IRS1-independent defects define major nodes of insulin resistance.
Insulin resistance is a common disorder caused by a wide variety of physiological insults, some of which include poor diet, inflammation, anti-inflammatory steroids, hyperinsulinemia, and dyslipidemia. The common link between these diverse insults and insulin resistance is widely considered to involve impaired insulin signaling, particularly at the level of the insulin receptor substrate (IRS). To test this model, we utilized a heterologous system involving the platelet-derived growth factor (PDGF) pathway that recapitulates many aspects of insulin action independently of IRS. We comprehensively analyzed six models of insulin resistance in three experimental systems and consistently observed defects in both insulin and PDGF action despite a range of insult-specific defects within the IRS-Akt nexus. These findings indicate that while insulin resistance is associated with multiple deficiencies, the most deleterious defects and the origin of insulin resistance occur independently of IRS.
Hoehn
Kyle L
KL
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
Hohnen-Behrens
Cordula
C
Cederberg
Anna
A
Wu
Lindsay E
LE
Turner
Nigel
N
Yuasa
Tomoyuki
T
Ebina
Yousuke
Y
James
David E
DE
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006946:Hyperinsulinism / Q000209:etiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015151:Immunoblotting; D007249:Inflammation; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D010168:Palmitates / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010168:Palmitates; D010982:Platelet-Derived Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt