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This Article Full Text Full Text (PDF) All Versions of this Article: 291/1/R131    most recent 00519.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ahrén, B. Articles by Pacini, G. Search for Related Content PubMed PubMed Citation Articles by Ahrén, B. Articles by Pacini, G.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

A novel approach to assess insulin sensitivity reveals no increased insulin sensitivity in mice with a dominant-negative mutant hepatocyte nuclear factor-1

¹Department of Medicine, Lund University, Lund, Sweden; and ²Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy

Submitted 18 July 2005 ; accepted in final form 30 January 2006

In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index (S_I) by this technique showed good correlation to S_I from a regular intravenous glucose tolerance test (r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter (-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1 [RIP-DN HNF-1 (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that S_I was the same in the two groups (0.78 ± 0.21 x 10^–4 min·pmol^–1·l^–1 in WT vs. 0.60 ± 0.11 in Tg; P = 0.45) as was the glucose elimination rate (P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-1 mice is not compensated with increased insulin sensitivity.

glucose effectiveness; glucose tolerance; minimal modeling; diazoxide; insulin action