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A Novel Approach to Assess Insulin Sensitivity Reveals No Increased Insulin Sensitivity in Mice with a Dominant-Negative Mutant Hepatocyte Nuclear Factor-1{alpha}

Ahrén, Bo LU and Pacini, G (2006) In American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 291(1). p.131-137
Abstract
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 (SI) by this technique showed good correlation to SI 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... (More)
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 (SI) by this technique showed good correlation to SI 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 SI 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{alpha} mice is not compensated with increased insulin sensitivity. (Less)
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author
and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
glucose tolerance, minimal modeling, insulin action, diazoxide, glucose effectiveness
in
American Journal of Physiology: Regulatory, Integrative and Comparative Physiology
volume
291
issue
1
pages
131 - 137
publisher
American Physiological Society
external identifiers
  • wos:000238121800016
  • pmid:16469839
  • scopus:33745726557
ISSN
0363-6119
DOI
10.1152/ajpregu.00519.2005
language
English
LU publication?
yes
id
96b68ae9-2c94-4070-bed0-61dc6a154fb6 (old id 153577)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16469839&dopt=Abstract
date added to LUP
2016-04-01 16:10:24
date last changed
2020-12-15 03:07:07
@article{96b68ae9-2c94-4070-bed0-61dc6a154fb6,
  abstract     = {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 (SI) by this technique showed good correlation to SI from a regular intravenous glucose tolerance test (r = 0.87; P &lt; 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 SI 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{alpha} mice is not compensated with increased insulin sensitivity.},
  author       = {Ahrén, Bo and Pacini, G},
  issn         = {0363-6119},
  language     = {eng},
  number       = {1},
  pages        = {131--137},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Regulatory, Integrative and Comparative Physiology},
  title        = {A Novel Approach to Assess Insulin Sensitivity Reveals No Increased Insulin Sensitivity in Mice with a Dominant-Negative Mutant Hepatocyte Nuclear Factor-1{alpha}},
  url          = {http://dx.doi.org/10.1152/ajpregu.00519.2005},
  doi          = {10.1152/ajpregu.00519.2005},
  volume       = {291},
  year         = {2006},
}