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Gene Review

IDDM2  -  insulin-dependent diabetes mellitus 2

Homo sapiens

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Disease relevance of IDDM2


Psychiatry related information on IDDM2

  • The IDDM-2 group reported increased psychological distress, as reflected by increased dysphoric or depressive symptoms, trait anxiety, perceived stress, and cynical hostility, as well as decreased optimism and interpersonal, but not family, social support [6].
  • BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) and eating disorders are relatively common among young women in North America. Their coexistence could lead to poor metabolic control and an increased risk of the microvascular complications of IDDM [7].
  • CONCLUSIONS: Disordered eating behavior is common and persistent in young women with IDDM and is associated with impaired metabolic control and a higher risk of diabetic retinopathy [7].
  • We studied 20 IDDM patients with brittle disease; despite use of a four-injection regimen with manipulation of insulin doses, diet, and physical activity, and frequent clinic visits for at least a year, these patients still had wide swings in blood glucose and frequent hypoglycaemic reactions [8].
  • Electrophysiological or psychometric abnormalities were not clearly correlated with the duration of IDDM or the degree of short-term metabolic control [9].

High impact information on IDDM2


Chemical compound and disease context of IDDM2


Biological context of IDDM2

  • Functional studies indicate, firstly, that the susceptible and protective HLA class II molecules HLA-DR and -DQ bind and present nonoverlapping peptides and, secondly, that the variable number of tandem repeats at the 5' end of the insulin gene (susceptibility interval IDDM2) regulates insulin expression in the thymus [19].
  • IDDM2 is encoded by a minisatellite locus embedded in the 5' regulatory region of the insulin gene [20].
  • Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes [21].
  • ID- alleles are only clearly distinguished from all other alleles by an MSPI(-) variant within IGF2 downstream of the minisatellite, suggesting that the apparent role of the minisatellite in susceptibility to T1DM may be modified by neighbouring haplotype and therefore that IDDM2 could have a multi-locus aetiology [1].
  • However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda S = 1.25), cannot account for all of the observed clustering of disease in families (lambda S = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome [22].

Anatomical context of IDDM2


Associations of IDDM2 with chemical compounds

  • This is evidence against the hypotheses that have suggested IGF2 is a mediator of IDDM2-encoded susceptibility and corroborates previous studies suggesting insulin is the gene involved [28].
  • We conclude that the disease risk in Finland appears to be most strongly related to specific Asp 57- alleles, although other HLA- or non-HLA-associated genes may also contribute to IDDM susceptibility in this population [15].
  • Genotypes for homozygous non-aspartic acid residue (NA/NA) at position 57 were positively associated with IDDM at a relative risk of 4.34 (P < 0.001), and those for homozygous aspartic acid (A/A) were negatively associated with IDDM at a relative risk of 0.14 (P < 0.001) [29].
  • Furthermore, we studied siblings positive for islet cell antibodies (ICAs) and/or insulin autoantibodies (IAAs) to evaluate the impact of the-23 HphI INS +/+ genotype on their beta-cell function assessed by sequential intravenous glucose tolerance tests and on their progression to IDDM [30].
  • FCPD patients, however, showed lower circulating concentrations of non-esterified fatty acids (0.73 +/- 0.11 mmol/l), glycerol (0.11 +/- 0.02 mmol/l) and 3-hydroxybutyrate (0.15 +/- 0.03 mmol/l) compared to IDDM patients (1.13 +/- 0.14, 0.25 +/- 0.05 and 0.29 +/- 0.08 mmol/l, respectively) [31].

Regulatory relationships of IDDM2


Other interactions of IDDM2

  • One identified locus has a major effect on type 1 diabetes susceptibility (IDDM1), whereas other loci have significant, yet small, individual effects (IDDM2, IDDM15) [35].
  • No temporal variation was found in the frequencies of genotypes at IDDM2 and IDDM12 [36].
  • Similar VNTR transcriptional effects on IGF2 have also been proposed as a mechanism by which the IDDM2 locus confers susceptibility in addition to, or instead of, effects on INS [28].
  • We studied the cellular immunity to GAD, antibodies to GAD and their association with the HLA DQB1 risk alleles for IDDM in patients with APECED [37].
  • Antibodies to glutamic acid decarboxylase (GAD) occur frequently in patients with APECED, although clinical insulin-dependent diabetes mellitus (IDDM) is seen only in a subgroup of the patients [37].

Analytical, diagnostic and therapeutic context of IDDM2

  • Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study [11].
  • RESULTS: The allele frequencies of allele A5 at D15S657 locus, allele A5 at D11S1369 locus and allele A4 at D6S2420 locus were increased significantly in patients with IDDM compared to those in the control group [38].
  • A sensitive C-peptide immunoreactivity radioimmunoassay demonstrated the presence of subtle, but definite residual beta-cell function in patients with IDDM of long duration [27].
  • We analysed cow's milk formula, betalactoglobulin, and bovine serum albumin antibodies by an enzyme-linked immunoassay in unselected children with newly diagnosed IDDM and in their non-diabetic siblings and inquired about infant feeding practices by questionnaire [39].
  • The role of defects in or near the insulin gene in a small subset of NIDDM or in IDDM must await direct investigation of the insulin gene in diabetic individuals with the most recent methods for gene amplification and sequence analysis [40].


