Classification of Diabetes Mellitus and the Metabolic Syndrome

In 2003, the American Diabetes Association (ADA) revised the etiologic classification of diabetes mellitus, removing the distinction between primary and secondary causes of diabetes15 (Table 1). The nomenclature now uses Arabic rather than Roman numerals to designate T1DM and T2DM. Terms such as insulin-dependent, non-insulin-dependent, juvenile-onset, maturity-onset, and adult-onset diabetes are eliminated. Thus, diabetes is now classified according to etiology and pathophysiology, without distinction as to age of onset or type of treatment. Type 1 Diabetes Mellitus Immune-mediated diabetes mellitus (Type 1A)

Immune-mediated diabetes, previously referred to as insulin-dependent diabetes, type I diabetes, and juvenile-onset diabetes, accounts for 5-10% of all cases of diabetes. Immune-mediated diabetes typically develops in childhood and adolescence, but has a variable age of onset ranging from infancy to the eighth and ninth decades of life. Abnormalities in glucose homeostasis result from severe insulin deficiency due to cell-mediated autoimmune inflammation (insulitis) and subsequent destruction of the b-cells of the pancreas. In T1DM, daily exogenous insulin administration is a life-sustaining intervention, and the absence of insulin can result in a state of acute metabolic decompensation known as diabetic ketoacidosis (DKA). Individuals with T1DM are at increased risk for other autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.

Table 1 Etiologic classification of diabetes mellitus

Type 1 Diabetes Mellitus (b-cell destruction, usually leading to absolute insulin deficiency) Immune mediated Idiopathic

Type 2 Diabetes Mellitus (insulin resistance and impairment of b-cell insulin secretion) Gestational Diabetes Mellitus (GDM) Other specific types

Genetic defects of b-cell function Chromosome 12, HNF-1a (MODY3) Chromosome 20, HNF-4a (MODY1) Chromosome 17, HNF-1b (MODY5) Mitochondrial DNA Genetic defects in insulin action Type A insulin resistance Rabson-Mendenhall syndrome Others

Diseases of the exocrine pancreas










Drug- or chemical-induced


Nicotinic acid

Thyroid hormone b-Adrenergic agonists




Congenital rubella Others

Uncommon forms of immune-mediated diabetes

'Stiff-man' syndrome


Other genetic syndromes sometimes associated with diabetes

Down's syndrome

Turner's syndrome

Friedreich's ataxia

Laurence-Moon-Biedl syndrome



Chromosome 7, glucokinase (MODY2) Chromosome 13, IPF-1 (MODY4) Chromosome 2, NeuroDl (MODY6) Others

Leprechaunism Lipoatrophic diabetes

Trauma/pancreatectomy Cystic fibrosis

Fibrocalculous pancreatopathy

Cushing's syndrome Pheochromocytoma Somatostatinoma Others




Thiazides a-Interferon


Anti-insulin receptor antibodies

Klinefelter's syndrome Wolfram's syndrome Huntington's chorea Myotonic dystrophy Prader-Willi syndrome

Copyright Ā© 2005 American Diabetes Association from Diabetes Care, 2005, 28, S37-S42. Reprinted with permission from the American Diabetes Association. Idiopathic diabetes mellitus (Type 1B)

Individuals who present with a phenotype suggestive of T1DM (insulinopenia and ketosis prone) without evidence of autoimmunity are classified as idiopathic or type 1B diabetes. This form of diabetes is rare, strongly inherited, and most commonly found in persons with African or Asian ancestry. Type 2 Diabetes Mellitus

T2DM accounts for approximately 90% of all cases of diabetes. Historically it has been referred to as adult-onset diabetes, non-insulin-dependent diabetes and type II diabetes. T2DM is characterized by a combination of insulin resistance (in skeletal muscle, adipose tissue, and liver) and impaired insulin secretion. As reviewed below (see Section individuals with similar levels of glucose intolerance vary widely in their severity of insulin resistance and deficiency of insulin secretion. The prevalence of T2DM increases with age, sedentary lifestyle, obesity, and family history of diabetes, including GDM. The genetic predisposition to T2DM is strong and suspected to be polygenic. Since insulin deficiency in T2DM is relative, individuals are not usually ketosis prone, but ketoacidosis can occur in the setting of severe stress or illness. However, as b-cell function deteriorates, many people with T2DM require exogenous insulin to achieve satisfactory glycemic control. Other Specific Types of Diabetes

Diabetes with pathophysiology not congruent with that of T1DM and T2DM is classified into a broad category of 'other specified types.' Genetic p-cell defects

Monogenic defects of pancreatic b-cells are characterized by impaired insulin secretion without obligatory abnormalities in insulin action. The most common defects involve the glucose-sensing enzyme glucokinase and various transcription factors such as hepatocyte nuclear factors (HNF-4a, HNF-1a, and HNF-1b) and insulin promoter factor (IPF-1). Collectively, these autosomal-dominantly inherited mutations are known as maturity onset diabetes of the young (MODY), and affected individuals typically develop hyperglycemia before the age of 25 years. Abnormalities in insulin sensitivity can still occur in these individuals from environmental factors, altering their clinical course and clouding their underlying pathophysiology and classification. Genetic defects in insulin action

Rarely, mutations of the insulin receptor or the postreceptor signal transduction pathways cause impairment of insulin action, resulting in metabolic abnormalities ranging from hyperinsulinemia with mild hyperglycemia to severe diabetes. Clinical manifestations usually develop within the first year of life, and each mutation commonly has a disease-specific phenotype that accompanies the metabolic abnormalities. Diseases of the exocrine pancreas

