Background: Several distinct disorders of glucose tolerance exist. The most widely used classification of diabetes mellitus and allied categories of glucose intolerance is that recommended by the World Health Organization (WHO) in 1985. Recently, the American Diabetes Association (ADA) proposed a system based on disease etiology instead of classification according to type of pharmacological treatment.

The major categories of the disorders of glycemia or glucose tolerance are type 1 diabetes mellitus, type 2 diabetes mellitus, other specific types of diabetes, gestational diabetes mellitus (GDM), impaired glucose tolerance (IGT), and impaired fasting glucose (IFG). Conditions secondarily associated with glucose intolerance also occur.

The assignment of a type of diabetes or glucose intolerance to a patient usually is based on the circumstances at the time of diagnosis; however, not all patients fit easily into a particular class. When hyperglycemia is present, its severity may change over time, depending on the nature of the underlying process. An appropriate management approach to any of the disorders of glucose intolerance depends on a good understanding of the mechanisms involved in the disease process.

Pathophysiology: Heterogeneity occurs within the diabetes mellitus syndromes and in most of the other disorders of glucose intolerance.

Type 1 diabetes is characterized by cellular-mediated autoimmune destruction of beta cells of the pancreas and by insulin deficiency. The disease process is initiated by an environmental factor, ie, an infectious or noninfectious agent in genetically susceptible individuals. Some of the genes in the histocompatibility leukocyte antigen (HLA) system are thought to be crucial. A stress-induced epinephrine release, which inhibits insulin release (with resultant hyperglycemia) sometimes occurs and may be followed by a transient asymptomatic period lasting weeks to months, known as the "honeymoon," which precedes the onset of overt permanent diabetes. Idiopathic forms of type 1 diabetes also occur in which no evidence of autoimmunity or HLA association is present. In health, normoglycemia is maintained by fine hormonal regulation of peripheral glucose uptake and hepatic production.

Type 2 diabetes mellitus results from a defect in insulin secretion and an impairment of insulin action in hepatic and peripheral tissues, especially muscle tissue and adipocytes. A postreceptor defect also is present, causing resistance to the stimulatory effect of insulin on glucose use to occur, and relative insulin deficiency develops, unlike the absolute deficiency found in patients with type 1 diabetes. The specific etiologic factors are not known, but genetic input is much stronger in type 2 than in type 1.

IGT is a transitional state from normoglycemia to frank diabetes; however, considerable heterogeneity is seen among patients with IGT. Type 2 diabetes, or glucose intolerance, is part of a dysmetabolic syndrome (syndrome X) that includes insulin resistance, hyperinsulinemia, obesity, hypertension, and dyslipidemia. Current knowledge suggests that development of glucose intolerance or diabetes is initiated by insulin resistance and is worsened by the compensatory hyperinsulinemia. The progression to type 2 diabetes is influenced by genetics and environmental or acquired factors such as a sedentary lifestyle and dietary habits that promote obesity. Most patients with type 2 diabetes are obese, and, as noted, obesity also is associated with insulin resistance. Central adiposity is more important than increased generalized fat distribution. In patients with frank diabetes, glucose toxicity may cause further impairment of insulin secretion by the beta cells.

GDM is described as any degree of glucose intolerance in which onset or first recognition occurs during pregnancy. Insulin requirements are increased during pregnancy. This is due to the presence of insulin antagonists, such as human placental lactogen or chorionic somatomammotropin, and cortisol, which promote lipolysis and decrease glucose use. Another factor is the production of insulinase by the placenta. Various genetic defects of the beta cell, insulin action, diseases of the exocrine pancreas, endocrinopathies, drugs, chemical agents, infections, immune disorders, and genetic syndromes can cause variable degrees of glucose intolerance, including diabetes.

Glucose intolerance may be present in many patients with cirrhosis due to decreased hepatic glucose uptake and glycogen synthesis. Other underlying mechanisms include hepatic and peripheral resistance to insulin and serum hormonal abnormalities. Abnormal glucose homeostasis also may occur in uremia as a result of increased peripheral resistance to the action of insulin.

