Diabetes Mellitus

Introduction

Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate.

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.

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 .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. Type 2 DM is preceded by a period of abnormal glucose homeostasis classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).

Etiologic Classification of Diabetes Mellitus

I. Type 1 diabetes (β-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)

A. Nonobese

B. Obese

III. Other specific types of diabetes

 A. Genetic defects of  cell function characterized by mutations in:

    1. Hepatocyte nuclear transcription factor (HNF) 4 α (MODY 1)-

    { MODY, maturity onset diabetes of the young}

    2. Glucokinase (MODY 2)

    3. HNF-1 α (MODY 3)

    4. Insulin promoter factor-1 (IPF-1; MODY 4)

    5. HNF-1β (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, , β -adrenergic agonists, thiazides, phenytoin, α-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)

Source: Adapted from American Diabetes Association, 2007.

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.

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.

Etiology of Type 1 Diabetes

The global incidence of type 1 diabetes is increasing (approximately 3% each year).This form of diabetes is immune-mediated in over 90% of cases and idiopathic in less than 10%. The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others.

A) Immune-mediated type 1 diabetes mellitus

Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors.

Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4.The other important gene that contributes to about 10% of the genetic risk is found at the 5' polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. 16 other genetic regions of the human genome have been identified as being important to pathogenesis but less is known about them.

Children of diabetic parents are at increased lifetime risk for developing type 1 diabetes. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child's father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic parent. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.

Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Up to 15% of "type 2" diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA).

 Environment- Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (rubella, Coxsackie B4) and consumption of cow's milk. None of these factors has so far been confirmed as the culprit.

Types of Auto antibodies (Immunological Markers)

1. Islet cell cytoplasmic antibodies: The primary antibodies found in 90% of type 1 diabetics are against islet cell cytoplasmic proteins (termed ICCA, islet cell cytoplasmic antibodies). In non-diabetics ICCA frequency is only 0.5%–4%. The presence of ICCA is a highly accurate predictor of future development of IDDM, the titer of the ICCA tends to decline over time.

2. Islet cell surface antibodies: Auto antibodies directed against cell-surface antigens (ICSA) have also been described in as many as 80% of type 1 diabetics. Similar to ICCA, the titer of ICSA declines over time. Some patients with type 2 diabetes have been identified that are ICSA positive.

3. Specific antigenic targets of islet cells: Antibodies to Glutamic acid decarboxylase (GAD) have been identified in over 80% of patients newly diagnosed with IDDM. Like ICCA, anti-GAD antibodies decline over time in type 1 diabetics. The presence of anti-GAD antibodies is a strong predictor of the future development of IDDM in high-risk populations. Anti-insulin antibodies (IAA) have been identified in IDDM patients and in relatives at risk to develop IDDM. These IAA are detectable even before the onset of insulin therapy in type 1 diabetics. IAA are detectable in around 40% of young children with IDDM.

B) Idiopathic type 1 diabetes mellitus

Less than 10% of subjects have no evidence of pancreatic B cell autoimmunity to explain their insulinopenia and ketoacidosis. This subgroup has been classified as "idiopathic type 1 diabetes" and designated as "type 1B." Although only a minority of patients with type 1 diabetes fall into this group, most of these are of Asian or African origin. 

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