The National Diabetes Data Group and World Health Organization (W.H.O) have issued diagnostic criteria for DM based on the following premises:
(1) The spectrum of fasting plasma glucose (FPG) and the response to an oral glucose load varies among normal individuals.
(2) Random testing is defined as without regard to time since the last meal.
(3) Fasting is defined as no caloric intake for at least 8 h.
The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water; not recommended for routine clinical use.
Note: In the absence of unequivocal hyperglycemia and acute metabolic decompositions, these criteria should be confirmed by repeating testing on a different day.
Criteria for the Diagnosis of Diabetes Mellitus;
I. Symptoms of diabetes mellitus plus random blood glucose concentration mmol/L (200 mg/dL) or
II. Fasting plasma glucose of 7.0 mmol /l (126 mg/dl) or
III. Two-hour plasma glucose =11 .1 mmol /l (200 mg/dl) during an oral glucose tolerance test.
Insulin resistance and abnormal insulin secretion are central to the development of type 2 DM. Although controversy remains regarding the primary defect, most studies support the view that insulin resistance precedes insulin secretory defects and that diabetes develops only if insulin secretion becomes inadequate.
Genetic considerations: Type 2 DM has a strong genetic component:
- Major genes that predispose to this disorder have yet to be identified, but it is clear that the disease is polygenic and multifactorial.
- Various genetic loci contribute to susceptibility and environmental factors such as nutrition and physical activity further modulate phenotypic expression of the disease. The concordance of type 2 DM in identical twins is between 70-90%.
Individuals with a parent affected by type 2 DM have an increased risk of diabetes ; if both parents have type 2 DM, the risk approaches 40%. Insulin resistance, as demonstrated by reduced glucose utilization in skeletal muscle, is present in many non-diabetic first-degree relatives of individuals with type 2 DM.
However, definition of the genetic susceptibility remains a challenge because the genetic defect in insulin secretion or action may not manifest itself unless an environmental event or another genetic defect, such as obesity, is superimposed.
Mutations in various molecules involved in insulin action (e.g., the insulin receptor and enzymes involved in glucose homeostasis) account for a very small fraction of type 2 DM.
Likewise, genetic defects in proteins involved in insulin secretion have not been found in most individuals with type2 DM.
Genome-wide scanning for mutations or polymorphisms associated with type 2 DM is being used in an effort to identify genes associated with type 2 DM. The gene for the protease, calpain 10, is associated with type 2 DM in Hispanic and some other populations.
Pathophysiology of Diabetes
Type 2 DM is characterized by three pathophysiologic abnormalities:
- Impaired insulin secretion,
- Peripheral insulin resistance, and 3- Excessive hepatic glucose production .
Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is very common in type 2 DM.
Adipocytes secrete a number of biologic products (leptin, TFN-a, free fatty acids, resistin, and adiponectin) that modulate insulin secretion, insulin action, and body weight and may contribute to the insulin resistance.
In the early stages of the disorder, glucose tolerance remains normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin output.
As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state.
IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue .
Markers of inflammation such as IL-6 and C-reactive protein are often elevated in type 2 diabetes .
∎ Insulin Resistance
The decreased ability of insulin to act effectively on peripheral target tissues (especially muscle and liver) is a prominent feature of type 2 DM and results from a combination of genetic susceptibility and obesity.
Insulin resistance is relative, however, since supernormal levels of circulating insulin will normalize the plasma glucose.
Insulin dose-response curves exhibit a rightward shift, indicating reduced sensitivity, and a reduced maximal response, indicating an overall decrease in maximum glucose utilization (30 to 60% lower than normal individuals) . Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to hyperglycemia.
∎ Impaired Insulin Secretion
Insulin secretion and sensitivity are interrelated in type 2 DM, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance.
Initially, the insulin secretory defect is mild and selectively involves glucose- stimulated insulin secretion. The response to other non glucose secretagogues, such as arginine, is preserved. Eventually the insulin secretory defect progresses to a state of grossly inadequate insulin secretion.
The reason for the decline in insulin secretory capacity in type 2 DM is unclear. Despite the assumption that a second genetic defect- superimposed upon insulin resistance-leads to beta cell failure, intense genetic investigation has so far excluded mutations in islet cells.
∎ Increased Hepatic Glucose Production
In type 2 DM, insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis, which results in fasting hyperglycemia and decreased glycogen storage by the liver in the postprandial state . Increased hepatic glucose production occurs early in the course of diabetes, though likely after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle.
– Insulin Resistance Syndromes
The insulin resistance condition comprises a spectrum of disorders, with hyperglycemia representing one of the most readily diagnosed features. The metabolic syndrome, the insulin resistance syndrome or syndrome X are terms used to describe a constellation of metabolic derangements that includes insulin resistance, hypertension, dyslipidemia [low high-density lipoprotein (HDL) and elevated triglycerides], central or visceral obesity, type 2 diabetes or IGT/IFG, and accelerated cardiovascular disease.
This syndrome is very common. The Centers for Disease Control and Prevention (CDC) estimates that 20% of U .S . adults have this syndrome . Epidemiologic evidence supports hyperinsulinemia as a marker for coronary artery disease risk, though an etiologic role has not been demonstrated, yet.
A number of relatively rare forms of severe insulin resistance include features of type 2 DM or IGT (Table 323-1) . Acanthosis nigricans and signs of hyperandrogenism (hirsutism, acne, and oligomenorrhea in women) are also common physical features.
Two distinct syndromes of severe insulin resistance have been described in adults:
(1) type A, which affects young women and is characterized by severe hyperinsulinemia, obesity, and features of hyperandrogenism ; and
(2) type B, which affects middle-aged women and is characterized by severe hyperinsulinemia, features of hyperandrogenism, and autoimmune disorders.
Individuals with type A insulin resistance syndrome have an undefined defect in the insulin-signaling pathway; individuals with the type B insulin resistance syndrome have autoantibodies directed at the insulin receptor. These receptor autoantibodies may block insulin binding or may stimulate the insulin receptor, leading to intermittent hypoglycemia.
Polycystic ovary syndrome (PCOS) is a common disorder that affects premenopausal women and is characterized by chronic anovulation and hyperandrogenism (Chap. 326). Insulin resistance is seen in a significant subset of women with PCOS, and the disorder substantially increases the risk for type 2 DM, independent of the effects of obesity.
Both metformin and the thiazolidinediones attenuate hyperinsulinemia, ameliorate hyperandrogenism, induce ovulation, and improve plasma lipids, but they are not approved for this indication.
Prevention of Diabetes
Type 2 DM is preceded by a period of IGT, and a number of life-style modifications and pharmacologic agents prevent or delay the onset of DM. The Diabetes Prevention Program (DPP) demonstrated that intensive changes in life-style (diet and exercise for 30 min/day five times/week) in individuals with IGT prevented or delayed the development of type 2 diabetes by 58% compared to placebo.
This effect was seen in individuals regardless of age, sex, or ethnic group.
In the same study, metformin prevented or delayed diabetes by 31% compared to placebo. The life-style intervention group lost 5 to 7% of their body weight during the 3 years of the study.