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Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1–deficient mice
Shoshana Yakar, … , John J. Kopchick, Derek LeRoith
Shoshana Yakar, … , John J. Kopchick, Derek LeRoith
Published January 1, 2004
Citation Information: J Clin Invest. 2004;113(1):96-105. https://doi.org/10.1172/JCI17763.
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Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1–deficient mice

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Abstract

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.

Authors

Shoshana Yakar, Jennifer Setser, Hong Zhao, Bethel Stannard, Martin Haluzik, Vaida Glatt, Mary L Bouxsein, John J. Kopchick, Derek LeRoith

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LID mice expressing the GHa transgene exhibit enhanced insulin sensitivi...
LID mice expressing the GHa transgene exhibit enhanced insulin sensitivity. (a) Blood glucose levels were measured in the fed state in control, LID, GHa, and LID + GHa mice. (b) Serum insulin levels were measured in the fed state in the four genotypes. (c) Insulin tolerance tests were performed on the four genotypes of mice, as described in Methods. Results are expressed as the mean percentage of basal blood glucose concentration ± SEM. (*P < 0.05 compared with control; #P < 0.05 compared with GHa.)

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