Type-1 diabetes is immune (autoimmune) mediated and insulin dependent diabetes. The autoimmune process of development of type-1 diabetes starts several years before clinical features/symptoms of diabetes are seen or diagnosis made in routine blood sugar test. The autoimmune process is directed against the islets of Langerhans. Most, but not all, individuals have evidence of antibodies against of islets of Langerhans.

The pathogenesis of type-1 diabetes is the result of interactions between genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency. There is high variation in the incidence of type-1 diabetes among different races and very high among Caucasians, low in Blacks and extremely low in Asians, which strongly suggest genetic influence in the causation of type-1 diabetes.

The development of type-1 diabetes occurs in series of stages which starts with genetic susceptibility and influenced by environmental and immunologic factors, which ultimately leads to destruction of beta cells of islets of Langerhans.

Genetic factors in type-1 diabetes:

Individuals with a genetic susceptibility to type-1 diabetes have normal beta cell mass at birth but begin to lose beta cells secondary to autoimmune destruction that occurs over months to years. The autoimmune process may be triggered by an infectious or environmental stimulus and in the majority of patients; immunologic markers appear after the triggering event which is much before diabetes becomes clinically overt.

The beta cell mass of pancreas begins to decline after autoimmune process start, and insulin secretion progressively decline, although normal glucose tolerance is maintained. The rate of decline in beta cell mass varies widely among individuals, with some individuals progressing rapidly to clinical diabetes and others evolving more slowly, although symptoms of diabetes do not become evident until approximately 80% of beta cells are destroyed. If beta cells are destroyed more than 80%, the insulin secretion is still present but is insufficient to maintain glucose tolerance. The overt development of diabetes may be triggered by increased insulin requirements, as might occur during infections or puberty.

Twin studies shows concordance of type-1 diabetes in 30 to 70% in identical twins. The major susceptibility gene for type-1 diabetes is located in the HLA (Human Leukocyte Antigen) region on chromosome-6.

Most individuals with type-1 diabetes have the HLA DR3 and/or HLA DR4 haplotype. Refinements in genotyping of HLA loci have proven that the haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are associated with type-1 diabetes. Most individuals with predisposing haplotypes do not develop diabetes. The above haplotypes are present in approximately 40% of children with type-1 diabetes in United States as compared to 2% of the normal population.

The haplotype DQA1*0102, DQB1*0602 is very rare in individuals with type-1 diabetes (occurs in less than 1%) and provide protection from type-1 diabetes.

Pathophysiology of Type-1 Diabetes:

Although other islet cell types such as alpha cells (glucagon-producing), delta cells (somatostatin-producing), and PP cells (pancreatic polypeptide-producing) are embryologically as well as functionally similar to beta cells (insulin producing) and express most of the same proteins as beta cells, they are spared from the autoimmune process that initiates development of type-1 diabetes.

Pathologically, the pancreatic islets are infiltrated with lymphocytes, a process called insulitis, which is characterized by infiltration of T-lymphocytes with macrophages and B lymphocytes and loss of most of the beta cells occur, without involvement of the glucagon-secreting cells. After destruction of all beta cells, the inflammatory process stops and the islets become atrophic and as a result most immunologic markers disappear. Studies of the autoimmune process in humans as well as in animal models of type-1 diabetes have shown certain abnormalities such as (1) islet cell autoantibodies (2) activated lymphocytes in the islets, peripancreatic lymph nodes, and systemic circulation; (3) proliferated T-lymphocytes and (4) release of cytokines within the insulitis. Beta cells of islets are more susceptible to the toxic effect of some cytokines such as tumor necrosis factor alpha (TNF-alpha), interferon-gamma, and interleukin-1 (IL-1). The death of beta cell may be due to formation of nitric oxide metabolites, apoptosis, and direct CD8+ T cell cytotoxicity, although not clear.

The destruction of islet cells is mediated by T lymphocytes and not by islet autoantibodies. Suppression of the autoimmune process by use of cyclosporine, T-lymphocyte antibodies etc. at the time of diagnosis of diabetes can slow the decline in beta cell destruction, but the safety is unknown.

Pancreatic islet molecules targeted by the autoimmune process are insulin, glutamic acid decarboxylase (GAD, which is the enzyme for biosynthesis of neurotransmitter GABA), ICA-512/IA-2 (homology with tyrosine phosphatases), and phogrin, which is an insulin secretory granule protein. Except insulin, none of the autoantigens are beta cell specific. Current theories suggests that an autoimmune process is initiated and directed at one beta cell molecule only, which then spreads to other molecules of beta cells as the immune process continues. The beta cells of individuals who develop type-1 diabetes do not differ from beta cells of normal individuals.

Immunological Markers in Type-1 Diabetes:

The immunological markers in Type-1 diabetes are GAD, insulin, and IA-2/ICA-512 and known as Islet cell autoantibodies (ICAs). Commercially available immunological markers include autoantibodies to GAD-65. ICAs can be demonstrated in approximately 75% of new-onset type-1 diabetes, 5%–10% of newly diagnosed type-2 diabetes and in less than 5% of gestational diabetes cases. ICAs are also present in 3%–4% of first-degree relatives of type-1 diabetes patients. ICAs can predict more than 50% risk of developing type 1 DM within 5 years in combination with impaired insulin secretion after IV (intravenous) glucose tolerance test.

At present, the measurement of ICAs in nondiabetic individuals is only a research tool because no treatment is approved for prevention of occurrence or progression to type-1 diabetes.

Environmental Factors in Type-1 Diabetes:

There are numerous environmental factors which are implicated in causation of type-1 diabetes, although none have been conclusively proven to cause type-1 diabetes. The reason of identification of environmental trigger is difficult because the event might precede the onset of diabetes by several years. At present some environmental factors such as viruses (coxsackie virus and rubella virus, which is most prominent), bovine milk proteins, and nitrosourea compounds are implicated to cause type-1 diabetes.

There 10 different types of type-1 diabetes identified each with genetic defect in a particular location of different chromosomes. The following are details:

• IDDM-1: 6p21 (location of defective chromosome)
• IDDM-2: 11p15
• IDDM-3: 15q26
• IDDM-4: 11p13
• IDDM-5: 6q
• IDDM-6: 18
• IDDM-7: 2q31
• IDDM-8: 6q27
• IDDM-9: 3q21-25
• IDDM-10: 10p11

IDDM (Insulin Dependent Diabetes Mellitus)