Glucose-fatty acid interactions in health and disease.
It is widely held that although obesity and type 2 diabetes are polygenic in origin, the primary defect causing both conditions is insulin resistance, which in turn gives rise to a constellation of other abnormalities, including hyperinsulinemia, dyslipidemia, glucose intolerance, and (in the genetically predisposed) frank hyperglycemia. Explored here is an alternative, albeit speculative, scenario in which hyperinsulinemia and insulin resistance arise either simultaneously or sequentially from some preexisting defect within the leptin signaling pathway. In either case, a central component of the model is that the breakdown of glucose homeostasis that is characteristic of the condition of obesity with type 2 diabetes is secondary to disturbances in lipid dynamics. The possibility is raised that abnormally high concentrations of malonyl-CoA in liver and skeletal muscle suppress the activity of mitochondrial carnitine palmitoyltransferase I and thus fatty acid oxidation 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 liver) interferes with glucose transport or metabolism or both, producing insulin resistance. Elevated circulating concentrations of fatty acids are also implicated in the etiology of type 2 diabetes by virtue of 1) their powerful acute insulinotropic effect, 2) their ability to exacerbate insulin resistance in muscle, and 3) their long-term detrimental action on pancreatic beta-cell function.
McGarry
J D
JD
Department of Internal Medicine, University of Texas, Southwestern Medical Center at Dallas, 75235-9135, USA. nparke@mednet.swmed.edu
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D009132:Muscles / Q000737:chemistry / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism
D004040:Dietary Carbohydrates; D004041:Dietary Fats; D005227:Fatty Acids; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose