Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities.
Defects in insulin action and insulin secretion are both present in type 2 diabetes, and both are believed to be genetically predetermined. In the absence of a defect in beta-cell function, individuals can compensate indefinitely for insulin resistance with appropriate hyperinsulinemia, as observed even in obese populations such as the Pima Indians of Arizona. However, loss of beta-cell function leads eventually to the postprandial and fasting hyperglycemia that characterizes type 2 diabetes. This progression occurs despite initially effective antidiabetic therapies, a situation clearly demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS). External factors (access to high-calorie foods, lack of exercise, weight gain), the increased insulin requirements imposed by insulin resistance, and toxicities from hyperglycemia and elevated free fatty acids may all contribute to beta-cell deterioration. Free fatty acids, resistin, and tumor necrosis factor (TNF)-alpha potentially worsen the insulin resistance. beta-Cell dysfunction resulting from glucose toxicity and lipotoxicity is potentially reversible with restoration of metabolic control. Therefore, attention to these toxicities may delay the deterioration of beta-cell function and suggest new approaches to the management of type 2 diabetes.
LeRoith
Derek
D
Clinical Endocrinology Branch of the National Institutes of Health, Bethesda, Maryland, USA. leroith@comcast.net
D000273:Adipose Tissue / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008099:Liver / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000166:cytology / Q000503:physiopathology
D001786:Blood Glucose; D007328:Insulin