Prevention of Type Diabetes Mellitus

Jay S. Skyler, Alberto Pugliese, Carlos Bernal, and Jennifer B. Marks

University of Miami School of Medicine. Miami, Florida, USA

INTRODUCTION

The ultimate goal of understanding the epidemiology of any disease is to use that information in the development of programs aimed to prevent or eradicate the disease in question. Such is certainly the case for Type 1 diabetes mellitus. Progress in our understanding of the epidemiology of Type 1 diabetes, including its etiology, genetic and non-genetic influences, changing incidence and prevalence, is reviewed in other chapters in this volume. These factors will be discussed here only as they relate to the purpose of this chapter, the case for implementation of programs for prediction and prevention of Type 1 diabetes.

The clinical symptoms of Type 1 diabetes are the overt expression of an insidious pathogenetic process which began years earlier. The consequence of immune-mediated destruction of the pancreatic islet insulin-secreting beta-cells, clinical disease becomes apparent only when a majority of beta-cells have been destroyed. The pathogenesis of Type 1 diabetes is generally thought to involve genetic predisposition to the disease, non-genetic (environmental) factors that appear to act as triggers in genetically susceptible individuals, activating immune mechanisms specifically targeted against pancreatic islet beta-cells. This may be an oversimplification. Rather, the pathogenesis of type 1 diabetes appears to involve a disruption of balance between forces propelling the progression of disease and forces retarding or preventing that progression (Figure 4A.1). This delicate balance appears to be in place for genetic factors, environmental factors, and immune regulation. Thus, there have been identified genes that confer susceptibility or predisposition to the disease, and genes that confer protection against development of the disease. Likewise, there are apparent environmental insults which have the potential of triggering development of disease in genetically susceptible individuals, while other environmental factors appear to be associated with protection from development of disease. In addition, there seem to be complex regulatory interactions amongst various elements of the immune response, with some elements of the immune circuitry being responsible for beta-cell destruction and others regulating that response and leading to beta-cell protection.

DETERMINANTS Genetic

There are both genetic and environmental determinants of the Type 1 diabetes disease process. The major genetic susceptibility locus for Type 1 diabetes, IDDM1, is localized within the HLA (human leukocyte antigen) region on the short arm of chromosome 6 (1). IDDM1 provides at least 50% of the genetic susceptibility to Type 1 diabetes (1,2). The susceptibility within the IDDM1 locus is mostly conferred by alleles of the HLA-DQ locus in the HLA class II region (3). However, a number of studies have shown that alleles at the DRB1 locus are also important and significantly modulate diabetes susceptibility. The HLA molecules DQA1 *0301-DQB1 *0302 (also known as DQ8), DQA1 *0501-DQB1 *0201 (also known as DQ2), DRA-DRB1 *0401 (also known as DR4) and DRA-DRB1 *0301 (also known as DR3) confer susceptibility to Type 1 diabetes.

A second gene, termed IDDM2, has been mapped to the VNTR (variable number of tandem repeats) minisatellite locus at the 5' end of the insulin gene on the short arm of chromosome

Figure 4A.1 Elements in the pathogenesis of Type 1 diabetes. Type 1 diabetes emerges when the disease-promoting elements in the left-hand column outweigh the protective elements in the right-hand column, i.e. when the balance of forces favors processes which eventuate in immune destruction of islet beta-cells

Figure 4A.1 Elements in the pathogenesis of Type 1 diabetes. Type 1 diabetes emerges when the disease-promoting elements in the left-hand column outweigh the protective elements in the right-hand column, i.e. when the balance of forces favors processes which eventuate in immune destruction of islet beta-cells

11, and accounts for about 10% of the genetic predisposition (4). At least 13 other minor loci have been discovered mostly through microsatellite typing and linkage analysis in large collections of diabetic families with affected sib-pairs, and may contribute to diabetes risk (5).

The best characterized loci, IDDM1 (HLA) and IDDM2 (INS-VNTR), encode true susceptibility genes. Yet, there is also clear evidence that certain alleles provide genetic resistance from the development of diabetes. In particular, genetic protection from Type 1 diabetes is associated with specific alleles at the IDDM1 (6) and IDDM2 loci (7,8). For example, the HLA molecule DQA1 *0102-DQB1 *0602 (also known as DQ6). There usually is dominance of protection over susceptibility for genes encoded at these loci. It is a fair speculation that IDDM1 may be involved in antigen presentation and control immune responsiveness to one or more islet cell antigens, while IDDM2 may control insulin gene expression in the thymus and in turn selectively influence immune responsiveness to insulin. These two susceptibility loci may influence the specificity of the autoimmune response rather than a generic predisposition to autoimmunity.

That genetics plays an important role in the development of Type 1 diabetes has been demonstrated from a number of careful studies. There is a higher concordance rate for Type 1 diabetes in monozygotic twins (35-50%) than in dizygotic twins (5-10%) (9). In siblings of probands of Europoids with Type 1 diabetes, the risk is 6% (10), while offspring of diabetic parents have a 3% risk if the mother has the disease, and a 6% risk if the father has the disease (11). The cumulative concordance or recurrence risk of Type 1 diabetes up to the age of 40 years in dizygotic twin pairs is twice as high as in ordinary first-degree relatives of patients up to the same age (12). The much higher concordance rate for diabetes among monozygotic than dizygotic twins implies that there is an inherited component to a disease. Yet, the substantial (50-65%) discordance rate in mono-zygotic twins indicates that environmental factors also must play a role in human Type 1 diabetes.

In contrast to the familial predisposition noted above, in the general population, the risk is much less. For example in the United States amongst Europoids the overall risk is 0.2 to 0.4%. However, there is considerable racial and ethnic variation in Type 1 diabetes incidence (e.g. 3.3 per 100 000 in African Americans in San Diego, CA, to 20.6 per 100 000 in whites in Rochester, MN), and about 40% of the incidence rate variation in the United States can be explained by racial composition (13).

A recent study examined the frequency of various islet cell antibodies—islet cytoplasmic antibodies (ICA), insulin autoantibodies (IAA), and glutamic acid decarboxylase antibodies (GADA) in 18 monozygotic and 36 dizygotic twin pairs with one or both partners having Type 1 diabetes (14). There was no difference between the prevalence of these three islet cell autoantibodies in dizygotic (26%, 49%, and 40%) and monozygotic (20%, 50%, and 40%) twins without diabetes, suggesting that islet cell autoimmunity is environmentally rather than genetically determined. Moreover, the prevalence of these antibodies was higher in the non-diabetic monozygotic and dizygotic twins than in other first degree relatives (~4%, 3%, and 4%) of patients with Type 1 diabetes (12). This implies that there is etiological importance to the prenatal or early postnatal period during which twins are exposed to the same environment, in contrast with that experienced by first-degree relatives.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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