Beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor-1alpha in mice: diabetes model with beta-cell dysfunction partially rescued by nonglucose secretagogues.
We studied islet function in mice with beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1alpha. 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 micromol/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 beta-cell HNF-1alpha 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.
Winzell
Maria Sörhede
MS
Department of Medicine, Lund University, B11 BMC, SE-221 84 Lund, Sweden.
Pacini
Giovanni
G
Wollheim
Claes B
CB
Ahrén
Bo
B
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005799:Genes, Dominant; D005947:Glucose / Q000494:pharmacology; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D019308:Palmitic Acid / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D014157:Transcription Factors / Q000235:genetics*
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D019308:Palmitic Acid; D011189:Potassium Chloride; D002217:Carbachol; D001120:Arginine; D005947:Glucose