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Classification of Diabetes Mellitus

Page history last edited by Ira D. Goldfine 13 years, 11 months ago

 

The Web diabetesmanager
 

 

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[1]. 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)
  1. Immune mediated
  2. 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
  1. Genetic defects of b-cell function ([2])
    1. Chromosome 20q, HNF-4a (MODY1)
    2. Chromosome 7p, glucokinase (MODY2)
    3. Chromosome 12q, HNF-1a (MODY3)
    4. Chromosome 13q, insulin promoter factor (MODY4)
    5. Chromosome 17q, HNF-1b (MODY5)
    6. Chromosome 2q, Neurogenic differentiation 1/b-cell e-box
      transactivator 2 (MODY 6)
    7. Mitochondrial DNA
    8. Others
  2. Genetic defects in insulin action
    1. Type 1 insulin resistance
    2. Leprechaunism
    3. Rabson-Mendenhall syndrome
    4. Lipoatrophic diabetes
    5. Others
  3. Diseases of the exocrine pancreas
    1. Pancreatitis
    2. Trauma/pancreatectomy
    3. Neoplasia
    4. Cystic fibrosis
    5. Hemochromatosis
    6. Fibrocalculous pancreatopathy
    7. Others
  4. Endocrinopathies
    1. Acromegaly
    2. Cushing's syndrome
    3. Glucagonoma
    4. Pheochromocytoma
    5. Hyperthyrodism
    6. Somatostatinoma
    7. Aldosteronoma
    8. Others
  5. Drug- or chemical-induced
    1. Vacor
    2. Pentamidine
    3. Nicotinic acid
    4. Glucocorticoids
    5. Thyroid hormone
    6. Diazoxide
    7. b-adrenergic agonists
    8. Thiazides
    9. Dilantin
    10. a-interferon
    11. Others
  6. Infections
    1. Congential rubella
    2. Cytomegalovirus
    3. Others
  7. Uncommon forms of immune-mediated diabetes
    1. "Stiff-man" syndrome
    2. Anti-insulin receptor antibodies
    3. Others
  8. Other genetic syndromes sometimes associated with diabetes
    1. Down's syndrome
    2. Klinefelter's syndrome
    3. Turner's syndrome
    4. Wolfram's syndrome
    5. Friedreich's ataxia
    6. Huntington's chorea
    7. Laurence-Moon-Bieldel syndrome
    8. Myotonic dystrophy
    9. Porphyria
    10. Prader-Willi syndrome
    11. 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 #[3] with permission.

 

 

 

TYPE 1 DIABETES MELLITUS

Type 1 diabetes results from autoimmune destruction of the pancreatic b-cells[4][5]. 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[6]. 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[7][8]. 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[9][10]. 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[11]. Most individuals with type 2 diabetes exhibit intra (abdominal (visceral) obesity, which is closely related to the presence of insulin resistance[12]. 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" [13][14]. 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 [15][16].

 

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 [17]. 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 [18]. 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 [19].

 

Genetic inability to convert proinsulin to insulin results in mild hyperglycemia and is inherited an autosomal dominant pattern [20]. Similarly, the production of mutant insulin molecules has been identified in a few families and results in mild glucose intolerance [21].

 

Several genetic mutations have been described in the insulin receptor and are associated with insulin resistance [22]. Type A insulin resistance refers to the clinical syndrome of acanthosis nigricans, virilization in women, polycystic ovaries, and hyperinsulinemia [23]. Leprechaunism is a pediatric syndrome with specific facial features and severe insulin resistance that results from a defect in the insulin receptor [24]. Lipoatrophic diabetes results from postreceptor defects in insulin signaling [25].

 

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 [26]. 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 [27][28][29]. 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 [30]. 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 [31].

