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

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

¹ Department of Medicine, Lund University, SE-221 84 Lund, Sweden
² Metabolic Unit, Institute of Biomedical Engineering (ISIB), National Research Council (CNR), Padova, Italy
³ Experimental Diabetology Group, Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland

We studied islet function in mice with ß-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1. 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 ß-cell HNF-1 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.

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