Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

  1. Filip K. Knop1,2
  1. 1Center for Diabetes Research, Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark;
  2. 2Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;
  3. 3Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy;
  4. 4Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;
  5. 5Department of Cardiology, Nephrology and Endocrinology, Hillerød Hospital, University of Copenhagen, Hillerød, Denmark;
  6. 6Department of Medicine, Herlev Hospital, University of Copenhagen, Copenhagen;
  7. 7Clinical Metabolomics Core Facility, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  1. Corresponding Author: Mikkel Christensen, E-mail: mch{at}


Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic and glucagon-like peptide 1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM).

Ten male subjects with T1DM (C-peptide negative, age: 26±1 years (mean±SEM); BMI: 24±0.5 kg/m2; HbA1c 7.3±0.2%) were studied in a randomized, double-blinded, cross-over study, with 2-hour iv administration of saline, GIP or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a ‘recovery phase’.

During the recovery phase GIP infusions elicited larger glucagon responses (164±50 (GIP) vs. 23±25 (GLP-1) vs. 17±46 (saline) min×pmol/l, P<0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 as compared to saline (P<0.02). On the GIP days significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/l (155±36 (GIP) vs. 232±40 (GLP-1) vs. 212±56 (saline) mg×kg-1, P<0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days.

Our results suggest that during hypoglycemia in patients with T1DM exogenous GIP increases glucagon responses during the ‘recovery phase’ after hypoglycemia and reduces the need for glucose administration.

  • Received March 18, 2014.
  • Accepted July 14, 2014.

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