 

 

 

 

 

Footnotes

  1. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 23 (Suppl 1):S5-S20, 2002.
  2. Stride A. Hattersley AT. Different genes, different diabetes: lessons from maturity-onset diabetes of the young. Ann Med 34:207-16, 2002.
  3. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183-1197, 1997
  4. Kukreja A, Maclaren NK. Autoimmunity and diabetes. J Clin Endocrinol Metab 84:4371-4378, 1999.
  5. Atkinson MA, Eisenbarth GS. Type I diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358:221-229, 2001.
  6. Zimmet PZ, Tuomi T, Mackay R, Rowley MJ, Knowles W, Cohen M, Lang DA: Latent autoimmune diabetes mellitus in adults (LADA): The role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11:299-303, 1994.
  7. DeFronzo RA. Lilly Lecture. The triumvariate: beta-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37:667-687, 1988.
  8. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 5:178-269, 1997.
  9. DeFronzo RA. Lilly Lecture. The triumvariate: beta-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37:667-687, 1988.
  10. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 5:178-269, 1997.
  11. Banerji MA, Lebovitz HE. Insulin action in black Americans with NIDDM. Diabetes Care 15:1295-1302, 1992.
  12. Zimmet PZ, Tuomi T, Mackay R, Rowley MJ, Knowles W, Cohen M, Lang DA: Latent autoimmune diabetes mellitus in adults (LADA): The role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11:299-303, 1994.
  13. Reaven GM. Banting Lecture. Role of insulin resistance in human disease. Diabetes 37:595-607, 1988.
  14. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD. Diabetes Care-Reviews 14:173-194, 1991.
  15. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 5:178-269, 1997
  16. van Tilburg J, van Haeften TW, Pearson P, Wijimenga C: Defining the genetic contribution of type 2 diabetes mellitus. J Med Genet 38:569-578, 2001.
  17. Engelgau MM, Herman WH, Smith PJ, German RR, Aubert RE: The epidemiology of diabetes and pregnancy in the U.S., 1988. Diabetes Care 18:1029-1033, 1995.
  18. Herman WH, Fajans SS, Ortiz FJ, Smith MJ, Sturis J, Bell GI, Polonsky KS, Halter JB: Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree. Diabetes 43:40-46, 1994.
  19. McCarthy MI, Frognel P. Genetic approaches to the molecular understanding of type 2 diabetes. Am J Physiol Endocrinol Metab 283:E217-E225, 2002.
  20. Robbins DC, Shoelson SE, Rubenstein AH, Tager HS: Familial hyperproinsulinemia: two cohorts secreting indistinguishable type II intermediates of proinsulin conversion. J Clin Invest 73:714-719, 1984.
  21. Given BD, Mako ME, Tager HS, Baldwin D, Markese J, Rubenstein AH, Olefsky J, Kobayashi M, Kolterman O, Poucher R: Diabetes due to secretion of an abnormal insulin. N Engl J Med 302:129-135, 1980.
  22. Taylor S, Arioglu E. Genetically defined forms of diabetes in children. J Clin Endocrinol Metab 84:4390-4396, 1999.
  23. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J: The syndromes of insulin resistance and acanthosis nigricans. N Engl J Med 294:739-745, 1976.
  24. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Human Mol Gen 11:1465-1475, 2002.
  25. Reitman ML, Arioglu E, Gavrilova O, Taylor SI. Lipoatrophy revisited. Trends in Endocrinol Metab 11:410-416, 2000.
  26. Tiengo A., Del Prato S, Briani G, Trevisan R, De Kreutzenberg S. Acute and chronic complications of diabetes secondary to pancratopathies. J Ann Diabet de Hotel-Dieu ___:179-189, 1995.
  27. McMahon M, Gerich J, Rizza R. Effects of glucocorticoids on carbohydrate metabolism. Diabetes/Metab Rev 4:17-30, 1988.
  28. Ganda OP, Simonson DS. Growth hormone, acromegaly, and diabetes. Diabetes Rev 1:286-302, 1993.
  29. Werbel SS, Ober KP. Pheochromocytoma. Update on diagnosis, localization, and management. Med Clin North Am 79:131-153, 1995.
  30. Menser MA, Forrest JM, Brensby RD. Rubella infection and diabetes mellitus. Lancet 1:57-60, 1978.
  31. Bressler P, DeFronzo RA. Drugs and Diabetes. Diabetes Rev 2:53-84, 1994.

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