KNOXing on the Door of Selective Insulin Resistance

Abstract

Insulin controls systemic nutrient homeostasis by promoting anabolic processes in various tissues, including the stimulation of glucose influx (into muscle and adipose), protein and glycogen synthesis (in muscle and liver), lipid synthesis and storage (in liver and adipose), and the inhibition of fatty acid oxidation, glycogenolysis, gluconeogenesis, and apoptosis and autophagy (especially in a damaged heart).1–3 Resistance to the action of insulin is associated with chronic physiological and inflammatory stress that develops during obesity and inactivity. In too many instances it progresses to type 2 diabetes mellitus when compensatory hyperinsulinemia fails to maintain glucose homeostasis. A combination of compensatory hyperinsulinemia and inconsistent levels of insulin resistance across body tissues can cause life-threatening sequela, especially nonalcoholic fatty liver disease and atherosclerosis.3,4 Thus, dissection of the insulin signaling pathways and the molecular mechanisms of tissue-specific insulin resistance might reveal novel strategies to arrest or reverse the progression of metabolic disease. See accompanying article on page 1236 Cell-based studies initiated decades ago and extended most recently with mouse genetics reveal a common insulin signaling cascade that begins by activation of the insulin receptor tyrosine kinase (IR) and propagates through the insulin receptor substrates (IRS1 and IRS2) to the phosphatidyl inositol 3 kinase→ v-akt murine thymoma viral oncogene homolog (AKT) cascade 1. AKT plays a particularly broad role as it phosphorylates many protein substrates—including the direct phosphorylation and inactivation of FoxO (forkhead box protein O1 family of transcription factors, FoxO1 and FoxO3) and the indirect phosphorylation of CRTC2 (cAMP response element binding protein–regulated transcription coactivator 2) that inactivates cAMP response element binding protein. Inactivation of these factors suppresses the expression of many hepatic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase that promote gluconeogenesis (Figure).5,6 Genetic disruption of hepatic insulin signaling by the ablation of the …