INSULIN-DEPENDENT DIABETES MELLITUS 1, INCLUDED
JOD DIABETES MELLITUS, INSULIN-DEPENDENT, 1, INCLUDED
DIABETES MELLITUS, TYPE I
JUVENILE-ONSET DIABETES
IDDM1, INCLUDED
IDDM
The type of diabetes mellitus called IDDM is a disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian ... The type of diabetes mellitus called IDDM is a disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of IDDM have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. The classical phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
The term diabetes mellitus is not precisely defined and the lack of a consensus on diagnostic criteria has made its genetic analysis difficult. Diabetes mellitus is classified clinically into 2 major forms of the primary illness, insulin-dependent diabetes ... The term diabetes mellitus is not precisely defined and the lack of a consensus on diagnostic criteria has made its genetic analysis difficult. Diabetes mellitus is classified clinically into 2 major forms of the primary illness, insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM; 125853), and secondary forms related to gestation or medical disorders. Appearance of the IDDM phenotype is thought to require a predisposing genetic background and interaction with other environmental factors. Rotter and Rimoin (1978) hypothesized that there are at least 2 forms of IDDM: a B8 (DR3)-associated form characterized by pancreatic autoimmunity, and a B15-associated form characterized by antibody response to exogenous insulin. Interestingly, the DR3 and DR4 alleles seem to have a synergistic effect on the predisposition to IDDM based on the greatly increased risk observed in persons having both the B8 and B15 antigens (Svejgaard and Ryder, 1977). Rotter and Rimoin (1979) hypothesized a combined form. Tolins and Raij (1988) cited clinical and experimental evidence to support the idea that those IDDM patients in whom diabetic nephropathy (see 603933) eventually develops may have a genetic predisposition to essential hypertension. Gambelunghe et al. (2001) noted heterogeneity of the clinical and immunologic features of IDDM in relation to age at clinical onset. Childhood IDDM is characterized by an abrupt onset and ketosis and is associated with HLA-DRB1*04-DQA1*0301-DQB1*0302 and a high frequency of insulin and IA-2 autoantibodies. On the other hand, the so-called latent autoimmune diabetes of the adult (LADA) is a slowly progressive form of adult-onset autoimmune diabetes that is noninsulin-dependent at the time of clinical diagnosis and is characterized by the presence of glutamic acid decarboxylase-65 (GAD65: 138275) autoantibodies and/or islet cell antibodies.
Todd et al. (1987) estimated that more than half of the inherited predisposition to IDDM maps to the region of the HLA class II genes on chromosome 6. Analysis of the DNA sequences from diabetics indicated that alleles ... Todd et al. (1987) estimated that more than half of the inherited predisposition to IDDM maps to the region of the HLA class II genes on chromosome 6. Analysis of the DNA sequences from diabetics indicated that alleles of HLA-DQ(beta) determined both disease susceptibility and resistance. A non-asp at residue 57 of the beta-chain in particular confers susceptibility to IDDM and the autoimmune response against the insulin-producing islet cells. Morel et al. (1988) found that HLA haplotypes carrying an asp in position 57 of the DQ-beta chain (146880) were significantly increased in frequency among nondiabetics, while non-asp57 haplotypes were significantly increased in frequency among diabetics. Ninety-six percent of the diabetic probands were homozygous non-asp/non-asp as compared to 19.5% of healthy, unrelated controls. This represented a relative risk of 107 for non-asp57 homozygous individuals. See critique by Klitz (1988). Khalil et al. (1990) presented evidence suggesting that asp57-negative DQ-beta as well as arg52-positive DQ-alpha chains are important to susceptibility to IDDM. Presumably, the modulation of susceptibility operates via the presentation of viral-antigenic peptide and/or autoantigen. I-Ag7, the only class II allele expressed by the nonobese diabetic mouse, lacks asp57. Corper et al. (2000) determined the crystal structure of the I-Ag7 molecule at 2.6-angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65 (138275). I-Ag7 has a substantially wider peptide-binding groove around beta-57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of asp-beta-57 leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T-cell receptor (see 186830). Nakanishi et al. (1999) sought to identify IDDM-susceptible HLA antigens in IDDM patients who did not have the HLA-DQA1*0301 allele and to correlate the relationship of these HLA antigens to the degree of beta-cell destruction. In 139 Japanese IDDM patients and 158 normal controls, they typed HLA-A, -C, -B, -DR, and -DQ antigens. Serum C-peptide immunoreactivity response (delta-CPR) to a 100-g oral glucose load of 0.033 nmol/L or less was regarded as complete beta-cell destruction. All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc of 0.0256 and 0.0080, respectively). Delta-CPR in IDDM patients with both HLA-DQA1*0301 and HLA-A24 was lower than in IDDM patients with HLA-DQA1*0301 only and in IDDM patients with HLA-A24 only. The authors concluded that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate beta-cell destruction in an additive manner. Donner et al. (1999) analyzed the presence of a solitary human endogenous retrovirus-K (HERV-K) long terminal repeat (LTR) in the HLA-DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from IDDM. Segregation analysis of 984 HLA-DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA-DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P less than 10-6), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA-DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P less than 10-6) compared with 1 of 6 DR-DQ-matched DQ-LTR3-negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3-negative haplotypes were also preferentially transmitted to patients (80%; P less than 10-6), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). The authors concluded that the presence of DQ-LTR3 on HLA-DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for IDDM. Pugliese et al. (1999) sequenced the DQB1*0602 and DQA1*0102 alleles in 8 ICA/DQB1*0602-positive relatives and in 6 rare patients with type I diabetes and DQB1*0602. They found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them had the mtDNA 3243A-G mutation (590050.0001) associated with late-onset diabetes in ICA-positive individuals. Because they did not find diabetes in ICA/DQB1*0602-positive relatives, the authors concluded that the development of diabetes in individuals with DQB1*0602 remains very unlikely, even in the presence of ICA. Cordell et al. (1995) applied to insulin-dependent diabetes mellitus an extension of the maximum lod score method of Risch (1990), which allowed the simultaneous detection and modeling of 2 unlinked disease loci. The method was applied to affected sib pair data, and the joint effects of IDDM1 (HLA) and IDDM2, the INS VNTR, and IDDM1 and IDDM4 (FGF3-linked) were assessed. In the presence of genetic heterogeneity, there seemed to be a significant advantage in analyzing more than 1 locus simultaneously. Cordell et al. (1995) stated that the effects at IDDM1 and IDDM2 were well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 followed a heterogeneity model. Cucca et al. (2001) predicted the protein structure of HLA-DQ by using the published crystal structures of different allotypes of the murine ortholog of DQ, IA. There were marked similarities both within and across species between type 1 diabetes protective class II molecules. Likewise, the type 1 diabetes predisposing molecules DR and murine IE showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. There was also inter-isotypic conservation between protective DQ, IA allotypes, and protective DR4 subtypes. The authors proposed a model for a joint action of the class II peptide-binding pockets P1, P4, and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. They suggested shared epitope(s) in the target autoantigen(s) and common pathways in human and murine type 1 diabetes. Kristiansen et al. (2003) demonstrated that the -174C variant of the -174G/C SNP in the IL6 gene (147620.0001) was significantly associated with IDDM in Danish females, but not in males, and that the association was not caused by preferential transmission distortion in females. Using reporter assay studies, they also demonstrated evidence suggesting that the repressed PMA-stimulated activity of the -174G variant was reverted by 17-beta-estradiol (E2), whereas the stimulated activity of the -174C variant was E2 insensitive and higher than the stimulated activity of the -174G variant in the absence of E2. Kristiansen et al. (2003) concluded that higher IL6 promoter activity may confer risk to IDDM in very young females and