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Diabetes - Diagnosis and Evaluation The pathogenesis of type 2 diabetes mellitus (formerly referred to as non-insulin-dependent diabetes) is not completely understood, but both genetic and environmental factors are involved. In genetically predisposed persons, the change in glucose metabolism from a state of normal glucose tolerance to type 2 diabetes is characterized by the development of insulin resistance, overproduction of hepatic glucose, glucose intolerance, and impaired pancreatic beta cell function. Diet and physical inactivity also contribute to these adverse metabolic changes.
Insulin resistance Insulin resistance is a pathophysiologic feature of type 2 diabetes that is also common to the clinical syndromes of obesity, hypertension, and atherosclerosis. Broadly speaking, insulin resistance is diminished effectiveness of insulin in lowering blood sugar levels; when it is present, steady-state plasma glucose levels are higher than expected for the existing insulin level. Because the precise mechanisms of insulin action are not clear, insulin resistance is difficult to quantify; one method, however, is to determine the rate of glucose infusion required to maintain normoglycemia within a predetermined range during a constant-rate infusion of insulin.Numerous changes in organ and cell function contribute to insulin resistance. Several mechanisms have been proposed: At the cellular level, these include prereceptor abnormalities (defects in insulin molecules or insulin antibodies that are present before insulin interacts with receptors); deficiencies in glucose transporter (GLUT) molecules; and abnormalities in postreceptor signal transduction involving tyrosine kinase. In addition, insulin resistance may be mediated by excessive adipose tissue production of nonesterified fatty acids, which serve as energy substrates for muscle and stimluate gluconeogenesis. Plasma concentrations of nonesterified fatty acids have been shown to be elevated in persons who are obese or have type 2 diabetes. Insulin resistance is expressed in theliver through overproduction of glucose and in peripheral tissues through impaired utilization of glucose by the skeletal msucle and adipose tissue. Insulin resistance appears to be a metabolic precursor of type 2 diabetes. Metabolic abnormalities – including defects in insulin activation of the enzyme glycogen synthase in skeletal muscles and impaired suppression of lipolysis – have been demonstrated in healthy, first-degree relatives of patients with type 2 diabetes.
Beta cell dysfunction In addition to insulin resistance, other metabolic abnormalities nay occur early in the course of type 2 diabetes, perhaps even before the onset of hyperglycemia. Abnormalities in pancreatic beta cell function are progressive and are manifested by changes in insulin secretion. During intravenous glucose challenge in normal subjects, insulin is secreted in two phases: The first facilitates the immediate disposal of glucose to prevent postprandial hyperglycemia and lasts about 10 minutes; the second persists throughout glucose stimulation. Loss of first-phase insulin secretion occurs early in the pathogenesis of type 2 diabetes. Disease progression is marked by impairment of both phases of glucose-stimulated insulin secretion. Insulin responses to secretagogues other than glucose may, however, remain intact.Other abnormalities in pancreatic beta cell function include increases in the ratio of proinsulin to insulin, accumulation of amyloid within the islet cells, defects in insulin secretory responses to nonglucose stimuli, and changes in pulsatile insulin secretion. In patients with type 2 diabetes, first-phase insulin secretion may be improved and the ratio of proinsulin to insulin may revert to normal with tight glycemic control. However, there is no evidence that glycemic control can improve other pancreatic beta cell defects. Beta cell dysfunction is thought to be genetically predetermined in some subpopulations. Vaag and colleagues found a high condordance rate for hypoinsulinemia in non-diabetic identical twins of patients with type 2 diabetes. Mutations in the gene for glucokinase (an enzyme that catalyzed the first rate-limiting step in beta cell glucose metabolism) have been found in some patients with a rare condition known as maturity onset diabetes of the young. Also, genetic mutations in the sulfonylurea receptor in beta cells have been associated with familial hyperinsulinism or an increased risk for type 2 diabetes.
Table 1. New diagnostic criteria for diabetes
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