The role of pathway-selective insulin resistance and responsiveness in diabetic dyslipoproteinemia.

OBJECTIVE

Type 2 diabetes mellitus (T2DM) 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 (SEIRR). Here, we review recent work on hepatic SEIRR indicating that deranged insulin signaling may have a remarkably simple molecular basis.

RESULTS

Comprehensive examination of a set of 18 insulin targets revealed that T2DM liver in vivo exhibits a specific defect in the ability of the NAD(P)H oxidase 4 (NOX4) to inactivate protein tyrosine phosphatase gene family members after stimulation with insulin, and that impairment of this single molecule, NOX4, in cultured hepatocytes recapitulates all features of hepatic SEIRR in vivo. These features include insulin-stimulated generation of an unusual monophosphorylated form of AKT at Thr308 (pT308-AKT) with only weak phosphorylation at Ser473, impaired insulin-stimulated pathways for lowering plasma levels of lipids and glucose, but continued lipogenic pathways and robust extracellular signal-regulated kinase activation. This new study, in combination with important prior work, provides clues to several long-standing mysteries, such as how AKT might regulate lipid-lowering and glucose-lowering pathways that become insulin-resistant but also lipogenic pathways that remain insulin-responsive, as well as a potential role for NOX4 in insulin-stimulated generation of oxysterol ligands for LXR, a key lipogenic factor.

CONCLUSIONS

These findings suggest a unified molecular explanation for fatty liver, atherogenic dyslipoproteinemia, hyperglycemia, and hence accelerated atherosclerosis and microvascular disease in T2DM, obesity, and related syndromes of positive caloric imbalance.