Beta-Cell-Targeted Expression of a Dominant-Negative Mutant of Hepatocyte Nuclear Factor-1α in Mice

Diabetes Model with β-Cell Dysfunction Partially Rescued by Nonglucose Secretagogues

  1. Maria Sörhede Winzell1,
  2. Giovanni Pacini2,
  3. Claes B. Wollheim3 and
  4. Bo Ahrén1
  1. 1Department of Medicine, Lund University, SE-221 84 Lund, Sweden
  2. 2Metabolic Unit, Institute of Biomedical Engineering (ISIB), National Research Council (CNR), Padova, Italy
  3. 3Experimental Diabetology Group, Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland
  1. Address correspondence and reprint requests to Dr. Bo Ahrén, Department of Medicine, Lund University, B11 BMC, SE-221 84 Lund, Sweden. E-mail: bo.ahren{at}med.lu.se

Abstract

We studied islet function in mice with β-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1α. At age 2–3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In other tests, the 5-min insulin response to intravenous arginine was impaired by 79% (P = 0.032) and the 15-min insulin response to gastric glucose was suppressed by 97% (P = 0.006). In islets incubated for 60 min, the insulin response to glucose (3.3–22.2 mmol/l) was impaired by >80% in transgenic mice. In contrast, insulin responses to nonglucose secretagogues were only partially suppressed (to GLP-1 [100 nmol/l] by 40%, to carbachol [1 μmol/l] by 20%, and to palmitate [0.5 mmol/l] by 15%), whereas the response to depolarization by KCl (50 mmol/l) was not reduced. Finally, the IVGTT data insulin sensitivity in transgenic mice was not significantly different from that of wild-type mice. Thus, mice with targeted suppression of β-cell HNF-1α represent a good diabetes model exhibiting severely impaired insulin secretion after glucose with marked glucose intolerance. In contrast, the insulin responses to nonglucose stimuli are not suppressed when the islet insulin content is taken into account.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 25, 2004.
    • Received March 11, 2004.
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