Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice.
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.
Yakar
Shoshana
S
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda Maryland 20892-1758, USA.
Setser
Jennifer
J
Zhao
Hong
H
Stannard
Bethel
B
Haluzik
Martin
M
Glatt
Vaida
V
Bouxsein
Mary L
ML
Kopchick
John J
JJ
LeRoith
Derek
D
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight; D015309:Glucose Clamp Technique; D013006:Growth Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size; D012016:Reference Values; D013002:Somatomedins / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone