Socs1 deficiency enhances hepatic insulin signaling.
Suppressor of cytokine signaling 1 (SOCS1) is an intracellular inhibitor of cytokine, growth factor, and hormone signaling. Socs1-/- mice die before weaning from a multiorgan inflammatory disease. Neonatal Socs1-/- mice display severe hypoglycemia and hypoinsulinemia. Concurrent interferon gamma gene deletion (Ifng-/-) prevented inflammation and corrected the hypoglycemia. In hyperinsulinemic clamp studies, however, Socs1-/- Ifng-/- mice had enhanced hepatic insulin sensitivity demonstrated by greater suppression of endogenous glucose production compared with controls with no difference in glucose disposal. Socs1-/- Ifng-/- mice had elevated liver insulin receptor substrate 2 expression (IRS-2) and IRS-2 tyrosine phosphorylation. This was associated with lower phosphoenolpyruvate carboxykinase mRNA expression. These effects were not associated with elevated hepatic AMP-activated protein kinase activity. Hepatic insulin sensitivity and IRS-2 levels play central roles in the pathogenesis of type 2 diabetes. Socs1 deficiency increases IRS-2 expression and enhances hepatic insulin sensitivity in vivo indicating that inhibition of SOCS1 may be a logical strategy in type 2 diabetes.
St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Emma
E
Jamieson
Mark M W
MM
Chong
Gregory R
GR
Steinberg
Valentina
V
Jovanovska
Barbara C
BC
Fam
Denise V R
DV
Bullen
Ye
Y
Chen
Bruce E
BE
Kemp
Joseph
J
Proietto
Thomas W H
TW
Kay
Sofianos
S
Andrikopoulos
D000818:Animals; D001786:Blood Glucose / Q000096:biosynthesis; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma