| First Author | Wu X | Year | 2012 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 32 |
| Issue | 5 | Pages | 1236-45 |
| PubMed ID | 22328777 | Mgi Jnum | J:196940 |
| Mgi Id | MGI:5490217 | Doi | 10.1161/ATVBAHA.111.244525 |
| Citation | Wu X, et al. (2012) NOX4 pathway as a source of selective insulin resistance and responsiveness. Arterioscler Thromb Vasc Biol 32(5):1236-45 |
| abstractText | OBJECTIVE: Type 2 diabetes mellitus and related syndromes exhibit a deadly triad of dyslipoproteinemia, which leads to atherosclerosis; hyperglycemia, which causes microvascular disease; and hypertension. These features share a common, but unexplained, origin-namely, pathway-selective insulin resistance and responsiveness. Here, we undertook a comprehensive characterization of pathway-selective insulin resistance and responsiveness in liver and hepatocytes by examining 18 downstream targets of the insulin receptor, surveying the AKT, ERK, and NAD(P)H oxidase 4 pathways. METHODS AND RESULTS: Injection of insulin into hyperphagic, obese type 2 diabetic db/db mice failed to inactivate hepatic protein tyrosine phosphatase gene family members, a crucial action of NAD(P)H oxidase 4 previously thought to be required for all signaling through AKT and ERK. Insulin-stimulated type 2 diabetic livers unexpectedly produced an unusual form of AKT that was phosphorylated at Thr308 (pT308), with only weak insulin-stimulated phosphorylation at Ser473. Remarkably, knockdown or inhibition of NAD(P)H oxidase 4 in cultured hepatocytes recapitulated the entire complicated pattern of pathway-selective insulin resistance and responsiveness seen in vivo-namely, monophosphorylated pT308-AKT, impaired insulin-stimulated pathways for lowering plasma lipids and glucose, but continued lipogenic pathways and robust ERK activation. CONCLUSIONS: Functional disturbance of a single molecule, NAD(P)H oxidase 4, is sufficient to induce the key harmful features of deranged insulin signaling in type 2 diabetes mellitus, obesity, and other conditions associated with hyperinsulinemia and pathway-selective insulin resistance and responsiveness. |
