CLASSIFICATION OF DIABETES MELLITUS
Charles Reasner, MD
Ralph A DeFronzo, MD
CLASSIFICATION OF DIABETES (Table 1)
Diabetes is a metabolic disorder characterized by resistance to the action of insulin, insufficient insulin secretion, or both. The major clinical manifestation of the diabetic state is hyperglycemia. However, insulin deficiency and/or insulin resistance also are associated with disturbances in lipid and protein metabolism. The vast majority of diabetic patients are classified into one of two broad categories: type 1 diabetes, which is caused by an absolute deficiency of insulin, and type 2 diabetes, which is characterized by the presence of insulin resistance with an inadequate compensatory increase in insulin secretion. In addition, women who develop diabetes during their pregnancy, are classified as having gestational diabetes. Finally, there are a variety of uncommon and diverse types of diabetes which are caused by infections, drugs, endocrinopathies, pancreatic destruction, and genetic defects. These unrelated forms of diabetes are classified separately.
Table 1: Etiologic Classification of Diabetes Mellitus |
I. Type 1 diabetes* (b-cell destruction, usually leading to absolute insulin deficiency) - Immune mediated
- Idiopathic
|
II. Type 2 diabetes* (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance) |
III. Other specific types - Genetic defects of b-cell function ()
- Chromosome 20q, HNF-4a (MODY1)
- Chromosome 7p, glucokinase (MODY2)
- Chromosome 12q, HNF-1a (MODY3)
- Chromosome 13q, insulin promoter factor (MODY4)
- Chromosome 17q, HNF-1b (MODY5)
- Chromosome 2q, Neurogenic differentiation 1/b-cell e-box
transactivator 2 (MODY 6)
- Mitochondrial DNA
- Others
- Genetic defects in insulin action
- Type 1 insulin resistance
- Leprechaunism
- Rabson-Mendenhall syndrome
- Lipoatrophic diabetes
- Others
- Diseases of the exocrine pancreas
- Pancreatitis
- Trauma/pancreatectomy
- Neoplasia
- Cystic fibrosis
- Hemochromatosis
- Fibrocalculous pancreatopathy
- Others
- Endocrinopathies
- Acromegaly
- Cushing's syndrome
- Glucagonoma
- Pheochromocytoma
- Hyperthyrodism
- Somatostatinoma
- Aldosteronoma
- Others
- Drug- or chemical-induced
- Vacor
- Pentamidine
- Nicotinic acid
- Glucocorticoids
- Thyroid hormone
- Diazoxide
- b-adrenergic agonists
- Thiazides
- Dilantin
- a-interferon
- Others
- Infections
- Congential rubella
- Cytomegalovirus
- Others
- Uncommon forms of immune-mediated diabetes
- "Stiff-man" syndrome
- Anti-insulin receptor antibodies
- Others
- Other genetic syndromes sometimes associated with diabetes
- Down's syndrome
- Klinefelter's syndrome
- Turner's syndrome
- Wolfram's syndrome
- Friedreich's ataxia
- Huntington's chorea
- Laurence-Moon-Bieldel syndrome
- Myotonic dystrophy
- Porphyria
- Prader-Willi syndrome
- Others
|
IV. Gestational diabetes-melllitus (GDM) |
*Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient. Adapted from reference # with permission. |
TYPE 1 DIABETES MELLITUS
Type 1 diabetes results from autoimmune destruction of the pancreatic b-cells. Markers of immune destruction of the b-cell are present at the time of diagnosis in 90% of individuals and include antibodies to the islet cell (ICAs), to glutamic acid decarboxylase (GAD), and to insulin (IAAs). While this form of diabetes usually occurs in children and adolescents, it can occur at any age. Younger individuals typically have a rapid rate of b -cell destruction and present with ketoacidosis, while adults often maintain sufficient insulin secretion to prevent ketoacidosis for many years. The more indolent adult-onset variety has been referred to as latent autoimmune diabetes in adults (LADA). Eventually, all type 1 diabetic patients will require insulin therapy to maintain normglycemia.
TYPE 2 DIABETES MELLLITUS
Type 2 diabetes is characterized by insulin resistance and, at least initially, a relative deficiency of insulin secretion. In absolute terms, the plasma insulin concentration (both fasting and meal-stimulated) usually is increased, although "relative" to the severity of insulin resistance, the plasma insulin concentration is insufficient to maintain normal glucose homeostasis. With time, however, there is progressive beta cell failure and absolute insulin deficiency ensues. In a minority of type 2 diabetic individuals, severe insulinopenia is present at the time of diagnosis and insulin sensitivity is normal or near normal. Most individuals with type 2 diabetes exhibit intra (abdominal (visceral) obesity, which is closely related to the presence of insulin resistance. In addition, hypertension, dyslipidemia (high triglyceride and low HDL-cholesterol levels; postprandial hyperlipemia), and elevated PAI-1 levels often are present in these individuals. This clustering of abnormalities is referred to as the "insulin resistance syndrome" or the "metabolic syndrome" . Because of these abnormalities, patients with type 2 diabetes are at increased risk of developing macrovascular complications (myocardial infarction and stroke). Type 2 diabetes has a strong genetic predisposition and is more common in minority ethnic groups, i.e. Mexican-Americans, Latinos, American Indians, Pacific Islanders, than in individuals of European ancestry. The genetic cause(s) of the common variety of type 2 diabetes is (are) not well defined and, at present, no specific genes have been identified in the pathogenesis of this common metabolic disorder .
