CLASSIFICATION OF DIABETES

Diabetes Mellitus: Introduction

Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of DM exist and are caused by a complex interaction of genetics and environmental factors

Depending on the etiology of the DM, factors contributing to hyperglycemia include

· reduced insulin secretion,

· decreased glucose utilization, and

· increased glucose production.

The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system.

In the United States, DM is the leading cause of end-stage renal disease (ESRD), nontraumatic lower extremity amputations, and adult blindness. It also predisposes to cardiovascular diseases. With an increasing incidence worldwide, DM will be a leading cause of morbidity and mortality for the foreseeable future

Classification

DM is classified on the basis of the pathogenic process that leads to hyperglycemia, as opposed to earlier criteria such as age of onset or type of therapy

The two broad categories of DM are designated

· type 1 and

· type 2 (Table 338-1).

Both types of diabetes are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progresses.

Type 1 diabetes is the result of complete or near-total insulin deficiency.

Type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Distinct genetic and metabolic defects in insulin action and/or secretion give rise to the common phenotype of hyperglycemia in type 2 DM and have important potential therapeutic implications now that pharmacologic agents are available to target specific metabolic derangements. Type 2 DM is preceded by a period of abnormal glucose homeostasis classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).

Table 338-1 Etiologic Classification of Diabetes Mellitus

I. Type 1 diabetes (Beta-cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. 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 of diabetes A. Genetic defects of Beta-cell function characterized by mutations in: 1. Hepatocyte nuclear transcription factor (HNF) 4 alfa (MODY 1) (MODY-Maturity Onset Diabetes of Young) 2. Glucokinase (MODY 2) 3. HNF-1 alfa (MODY 3) 4. Insulin promoter factor-1 (IPF-1; MODY 4) 5. HNF-1 beta (MODY 5) 6. NeuroD1 (MODY 6) 7. Mitochondrial DNA 8. Subunits of ATP-sensitive potassium channel 9. Proinsulin or insulin conversion B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4. Lipodystrophy syndromes C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipase D. Endocrinopathies—acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma E. Drug- or chemical-induced—Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, beta-adrenergic agonists, thiazides, phenytoin, alfa-interferon, protease inhibitors, clozapine F. Infections—congenital rubella, cytomegalovirus, coxsackie G. Uncommon forms of immune-mediated diabetes—"stiff-person" syndrome, anti-insulin receptor antibodies H. 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-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome IV. Gestational diabetes mellitus (GDM)

Two features of the current classification of DM diverge from previous classifications.

First, the terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually require insulin treatment for control of glycemia, the use of the term NIDDM generated considerable confusion.

A second difference is that age is not a criterion in the classification system. Although type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.

Other Types of DM

Other etiologies for DM include specific genetic defects in insulin secretion or action, metabolic abnormalities that impair insulin secretion, mitochondrial abnormalities, and a host of conditions that impair glucose tolerance (Table 338-1).

Maturity onset diabetes of the young (MODY) is a subtype of DM characterized by autosomal dominant inheritance, early onset of hyperglycemia (usually <25 years), and impairment in insulin secretion (discussed below).

Mutations in the insulin receptor cause a group of rare disorders characterized by severe insulin resistance.

DM can result from pancreatic exocrine disease when the majority of pancreatic islets are destroyed.

Hormones that antagonize insulin action can also lead to DM. Thus, DM is often a feature of endocrinopathies such as acromegaly and Cushing's disease.

Viral infections have been implicated in pancreatic islet destruction but are an extremely rare cause of DM. A form of acute onset of type 1 diabetes, termed fulminant diabetes, has been noted in Japan and may be related to viral infection of islets.

Gestational Diabetes Mellitus (GDM)

Glucose intolerance may develop during pregnancy. Insulin resistance is related to the metabolic changes of late pregnancy, and the increased insulin requirements may lead to IGT. GDM occurs in ~4% of pregnancies in the United States; most women revert to normal glucose tolerance post-partum but have a substantial risk (30–60%) of developing DM later in life.