Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice

J Clin Invest. 2004 Jan;113(1):96-105. doi: 10.1172/JCI17763.


Liver IGF-1-deficient (LID) mice have a 75% reduction in circulating IGF-1 levels and, as a result, a fourfold increase in growth hormone (GH) secretion. To block GH action, LID mice were crossed with GH antagonist (GHa) transgenic mice. Inactivation of GH action in the resulting LID + GHa mice led to decreased blood glucose and insulin levels and improved peripheral insulin sensitivity. Hyperinsulinemic-euglycemic clamp studies showed that LID mice exhibit severe insulin resistance. In contrast, expression of the GH antagonist transgene in LID + GHa mice led to enhanced insulin sensitivity and increased insulin-stimulated glucose uptake in muscle and white adipose tissue. Interestingly, LID + GHa mice exhibit a twofold increase in white adipose tissue mass, as well as increased levels of serum-free fatty acids and triglycerides, but no increase in the triglyceride content of liver and muscle. In conclusion, these results show that despite low levels of circulating IGF-1, insulin sensitivity in LID mice could be improved by inactivating GH action, suggesting that chronic elevation of GH levels plays a major role in insulin resistance. These results suggest that IGF-1 plays a role in maintaining a fine balance between GH and insulin to promote normal carbohydrate and lipid metabolism.

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Body Weight
  • Glucose Clamp Technique
  • Growth Hormone / antagonists & inhibitors*
  • Growth Hormone / metabolism
  • Insulin / physiology*
  • Insulin-Like Growth Factor I / deficiency*
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / physiology
  • Liver / drug effects
  • Liver / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Organ Size
  • Reference Values
  • Somatomedins / metabolism


  • Blood Glucose
  • Insulin
  • Somatomedins
  • Insulin-Like Growth Factor I
  • Growth Hormone