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  2. Autoimmune polyglandular syndromes. Obermayer-Straub, P., Manns, M.P. Baillieres Clin. Gastroenterol. (1998) [Pubmed]
  3. Screening for an AIRE-1 mutation in patients with Addison's disease, type 1 diabetes, Graves' disease and Hashimoto's thyroiditis as well as in APECED syndrome. Meyer, G., Donner, H., Herwig, J., Böhles, H., Usadel, K.H., Badenhoop, K. Clin. Endocrinol. (Oxf) (2001) [Pubmed]
  4. Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2? Královicová, J., Gaunt, T.R., Rodriguez, S., Wood, P.J., Day, I.N., Vorechovsky, I. Diabetes (2006) [Pubmed]
  5. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Cornélis, F., Fauré, S., Martinez, M., Prud'homme, J.F., Fritz, P., Dib, C., Alves, H., Barrera, P., de Vries, N., Balsa, A., Pascual-Salcedo, D., Maenaut, K., Westhovens, R., Migliorini, P., Tran, T.H., Delaye, A., Prince, N., Lefevre, C., Thomas, G., Poirier, M., Soubigou, S., Alibert, O., Lasbleiz, S., Fouix, S., Bouchier, C., Lioté, F., Loste, M.N., Lepage, V., Charron, D., Gyapay, G., Lopes-Vaz, A., Kuntz, D., Bardin, T., Weissenbach, J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Aberrant parasympathetic and hemodynamic function distinguishes a subgroup of psychologically distressed individuals with asymptomatic type-I diabetes mellitus. Motivala, S.J., Hurwitz, B.E., LaGreca, A.M., Llabre, M.M., Marks, J.B., Skyler, J.S., Schneiderman, N. International journal of behavioral medicine. (1999) [Pubmed]
  7. Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. Rydall, A.C., Rodin, G.M., Olmsted, M.P., Devenyi, R.G., Daneman, D. N. Engl. J. Med. (1997) [Pubmed]
  8. Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus. Aoki, T.T., Benbarka, M.M., Okimura, M.C., Arcangeli, M.A., Walter, R.M., Wilson, L.D., Truong, M.P., Barber, A.R., Kumagai, L.F. Lancet (1993) [Pubmed]
  9. Abnormalities of cognitive functions in IDDM revealed by P300 event-related potential analysis. Comparison with short-latency evoked potentials and psychometric tests. Pozzessere, G., Valle, E., de Crignis, S., Cordischi, V.M., Fattapposta, F., Rizzo, P.A., Pietravalle, P., Cristina, G., Morano, S., di Mario, U. Diabetes (1991) [Pubmed]
  10. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. Imagawa, A., Hanafusa, T., Miyagawa, J., Matsuzawa, Y. N. Engl. J. Med. (2000) [Pubmed]
  11. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Concannon, P., Gogolin-Ewens, K.J., Hinds, D.A., Wapelhorst, B., Morrison, V.A., Stirling, B., Mitra, M., Farmer, J., Williams, S.R., Cox, N.J., Bell, G.I., Risch, N., Spielman, R.S. Nat. Genet. (1998) [Pubmed]
  12. 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. Pugliese, A., Zeller, M., Fernandez, A., Zalcberg, L.J., Bartlett, R.J., Ricordi, C., Pietropaolo, M., Eisenbarth, G.S., Bennett, S.T., Patel, D.D. Nat. Genet. (1997) [Pubmed]
  13. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Vafiadis, P., Bennett, S.T., Todd, J.A., Nadeau, J., Grabs, R., Goodyer, C.G., Wickramasinghe, S., Colle, E., Polychronakos, C. Nat. Genet. (1997) [Pubmed]
  14. Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7. Rowe, R.E., Wapelhorst, B., Bell, G.I., Risch, N., Spielman, R.S., Concannon, P. Nat. Genet. (1995) [Pubmed]
  15. HLA-DQB1 alleles and absence of Asp 57 as susceptibility factors of IDDM in Finland. Reijonen, H., Ilonen, J., Knip, M., Akerblom, H.K. Diabetes (1991) [Pubmed]
  16. Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles. Ueki, A., Isozaki, Y., Kusaka, M. Journal of occupational health. (2005) [Pubmed]
  17. Clinical studies of IGFBP-2 by radioimmunoassay. Blum, W.F., Horn, N., Kratzsch, J., Jørgensen, J.O., Juul, A., Teale, D., Mohnike, K., Ranke, M.B. Growth Regul. (1993) [Pubmed]
  18. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. Kadowaki, T., Kadowaki, H., Mori, Y., Tobe, K., Sakuta, R., Suzuki, Y., Tanabe, Y., Sakura, H., Awata, T., Goto, Y. N. Engl. J. Med. (1994) [Pubmed]
  19. Genetic susceptibility factors in type 1 diabetes: linkage, disequilibrium and functional analyses. She, J.X., Marron, M.P. Curr. Opin. Immunol. (1998) [Pubmed]
  20. Multifactorial inheritance in type 1 diabetes. Cordell, H.J., Todd, J.A. Trends Genet. (1995) [Pubmed]
