Fatty Acid Oxidation and Insulin Action

Abstract

Type 2 diabetes is a disease of metabolic dysregulation involving impaired uptake and utilization of glucose, altered lipid metabolism, accumulation of various lipid species in the circulation and in tissues, and disruption of metabolic signaling pathways that regulate insulin secretion from pancreatic islet β-cells. Normal fuel homeostasis involves reciprocal regulation of glucose and lipid catabolism. Fundamental contributions to our understanding of the interplay between these two key groups of metabolic fuels came from the work of Randle (1), who demonstrated that increased rates of fatty acid oxidation in the fasted state lead to suppression of glucose oxidation and activation of gluconeogenesis, thereby preserving blood glucose for use by the brain and central nervous system. Conversely, the transition from the fasted to the fed state involves a coordinated shift from fatty acid to glucose oxidation. A key element in the latter switch, as elegantly demonstrated by the work of McGarry (2), is the glucose-induced rise in malonyl CoA, which inhibits fatty acid oxidation via direct binding to and allosteric inhibition of carnitine palmitoyltransferase-1 (CPT-1), the rate limiting enzyme for transport of cytosolic long-chain acyl CoA molecules into the mitochondria for oxidation. The multifaceted roles of malonyl CoA as a key glucose-derived metabolite, an allosteric inhibitor of fatty acid oxidation, and a biosynthetic precursor for fatty acid synthesis has led to a series of recent studies investigating the effects of manipulating this metabolite in various tissues. A bonus of such experiments is the opportunity to assess the physiological impact of enhanced or diminished fat oxidation in different cell types and in whole animals. In this issue of Diabetes …