Journal
GENES & DEVELOPMENT
Volume 16, Issue 24, Pages 3213-3222Publisher
COLD SPRING HARBOR LAB PRESS
DOI: 10.1101/gad.1034802
Keywords
lipoatrophic diabetes; adipogenesis; leptin; insulin receptor substrate
Categories
Funding
- NIDDK NIH HHS [DK 42816, K08 DK002885, R01 DK033201, DK 02885-K08, DK 33201, R01 DK042816, R56 DK042816, P30 DK057521] Funding Source: Medline
Ask authors/readers for more resources
Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. However, in contrast to other models of lipoatrophic diabetes, there was no accumulation of fat in liver or muscle. Furthermore, plasma leptin levels were markedly decreased, and adenovirus-mediated expression of leptin in liver reversed the hyperglycemia and hyperinsulinemia. The results indicate that IRS-1 and IRS-3 play important complementary roles in adipogenesis and establish the Irs1(-/-)/Irs3(-/-) double knockout mouse as a novel model of lipoatrophic diabetes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available