anja Schweizer

Department of Medicine (B.A., M.L.-O.), Lund University B11 Biomedical Centre, SE-21184 Lund, Sweden; Department of Medicine (P.-A.J.), Göteborg University, SE-41345 Göteborg, Sweden; Department of Medicine (M.S.), Umeå University, SE-90185 Umeå, Sweden; and Novartis Pharmaceuticals (D.H., A.S.), CH4002 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Bo Ahrén, Department of Medicine, B11 Biomedical Centre, SE-221 84 Lund, Sweden.

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 ± 8 yr (SD), body mass index: 27.3 ± 3.3 kg/m2, fasting plasma glucose: 9.0 ± 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 ± 8 pg/ml before treatment vs. 77 ± 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.

This work was supported by Swedish Research Council Grant 6834, Lund University Hospital and the Faculty of Medicine (Lund, Sweden), and Novartis Pharmaceuticals (Basel, Switzerland).

Abbreviations: DPP, Dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated hemoglobin; LAF237, (1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine); NS, not significant; PACAP, pituitary adenylate cyclase activating polypeptide.




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