Type Diabetes

Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes, is characterized by autoimmune destruction of insulin-producing P cells in the pancreas and severe insulin deficiency (233) . Type 1 diabetes accounts for around 10% of all cases of diabetes, occurs more frequently in people of European descent, and affects 2 million people in Europe and North America (234). Currently, there is a 3% global increase in incidence per year, but this is predicted to increase considerably within the next few years (235).

Type 1 diabetes is a complex trait, the etiology of which has only been partially characterized. It is generally recognized though that the disease has both genetic (Fig. 1) and environmental influences. The advances in our understanding of the pathophysi-ology and the genetic factors underlying type 1 diabetes have benefited immensely from studies on spontaneous or genetically manipulated animal models of the disease. Autoimmune diabetes in such models shares many molecular and genetic characteristics to human type 1 diabetes. Animal models have therefore provided valuable information that can be applied on studies of human type-1-diabetes-associated molecular and cellular pathways. The nonobese diabetic (NOD) mouse represents the most studied animal model for type 1 diabetes and has been utilized for the determination of over 20 non-HLA regions (known as insulin-dependent diabetes, Idd) associated with disease risk in this diabetic mouse strain (236). By narrowing down genetic intervals in animal models, a small number of candidate genes have been highlighted for association testing in human patients. An example of this is illustrated by the IL-2 pathway, which was considered as a candidate for the Idd3 locus in the nonobese diabetic mouse. Following extensive investigation, its involvement in human disease was revealed. Analysis of its orthologue gene in humans confirmed its association in type 1 diabetes, therefore providing an example where genes discovered in animal models can be considered as primary candidates for investigation in humans (236). Other widely used animal models include the BioBreeding diabetes-prone rat and the Komeda diabetes-prone rat (237). In addition to the naturally occurring animal models, a range of transgenic animals have been generated for a long series of different genes, including major histocompatibility molecules (e.g., D57, HLA-DRa, HLA-DQ6), cytokines (Il2, Tnfa, Tglfil), autoantigens (proinsulin, HSP60, GAD), costimulatory molecules (Cd152, Cd80), and T-cell receptors (BDC2.5, 8.3) (69).

Through association studies and linkage analysis in humans, an increasing number -19 to date - of IDDM susceptibility loci have been identified (named by the abbreviation IDDM and a number reflecting the order with which they were reported, e.g., IDDM1, IDDM2, etc.) (69,238,239). The human leukocyte antigen (HLA) locus on chromosome 6p21 was the first to be associated with the disease and is thought to contribute for around 50% of the familial basis of type 1 diabetes (234,240-242). It has been shown that the HLA-DR4-DQ8 and HLA-DR3-DQ2 haplotypes are present in 90% ofchildren with type 1 diabetes, whereas HLA-DR15-DQ6 is found in only 1% of affected children but more than 20% in the general population, therefore suggesting that it is protective (243). The genotype combining the two susceptibility haplotypes (DR4-DQ8/DR3-DQ2) contributes the greatest risk for the disease. Despite extensive research, the specific details as to how genes in this region modulate type 1 diabetes risk have still not been fully elucidated.

The insulin gene, or IDDM2 locus, on chromosome 11p15.5 was the second locus to be identified and is the second most common factor, contributing to 10% of the genetic susceptibility of type 1 diabetes (244). Susceptibility in the insulin gene has been primarily mapped to a variable number of tandem repeats located in the promoter region of the gene. Shorter forms of these repeats are associated with susceptibility to the diseases whereas longer repeats are associated with protection (245).

Other genes associated with type 1 diabetes include cytotoxic T-lymphocyte antigen 4 (CTLA4), protein tyrosine phosphatase, nonreceptor type 22 (PTPN22), small ubiq-uitin-like modifier 4 (SUMO4), and the a-chain of interleukin-2 receptor gene (IL2R) (246-248,275,276,277). The KIAA0350 gene, encoding for a protein with predicted sugar binding properties, was the latest one identified (249). Overall, a number of whole genome scans using families and affected sibling pairs performed over the past decade have provided evidence for the existence of many additional loci associated with type 1 diabetes, including but not limited to the IDDM loci (211,250-254,278).

In a coordinated effort on the analysis of existing type 1 diabetes families for the elucidation of the genetic etiology of the disease, the type 1 Diabetes Genetics Consortium (T1DGC) (http://www.t1dgc.org) has been established. The T1DGC represents a worldwide collaboration on the study of a large collection of patients and their families from around the world. The first report from this consortium was published in 2005, and it included a combined linkage analysis of four datasets, three previously published genome scans, and a new dataset of 254 families (252). The T1DGC analysis included 1,435 families with 1,636 affected sibling pairs from the UK, the USA, and Scandinavia, representing one of the largest linkage studies performed so far. In addition to HLA, this large study determined evidence for linkage to ten other chromosomal regions. In particular chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-24 showed genome-wide significance, therefore indicating a strong non-HLA genetic contribution to type 1 diabetes (252).

The T1Dbase database (http://T1DBase.org) represents a powerful resource, which combines and organizes data for type 1 diabetes, focusing on the molecular genetics and biology of disease susceptibility and pathogenesis (255). This public database allows scientists to search across different data sources/types, and thus find new relationships among factors contributing to the complex pathogenesis of type 1 diabetes (256).

In addition to the genetic contributions of type 1 diabetes, it is becoming evident that additional factors, such as environmental influences, are also involved in the development of the disease. Such factors include viruses, such as enteroviruses, rotavirus, and rubella (257,258). Nevertheless, even though Finland has effectively eradicated rubella through vaccination, it has one of the highest incidences of type 1 diabetes. This therefore supports the hygiene hypothesis, which proposes that environmental exposure to microbes early in life promotes innate immune responses that suppress atopy and autoimmunity. To address the role of environmental factors in type 1 diabetes, large-scale studies are required. For this purpose, the international consortium Environmental Determinants of Diabetes in the Young (TEDDY; http://www.niddk.nih. gov/patient/TEDDY/TEDDY.htm) has been established so as to follow large number of babies with high-risk HLA genotypes during early life and thus identify infectious agents, dietary factors, or other environmental factors that could trigger autoimmunity in susceptible populations (234).

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