Diabetes Part III

Type 2 Diabetes Mellitus*

This represents a heterogeneous group of conditions that used to occur predominantly in adults, but it is now more frequently encountered in children and adolescents. More than 90% of all diabetic persons 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 (insulin resistance).

Pathophysiology**

Hyperglycemia is produced by lack of endogenous insulin, which is either absolute, as in type 1 diabetes mellitus, or relative, as in type 2 diabetes mellitus. Relative insulin deficiency usually occurs because of resistance to the actions of insulin in muscle, fat, and the liver and an inadequate response by the pancreatic beta cell. This pathophysiologic abnormality results in decreased glucose transport in muscle, elevated hepatic glucose production, and increased breakdown of fat.

The genetics of type 2 diabetes are complex and not completely understood, but presumably this disease is related to multiple genes (with the exception of maturity-onset diabetes of the young [MODY]). Evidence supports inherited components for both pancreatic beta cell failure and insulin resistance. Considerable debate exists regarding the primary defect in type 2 diabetes mellitus. Most patients have both insulin resistance and some degree of insulin deficiency. However, insulin resistance per se is not the sine qua non for type 2 diabetes mellitus because many people with insulin resistance (particularly patients who are obese) do not develop glucose intolerance. Therefore, insulin deficiency is necessary for the development of hyperglycemia. Patients may have high insulin levels, but the insulin concentrations are inappropriately low for the level of glycemia.

MODY is associated with autosomal dominant inheritance and is characterized by onset in at least 1 family member younger than 25 years, correction of fasting hyperglycemia without insulin for at least 2 years, and absence of ketosis. At least 6 genetically different types of MODY have been described. Some patients ultimately require insulin to control glycemia.

Recent work has suggested that elevated free fatty acids may be the driving force behind insulin resistance and perhaps even beta cell dysfunction. If this defect is more proximal than defects specifically related to glycemia, then therapies aimed at correcting this phenomenon would be highly beneficial.

Presumably, the defects of type 2 diabetes mellitus occur when a diabetogenic lifestyle (ie, excessive calories, inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype. The extent of excess weight may vary with different groups. For example, overweight patients from Asia may not be overweight by Western standards, but excess weight is often much more pronounced in these ethnic groups. Recent work suggests that in utero environment resulting in low birth weight may predispose some individuals to develop type 2 diabetes mellitus.

Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However, glycemia is much less related to macrovascular disease. Insulin resistance with concomitant lipid (ie, small dense low-density lipoprotein [LDL] particles, low high-density lipoprotein-cholesterol [HDL-C] levels, elevated triglyceride-rich remnant lipoproteins) and thrombotic (ie, elevated type-1 plasminogen activator inhibitor [PAI-1], elevated fibrinogen) abnormalities, as well as conventional atherosclerotic risk factors (eg, family history, smoking, hypertension, elevated low-density lipoprotein-cholesterol [LDL-C], low HDL-C), determine cardiovascular risk.

Increased cardiovascular risk appears to begin prior to the development of frank hyperglycemia, presumably because of the effects of insulin resistance. Stern in 1996 and Haffner and D'Agostino in 1999 developed the "ticking clock" hypothesis of complications, asserting that the clock starts ticking for microvascular risk at the onset of hyperglycemia, while the clock starts ticking for macrovascular risk at some antecedent point, presumably with the onset of insulin resistance.

Genetic and environmental factors combine to cause both the insulin resistance and the beta cell loss. 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 type 2 diabetes develops in one twin. Attempts to identify genes for type 2 diabetics that cause the insulin resistance and the beta cell failure have as yet been unsuccessful, although 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.

Early in the disease process, hyperplasia of pancreatic B cells occurs and probably accounts for the fasting hyperinsulinism and exaggerated insulin and proinsulin responses to glucose and other stimuli. With time, chronic deposition of amyloid in the islets may combine with inherited genetic defects progressively to impair B cell function.

Obesity is the most important environmental factor causing insulin resistance. The degree and prevalence of obesity varies among different racial groups with type 2 diabetes. 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.

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 by inhibiting glucose transport (acquired glucose toxicity). Correction of hyperglycemia reverses this acquired insulin resistance.

While many patients with type 2 diabetes present with increased urination and thirst, many others have an insidious onset of hyperglycemia and are asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after glycosuria or hyperglycemia is noted during routine laboratory studies. Occasionally, type 2 patients may present with evidence of neuropathic or cardiovascular complications because of occult disease present for some time prior to diagnosis. Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women. Diabetes should be suspected in women with chronic candidal vulvovaginitis as well as in those who have delivered large babies (> 9 lb, or 4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses.

Obese diabetics may have any variety of fat distribution; however, diabetes seems to be more often associated in both men and women with localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. Standardized tables of waist-to-hip ratio indicate that ratios of "greater than 0.9" in men and "greater than 0.8" in women are associated with an increased risk of diabetes in obese subjects. Mild hypertension is often present in obese diabetics. Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.

*Text/Info/Stats from CMDT 2008

**by KPL Ligaray, MD from WebMD