GLUCOSE FATTY-ACID INTERACTIONS IN HEALTH AND DISEASE

It is widely held that although obesity and type 2 diabetes are polyge nic in origin, the primary defect causing both conditions is insulin r esistance? which in turn gives rise to a constellation of other abnorm alities, including hyperinsulinemia, dyslipidemia, glucose intolerance , and (in the genetically predisposed) frank hyperglycemia. Explored h ere is an alternative, albeit speculative, scenario in which hyperinsu linemia and insulin resistance arise either simultaneously or sequenti ally from some preexisting defect within the leptin signaling pathway. Ln either case? a central component of the model is that the breakdow n of glucose homeostasis that is characteristic of the condition of ob esity with type 2 diabetes is secondary to disturbances in lipid dynam ics. The possibility is raised that abnormally high concentrations of malonyl-CoA in liver and skeletal muscle suppress the activity of mito chondrial carnitine palmi toyltransferase I and thus fatty acid oxidat ion in both sites. It is suggested that the buildup of fat within the muscle cell (caused in part by excessive delivery of VLDLs from the li ver) interferes with glucose transport or metabolism or both, producin g insulin resistance. Elevated circulating concentrations of fatty aci ds are also implicated in the etiology of type 2 diabetes by virtue of 1) their powerful acute insulinotropic effect, 2) their ability to ex acerbate insulin resistance in muscle, and 3) their long-term detrimen tal action on pancreatic beta-cell function.