Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice.
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.
Laustsen
Palle G
PG
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Michael
M Dodson
MD
Crute
Barbara E
BE
Cohen
Shmuel E
SE
Ueki
Kohjiro
K
Kulkarni
Rohit N
RN
Keller
Susanna R
SR
Lienhard
Gustav E
GE
Kahn
C Ronald
CR
D000256:Adenoviridae; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003923:Diabetes Mellitus, Lipoatrophic / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D006946:Hyperinsulinism / Q000209:etiology / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000502:physiology*; D014162:Transfection; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C108872:Irs3 protein, mouse; C491531:Irs4 protein, mouse; D020738:Leptin; D010750:Phosphoproteins; D014280:Triglycerides; D005947:Glucose