symptoms of type 2 diabetes

B. Type 2 Diabetes
This represents a heterogeneous group comprising milder forms of diabetes that occur predominantly in adults but occasionally in juveniles. More than 90% of all diabetics in the United States are included under this classification. Circulating endogenous insulin is sufficient to prevent ketoacidosis but is inadequate to prevent hyperglycemia in the face of increased needs owing to tissue insensitivity. In most cases of this type of diabetes, the cause is unknown.
Tissue insensitivity to insulin has been noted in most type 2 patients irrespective of weight and has been attributed to several interrelated factors. These include a putative (and as yet undefined) genetic factor, which is aggravated in time by additional enhancers of insulin resistance such as aging, a sedentary lifestyle, and abdominal-visceral obesity. In addition, there is an accompanying deficiency in the response of pancreatic B cells to glucose. Both the tissue resistance to insulin and the impaired B cell response to glucose appear to be further aggravated by increased hyperglycemia (glucose toxicity), and both defects are ameliorated by treatment that reduces the hyperglycemia toward normal. Most epidemiologic data indicate strong genetic influences, since in monozygotic twins over 40 years of age, concordance develops in over 70% of cases within a year whenever one twin develops type 2 diabetes. Attempts to identify genetic markers for type 2 have as yet been unsuccessful, though linkage to a gene on chromosome 2 encoding a cysteine protease, calpain-10, has been reported in a Mexican-American population. However, its association with other ethnic populations and any role it plays in the pathogenesis of type 2 diabetes remain to be clarified.
Two subgroups of patients are currently distinguished by the absence or presence of obesity. The degree and prevalence of obesity varies among different racial groups. While obesity is apparent in no more than 30% of Chinese and Japanese patients with type 2, it is found in 60-70% of North Americans, Europeans, or Africans with type 2 and approaches 100% of patients with type 2 among Pima Indians or Pacific Islanders from Nauru or Samoa.
1. Obese type 2 patients —
Patients with this most common form of diabetes have an insensitivity to endogenous insulin. When an associated defect of insulin production prevents adequate compensation for this insulin resistance, nonketotic mild diabetes occurs. Hyperplasia of pancreatic B cells is often present and probably accounts for the fasting hyperinsulinism and exaggerated insulin and proinsulin responses to glucose and other stimuli seen early in the disease. After several years' duration of diabetes, chronic deposition of amyloid in the islets may combine with inherited genetic defects to progressively impair B cell function.
The mechanisms underlying the insulin resistance of type 2 diabetes are poorly understood. Obesity is generally associated with abdominal distribution of fat, producing an abnormally high waist-to-hip ratio. This "visceral" obesity, due to accumulation of fat in the omental and mesenteric regions, correlates with insulin resistance; subcutaneous abdominal fat seems to have less of an association with insulin insensitivity. Exercise may affect the deposition of visceral fat as suggested by CT scans of Japanese wrestlers, whose extreme obesity is predominantly subcutaneous. Their daily vigorous exercise program prevents accumulation of visceral fat, and they have normal serum lipids and euglycemia despite daily intakes of 5000-7000 kcal and development of massive subcutaneous obesity. Several adipokines, secreted by fat cells, can affect insulin action in obesity. Two of these, leptin and adiponectin, seem to increase sensitivity to insulin, presumably by increasing hepatic responsiveness. Two others — tumor necrosis factor-a, which inactivates insulin receptors, and the newly discovered peptide resistin — interfere with insulin action on glucose metabolism and have been reported to be elevated in obese animal models. Mutations or abnormal levels of these adipokines may contribute to the development of insulin resistance in human obesity.
Hyperglycemia per se can impair insulin action by causing accumulation of hexosamines in muscle and fat tissue and inhibiting glucose transport (acquired glucose toxicity). Correction of hyperglycemia reverses this acquired insulin resistance.
2. Nonobese type 2 patients —
These patients generally show an absent or blunted early phase of insulin release in response to glucose; however, it can be elicited in response to other insulinogenic stimuli such as acute intravenous administration of sulfonylureas, glucagon, or arginine.
Although insulin resistance may be detected with special tests, it does not seem to be clinically relevant to the treatment of most nonobese type 2 patients, who generally respond to appropriate therapeutic supplements of insulin in the absence of rare associated conditions such as lipoatrophy or acanthosis nigricans.
Among this heterogeneous subgroup of patients with nonobese type 2 diabetes, the majority are idiopathic. However, with increasing frequency, a variety of etiologic genetic abnormalities have been documented in a subset of these patients who have recently been reclassified within a group designated "other specific types." (current MD&T 2005)