The Role of Endogenous Incretin Secretion as Amplifier of Glucose-Stimulated Insulin Secretion in Healthy Subjects and Patients With Type 2 Diabetes

  1. Jörg Schirra
  1. Department of Internal Medicine II, Clinical Research Unit, Clinical Center of the Ludwig-Maximilians-University, Campus Großhadern, Munich, Germany
  1. Corresponding author: Jörg Schirra, joerg.schirra{at}
  1. H.J.W. and L.C. contributed equally to this work.


In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non–GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.

  • Received December 10, 2011.
  • Accepted March 23, 2012.

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  1. Diabetes vol. 61 no. 9 2349-2358
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