Any disease process involving the pancreatic parenchyma can affect glucose homeostasis. Acute and chronic pancreatitis, pancreatic carcinoma, trauma, infection, cystic fibrosis, and infiltrating diseases such as hemochromatosis can all affect islet cell function and insulin secretion. To elicit endocrine dysfunction, a significant loss of b-cell mass is required. Endocrinopathies

Many hormones are involved in glucose homeostasis, and excess secretion of any of them can affect insulin resistance. When present in excess, counterregulatory hormones (growth hormone, cortisol, glucagon, and epinephrine) that normally protect against hypoglycemia antagonize insulin action. Acromegaly, Cushing's syndrome, glucagonoma, and pheochromocytoma are associated with overt diabetes in individuals with an underlying genetic predisposition. Other endocrinopathies such as hyperthyroidism (which increases b-adrenergic activity) and primary hyperaldosteronism (which impairs insulin secretion due to hypokalemia) are infrequently associated with T2DM. Neuroendocrine tumors of the pancreas, specifically those secreting glucagon, vasoactive intestinal peptide, and somatostatin can also affect glucose homeostasis. In all these disorders, glycemic abnormalities may be reversible with treatment of the underlying condition. Drug or chemical-induced diabetes

Medications do not usually cause overt diabetes independently. Drugs that impair insulin secretion, alter insulin sensitivity, or lead to b-cell destruction may precipitate diabetes in an individual with underlying glucose intolerance. Antihypertensive agents including b-adrenoceptor antagonists, calcium channel antagonists, diuretics, some antipsychotics, and calcineurin inhibitors may reversibly inhibit insulin secretion. Pentamidine and toxins such as Vacor can result in permanent b-cell destruction. Use of glucocorticoids increases insulin resistance and may be associated with the development of diabetes. Several chemotherapeutic agents (mithramycin, asparaginase, and ainterferon) are associated with the development of diabetes, although the precise mechanism is unknown. Infections

Certain viruses, including congenital rubella, Coxsackie virus B, cytomegalovirus, adenovirus, and mumps, have been associated with b-cell destruction and have been implicated as an environmental trigger for the immune response in T1DM. However, no specific virus appears to be responsible for the majority of cases. Uncommon forms of immune-mediated diabetes

Autoantibodies to insulin or the insulin receptor are associated with rare forms of diabetes. Stiff-man syndrome, an autoimmune disease of the central nervous system resulting in axial muscle stiffness and spasms, is commonly associated with high titers of the autoantibodies to glutamic acid decarboxylase (GAD) and a predilection to develop diabetes. Individuals with other autoimmune diseases, such as systemic lupus erythematosus or dermatomyositis, can develop autoantibodies to the insulin receptor that act as competitive inhibitors of insulin or, in some cases, activators of the insulin receptor resulting in hypoglycemia. Genetic syndromes sometimes associated with diabetes

Impaired glucose tolerance or diabetes appear with increased frequency in a number of congenital disorders, including Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, and Prader-Willi syndrome. Gestational Diabetes Mellitus

GDM is defined as glucose intolerance with onset or recognition during pregnancy. Individuals with pre-existing T1DM or T2DM are excluded from this classification. Individuals are at increased risk of developing GDM if they have a family history of diabetes or GDM, are a member of a racial/ethnic group with a high prevalence of T2DM (e.g., Native American, African American, Hispanic American, or Asian American), are obese, or of high maternal age, (e.g., >38-40 years). GDM is associated with increased risk of pregnancy-induced hypertension, macrosomia, cesarean delivery, and other obstetric complications. Women are treated with lifestyle modifications and may require insulin for optimal glycemic control. GDM identifies women at very high risk for GDM in future pregnancies and T2DM later in life. Diagnostic Criteria for Diabetes

In 1979, the National Diabetes Data Group (NDDG) established criteria that included diagnostic levels for fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT). FPG >140mgdL_ 1 and/or 2-h plasma glucose value (2hPG) >200 mgdL_ 1 during an OGTT were chosen as the diagnostic threshold because individuals with average glucose levels above these values had been found to develop microvascular complications. Those with OGTT 2hPG values >140 mgdL_ 1, but below the threshold for diabetes (200 mgdL _ 1) were classified as having impaired glucose tolerance (IGT).

In 1997, an ADA'Expert Panel' recommended a reduction in the FPG threshold for the diagnosis of diabetes to >126 mgdL_ 1 (7.0 mmol L_ 1) as it correlated better with a 75 g OGTT 2-h value >200 mg dL_ 1. By reducing the FPG criteria, some individuals previously diagnosed as IGTwere reclassified as having diabetes, resulting in a modest increase in the prevalence of diabetes. A new category, called impaired fasting glucose (IFG), was added for those individuals with a FPG >110 and <126mgdL"1. In 2003, the ADA lowered the threshold for IFG to 100mgdL"1 and reinstated an old term, 'Pre-diabetes,' to describe individuals with either IGTor IFG. As a result, risk stratification and lifestyle modifications can be initiated earlier to prevent the development of overt diabetes and other associated vascular complications.

The current ADA diagnostic criteria16 (Table 2) identify three independent parameters by which the diagnosis of diabetes can be made: FPG, 75 g 2-h OGTT, and random plasma glucose in the setting of symptoms suggestive of diabetes. Any combination of two abnormal tests performed on different days confirms a diagnosis of diabetes. The OGTT remains the diagnostic test for GDM and is preferred by many experts for postpartum evaluation for persistent abnormalities in glucose homeostasis. Diagnostic Criteria for the Metabolic Syndrome

The metabolic syndrome (MetS), also known as the insulin-resistance syndrome or syndrome X, is characterized by insulin resistance, abdominal obesity, elevated blood pressure, and lipid abnormalities consisting of elevated levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol (see 6.17 Obesity/Metabolic Syndrome

Table 2 Criteria for the diagnosis of diabetes mellitusĀ®
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