Insulin gene

The insulin gene, the second locus to be linked with susceptibility to type 1 diabetes, was identified in the 1980s. The insulin gene (INS) on chromosome 11p15 encompasses 1430 base pairs (bp) and results in the translation of preproinsulin, the precursor of mature insulin. Preproinsulin is processed to proinsulin by removal of the signal peptide and then to mature biologically active insulin by removal of the C-peptide. Insulin has been proposed as the primary autoantigen in type 1 diabetes. A variable number tandem repeat (VNTR) region consisting of a 14 to 15 bp consensus sequence upstream of the INS gene, in the INS promoter, is comprised of three classes of alleles: there is a higher frequency of class I alleles with shorter repeat sequences in individuals with type 1 diabetes, whereas individuals with longer class III alleles are relatively protected from type 1 diabetes. The VNTR regulates transcription rates of insulin and its precursors.

Figure 1
Figure 1

Background

The insulin gene (INS) on chromosome 11p 15 codes for the islet beta cell protein, pre-proinsulin, a peptide of 110 amino acids. Preproinsulin, a precursor, is processed by proteases to proinsulin by removal of the signal peptide and ultimately to biologically active insulin after the cleavage of C-peptide (figure 1).

Autoimmunity to insulin in diabetes

In type 1 diabetes insulin producing beta cells are the focus of autoimmune destruction, and their loss results in diabetes. Evidence from the NOD mouse model of autoimmune diabetes suggests that insulin is the primary autoantigen in this model [1] [2] and autoantibodies to insulin can indeed be detected in humans in the first year of life[3].

Type 1 diabetes associates with the insulin gene.

Further evidence that insulin itself plays a fundamental role in the pathogenesis of autoimmune diabetes emerged when genetic associations between INS and type 1 diabetes were reported by Bell and colleagues in 1984 in a relatively small study of 113 affected individuals compared with 83 healthy controls and 76 with type 2 diabetes[4]. This association has been consistently replicated in every genetic analysis since: genome wide association studies (GWAS) have confirmed that the insulin gene locus is the second most important susceptibility locus after the HLA locus, contributing about 10% of genetic susceptibility.

Molecular Biology of the insulin Gene

The insulin gene comprises 3 exons and 2 introns interspersed with several polymorphisms in linkage disequilibrium. Type 1 diabetes is most closely associated with a variable number tandem repeat (VNTR) in the INS promoter [5][6] about 0.5Kb upstream of the transcription start site.

Although highly polymorphic, three different classes of alleles exist at this locus, short class 1 variants (26-63 repeats), intermediate class II repeats and larger class III variants (140-210) repeats.

Homozygosity for the short class I allele is found in about 80% of patients with type 1 diabetes as compared with approximately 60% of individuals in the general population. In contrast the longer class III alleles are rare in type 1 diabetes, suggesting protection. Class II alleles are rare in Caucasians.

Mechanism of Genetic Susceptibility

A mechanism underlying INS mediated susceptibility was proposed several years ago. This goes as follows: protective class III alleles are associated with increased levels of INS transcription relative to class I alleles in the thymus where positive and negative selection of T cells occurs[7][8]. Lower levels of expression of INS associated with class I alleles is therefore likely to be associated with less effective negative selection of INS reactive T cells. In contrast, the opposite expression pattern was observed in the pancreas.

Summary

Insulin is therefore a key player in all aspects of type 1 diabetes, and clinical, genetic and immunological efforts to re-educate immune recognition of insulin underlie several completed or ongoing clinical intervention trials, such as the DPT-1 Oral Insulin Trial.

References

  1. ^ Moriyama H et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse.

  2. ^ Nakayama M et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005 12:435:220-3.

  3. ^ Roll U et al. Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes. 1996 :45:967-73.

  4. ^ Bell GI et al. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984:33:176-83.

  5. ^ Bennett ST et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group. Nat Genet. 1997 17:350-2.

  6. ^ Barratt BJ et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes. 2004 53:1884-9.

  7. ^ Pugliese A et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 1997 15:293-7.

  8. ^ Vafiadis P et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet. 1997 15:289-92.

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