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

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 (beta-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1 alpha [RIP-DN HNF-1 alpha (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 center dot pmol(-1)center dot 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 alpha mice is not compensated with increased insulin sensitivity.