Frequency:

• In the US: Approximately 16 million individuals in the United States have diabetes. More than 5 million of these cases are undiagnosed.
• IGT constitutes approximately two thirds of all glucose intolerance in the United States and is present in 11% of the general population. Prevalence of IFG is 6.9% (13.4 million) of Americans.
• Type 1 diabetes, usually occurring in children and adolescents, accounts for 5-10% of diabetes cases.
• Type 2 diabetes, commonly occurring in middle age, is the predominant form of clinical disease, constituting 90-95% of diabetes cases. This type of diabetes is reaching epidemic proportions. Minority populations, especially American Indians, Hispanics, and African Americans, are particularly at high risk.
• Gestational diabetes develops in approximately 4% of all pregnancies in the United States. Prevalence is 1-14%, depending on the population studied and the diagnostic criteria used.

• Internationally: Lowest prevalence rates of diabetes (<1%) are found among certain African and Chinese populations and in rural populations of the Mapuche Indians of Chile.
• The Pima Indians of Arizona and a group of Pacific Islanders, the Naurans, have the highest prevalence of type 2 diabetes in the world among patients older than 30 years, with rates of 50% and 35%, respectively. The risk in other populations is classified as ranging from low to high-medium.
• The overall range for IGT (1-25%) is considerable, although not as wide as for diabetes (0-50%). IGT is rare in Mapuche Indians but is common in many other population groups. Generally, those living in developing countries and migrant or ethnic minorities in industrialized countries are at higher risk of diabetes and IGT.
• The highest rates of type 1 diabetes occur in whites, especially of northern European descent. The disease is unknown or rare in certain groups (eg, Japanese, Chinese, Africans).
• Incidence and prevalence rates of many specific types of diabetes or glucose intolerance, such as the genetic syndromes, presently are unknown in general populations.

Mortality/Morbidity: Several studies demonstrate a relationship between high plasma glucose distributions and risk of cardiovascular disease and increased mortality, even within the normoglycemic range. The total annual economic cost (direct and indirect costs) of diabetes in the United States is nearly $100 billion. The overall cost of all categories of glucose tolerance and related cardiovascular risk factors surpasses this estimate.

• Diabetes - (1) sixth leading cause of death by disease, (2) seventh leading cause of death in the United States, (3) propensity for acute metabolic complications, (4) leading cause of end-stage renal disease, (5) leading cause of blindness, (6) much higher risk of heart disease, (7) higher risk of stroke, (8) high risk of neuropathy, and (9) high risk of gangrene

• Gestational diabetes mellitus ? (1) increased risk of fetal and neonatal morbidity and mortality; (2) obstetric complications; and (3) offspring have increased risk of obesity, glucose intolerance, and type 2 diabetes

• Impaired glucose tolerance ? (1) major risk factor for diabetes, with 20-50% progressing to diabetes within 10 years; (2) baseline plasma glucose is the most consistent predictor of progression to diabetes; (3) individuals with IGT have rates of cardiovascular risk factors that are intermediate between those with normal glucose tolerance and those with diabetes; (4) increased risk of macrovascular complications (eg, coronary artery disease, gangrene, stroke); and (5) not clearly associated with microvascular complications (eg, nephropathy, retinopathy, neuropathy)
  
   
• Impaired fasting glucose - (1) not associated with the same risk level as IGT and (2) risk of cardiovascular disease much lower in IFG

Race:

• American Indians and certain Pacific Islanders have the highest risk of glucose intolerance.

• African Americans and Hispanics have higher rates than non-Hispanic whites.

Sex:

• In the WHO global data, the prevalence ratio of diabetes between men and women varies markedly, with no consistent trend. However, IGT is more common in women than in men.

• The relative difference in frequency between the sexes probably is related to the presence of underlying factors such as pregnancy and obesity rather than a sex-specific genetic tendency.

Age:

• Type 1 diabetes occurs most commonly in children and adolescents, but it may occur at any age.

• Type 2 diabetes typically begins in middle life or later, usually after age 30 years; the prevalence rises with age.

• Maturity-onset diabetes of youth (MODY) can be expressed in childhood or early adolescence.