GESTATIONAL DIABETES MELLITUS (GDM)
Gestational diabetes mellitus (GDM) is defined as glucose intolerance, which is first recognized during pregnancy. In most women who develop GDM, the disorder has its onset in the third trimester of pregnancy. At least 6 weeks after the pregnancy ends, the woman should receive an oral glucose tolerance test and be reclassified as having diabetes, normal glucose tolerance, impaired glucose tolerance, or impaired fasting glucose. Gestational diabetes complicates about 4% of all pregnancies . Clinical detection is important, since therapy will reduce perinatal morbidity and mortality. Risk assessment for GDM should occur at the first prenatal visit. Women at high risk (positive family history, history of GDM, marked obesity, high risk ethnic group) should be screened as soon as feasible. If the initial screening is negative, they should undergo retesting at 24-48 weeks. Women of average risk should have the initial screen performed at 24-48 weeks. A fasting plasma glucose concentration greater than 126 mg/dl (7.0 mmol/l) or a postprandial glucose greater than 200 mg/dl (11.1 mmol/l) establishes the diagnosis of diabetes and obviates the need for more formal glucose tolerance testing. Women who require more formal testing should receive a 100 gram oral glucose load with plasma glucose levels determined at baseline, 1 hour, 2 hours, and 3 hours (Table 2). The diagnosis of GDM is made if two or more of the plasma glucose values in Table 2 are met or exceeded.
Table 2-Diagnosis of GDM with a 100 g glucose load |
TIME |
PLASMA GLUCOSE |
Fasting |
≥95 mg/dl (5.3 mmol/L) |
1-h |
≥180 mg/dl (10.0mmol/L) |
2-h |
≥155 mg/dl (8.6 mmol/L) |
3-h |
≥140 mg/dl (7.8 mmol/L) |
Two or more values must be met or exceeded for a diagnosis of diabetes to be made. The test should be done in the morning after a 8 to 14 hour fast. |
SPECIFIC TYPES OF DIABETES
Genetic Defects
Maturity Onset Diabetes of the Young (MODY) is characterized by impaired insulin secretion with minimal or no insulin resistance . Patients typically exhibit mild hyperglycemia at an early age. The disease is inherited in an autosomal dominant pattern and, at present, six different genetic abnormalities have been identified .
Genetic inability to convert proinsulin to insulin results in mild hyperglycemia and is inherited an autosomal dominant pattern . Similarly, the production of mutant insulin molecules has been identified in a few families and results in mild glucose intolerance .
Several genetic mutations have been described in the insulin receptor and are associated with insulin resistance . Type A insulin resistance refers to the clinical syndrome of acanthosis nigricans, virilization in women, polycystic ovaries, and hyperinsulinemia . Leprechaunism is a pediatric syndrome with specific facial features and severe insulin resistance that results from a defect in the insulin receptor . Lipoatrophic diabetes results from postreceptor defects in insulin signaling .
A variety of genetic syndromes have been described in which diabetes mellitus occurs with increased frequency. The etiology of the disturbance in glucose homeostasis in these diverse and seemingly unrelated syndromes remains undefined.
DISEASES OF THE EXOCRINE PANCREAS
Damage of the pancreas must be extensive for diabetes to occur . The most common causes are pancreatitis, trauma, and carcinoma. Cystic fibrosis and hemochromatosis also have been associated with impaired insulin secretion.
ENDOCRINOPATHIES
Since growth hormone, cortisol, glucagon, and epinephrine increase hepatic glucose production and induce insulin resistance in peripheral (muscle) tissues, excess production of these hormones can cause or exacerbate underlying diabetes . Although the primary mechanism of action of these counter regulatory hormones is the induction of insulin resistance in muscle and liver, overt type 2 diabetes mellitus does not develop in the absence of beta cell failure.
INFECTIONS
A variety of infections have been etiologically related to the development of diabetes mellitus. Of these, the most clearly established is congenital rubella . Approximately 20% of infants who are infected with the rubella virus at birth develop autoimmune type 2 diabetes later in life. These individuals have the typical type 1 susceptibility genotype, DR3/DR4.
DRUGS
A large number of commonly used drugs have been shown to induce insulin resistance and/or impair beta cell function and can lead to the development of diabetes mellitus in susceptible individuals. An extensive review of these drugs and their mechanism of action has been published .
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