  21. Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes. Cordell, H.J., Todd, J.A., Bennett, S.T., Kawaguchi, Y., Farrall, M. Am. J. Hum. Genet. (1995) [Pubmed]
  22. Panning for gold: genome-wide scanning for linkage in type 1 diabetes. Todd, J.A., Farrall, M. Hum. Mol. Genet. (1996) [Pubmed]
  23. Divergence between genetic determinants of IGF2 transcription levels in leukocytes and of IDDM2-encoded susceptibility to type 1 diabetes. Vafiadis, P., Bennett, S.T., Todd, J.A., Grabs, R., Polychronakos, C. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  24. Genetics of type 1A diabetes. Redondo, M.J., Fain, P.R., Eisenbarth, G.S. Recent Prog. Horm. Res. (2001) [Pubmed]
  25. Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. Vafiadis, P., Bennett, S.T., Colle, E., Grabs, R., Goodyer, C.G., Polychronakos, C. J. Autoimmun. (1996) [Pubmed]
  26. Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. Fox, C.J., Paterson, A.D., Mortin-Toth, S.M., Danska, J.S. Am. J. Hum. Genet. (2000) [Pubmed]
  27. Association of HLA-A24 with complete beta-cell destruction in IDDM. Nakanishi, K., Kobayashi, T., Murase, T., Nakatsuji, T., Inoko, H., Tsuji, K., Kosaka, K. Diabetes (1993) [Pubmed]
  28. A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes. Vafiadis, P., Grabs, R., Goodyer, C.G., Colle, E., Polychronakos, C. Diabetes (1998) [Pubmed]
  29. HLA-DQB1 codon 57 and IDDM in Chinese living in Taiwan. Chuang, L.M., Jou, T.S., Hu, C.Y., Wu, H.P., Tsai, W.Y., Lee, J.S., Hsieh, R.P., Chen, K.H., Tai, T.Y., Lin, B.J. Diabetes Care (1994) [Pubmed]
  30. Effect of polymorphism in the insulin gene region on IDDM susceptibility and insulin secretion. The Childhood Diabetes in Finland (DiMe) Study Group. Halminen, M., Veijola, R., Reijonen, H., Ilonen, J., Akerblom, H.K., Knip, M. Eur. J. Clin. Invest. (1996) [Pubmed]
  31. The ketosis-resistance in fibro-calculous-pancreatic-diabetes. 1. Clinical observations and endocrine-metabolic measurements during oral glucose tolerance test. Yajnik, C.S., Shelgikar, K.M., Naik, S.S., Kanitkar, S.V., Orskov, H., Alberti, K.G., Hockaday, T.D. Diabetes Res. Clin. Pract. (1992) [Pubmed]
  32. Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus. Sabater, L., Ferrer-Francesch, X., Sospedra, M., Caro, P., Juan, M., Pujol-Borrell, R. J. Autoimmun. (2005) [Pubmed]
  33. Distribution of HLA-DRB1, -DQA1 and -DQB1 alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus. Rønningen, K.S., Spurkland, A., Iwe, T., Vartdal, F., Thorsby, E. Tissue Antigens (1991) [Pubmed]
  34. Contribution of the absence of aspartic acid at position 57 of the HLA-DQ beta chain to predisposition to insulin-dependent diabetes mellitus in a southern Chinese population. Zhang, S., Cheng, H., Fu, Z., Zhong, G., Yan, T. Chin. Med. J. (1998) [Pubmed]
  35. Challenges and strategies for investigating the genetic complexity of common human diseases. Rich, S.S., Concannon, P. Diabetes (2002) [Pubmed]
  36. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes--indication of an increased environmental pressure? Hermann, R., Knip, M., Veijola, R., Simell, O., Laine, A.P., Akerblom, H.K., Groop, P.H., Forsblom, C., Pettersson-Fernholm, K., Ilonen, J. Diabetologia (2003) [Pubmed]
  37. Autoimmunity to glutamic acid decarboxylase in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Klemetti, P., Björses, P., Tuomi, T., Perheentupa, J., Partanen, J., Rautonen, N., Hinkkanen, A., Ilonen, J., Vaarala, O. Clin. Exp. Immunol. (2000) [Pubmed]
  38. Preliminary studies on associations of IDDM3, IDDM4, IDDM5 and IDDM8 with IDDM in Chengdu population. Zhoucun, A., Zhang, S., Xiao, C. Chin. Med. Sci. J. (2001) [Pubmed]
  39. Significance of cow's milk protein antibodies as risk factor for childhood IDDM: interactions with dietary cow's milk intake and HLA-DQB1 genotype. Childhood Diabetes in Finland Study Group. Saukkonen, T., Virtanen, S.M., Karppinen, M., Reijonen, H., Ilonen, J., Räsänen, L., Akerblom, H.K., Savilahti, E. Diabetologia (1998) [Pubmed]
  40. Insulin gene in diabetes. Analysis through RFLP. Permutt, M.A., Elbein, S.C. Diabetes Care (1990) [Pubmed]
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