Defining the Role of GLP-1 in the Enteroinsulinar Axis in Type 2 Diabetes (T2D) utilizing DPP-4 inhibition and GLP-1-Receptor Blockade

  1. Jörg Schirra1
  1. 1Department of Internal Medicine II, Clinical Research Unit, Clinical Center of the Ludwig-Maximilians University, Campus Großhadern, Munich, Germany
  2. 2The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Denmark
  1. Corresponding author: J Schirra, Email: Joerg.Schirra{at}


Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, 4-period, crossover study in 24 patients with T2D dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose lowering actions were tested after an oral glucose tolerance test (OGT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect. Glucagon was suppressed and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion. It attenuated insulinemia and the incretin effect. It accelerated GE. Under the GLP-1r antagonist the glucose-lowering effects of DPP-4 inhibition were reduced by about 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, while the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. So in this cohort of diabetic patients with a substantial incretin effect, GLP-1 contributed about 50% to the insulin excursion after an OGT both with and without DPP-4 inhibition. Thus, a significant DPP-4 sensitive glucose lowering mechanism contributes to glycemic control in diabetic patients that may be not mediated by circulating GLP-1.

  • Received September 20, 2013.
  • Accepted November 22, 2013.

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