that this risk may be negated with increasing age, possibly by the increasing E2 levels in puberty. Bottini et al. (2004) demonstrated association of a missense SNP in the PTPN22 gene (R620W; 600716.0001) with type I diabetes. Kawasaki et al. (2006) identified a promoter SNP in the PTPN22 gene (600716.0002) that associated with type 1 diabetes in Japanese and Korean IDDM patients. Tessier et al. (2006) confirmed association of type 1 diabetes with 2 SNPs in the OAS1 gene (164350.0001, 164350.0002). Smyth et al. (2008) identified a significant association between an insertion-deletion variant in the CCR5 gene on chromosome 3p21 (601373.0001) and a reduced risk for type 1 diabetes (IDDM22; 612522). Concannon et al. (2009) reviewed the genetics of type 1A (immune-mediated) diabetes, noting that genes within the HLA region, predominantly those that encode antigen-presenting molecules, confer the greatest part of the genetic risk for type 1A diabetes. The authors concluded that the existence of other loci with individual effects on risk of a similar magnitude is very unlikely, and suggested that the remaining non-HLA loci will make only modest individual contributions to risk, with odds ratios of 1.3 or less. Concannon et al. (2009) noted that a majority of the other loci appear to exert their effects in the immune system, particularly on T cells. Zalloua et al. (2008) identified homozygous or compound heterozygous mutations in the WFS1 gene (see, e.g., 606201.0024) in 22 (5.5%) of 399 Lebanese probands ascertained with juvenile-onset insulin-dependent diabetes, of whom 17 had Wolfram syndrome (WFS1; 222300) and 5 had nonsyndromic nonautoimmune diabetes mellitus. There were 2 additional probands who were given an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study, and Zalloua et al. (2008) noted that longer follow-up of the nonsyndromic DM patients or a specific study of WFS adult patient populations would be needed to determine whether a subset of the WFS1-mutated nonsyndromic DM patients are exempted from extrapancreatic manifestations during their lifetime.
IDDM occurs about 20 times more frequently among children in the United States than among those in China. Bao et al. (1989) examined the question of whether this was due to a difference in the frequency of the ... IDDM occurs about 20 times more frequently among children in the United States than among those in China. Bao et al. (1989) examined the question of whether this was due to a difference in the frequency of the allele leading to aspartic acid in position 57 of the HLA-DQ-beta chain. The presence of asp57 (or A) seems to protect against IDDM, while a noncharged amino acid in the same position (NA) is associated with increased susceptibility. Among probands in the IDDM registries in Allegheny County, Pa., 96% were homozygous NA, 4% were heterozygous, and none was homozygous A. In studies of 18 Chinese IDDM patients and 25 unrelated healthy Chinese controls, Bao et al. (1989) found that only 1 patient was homozygous NA and 13 were heterozygous, while among the 25 Chinese controls, 23 were homozygous A. The large proportion of homozygous A persons in the Chinese population is consistent with the low incidence of IDDM in China. The association between NA and IDDM may be strong in both populations. Dorman et al. (1990) hypothesized that the 30-fold difference in IDDM incidence across racial groups and countries is related to variability in the frequency of NA alleles. To test the hypothesis, they evaluated diabetic and nondiabetic persons in 5 populations, with risks that were low, moderate, and high. NA alleles were significantly associated with IDDM in all areas, with population-specific odds ratios for NA homozygotes relative to A homozygotes ranging from 14 to 111. Dorman et al. (1990) used estimated genotype-specific incidence rates for Allegheny County, Pa., Caucasians to predict the overall incidence rates in the remaining populations. These predictions fell within the 95% confidence limits of the actual rates established from incidence registries. Results were considered consistent with the hypothesis that population variation in the distribution of NA alleles explains much of the geographic variation in IDDM incidence. Concannon et al. (1990) excluded close linkage of a gene making a major contribution to susceptibility to IDDM and the genes for 2 T-cell receptors, TCRA (see 186880) and TCRB (see 186930). In a Japanese study, Imagawa et al. (2000) described what appeared to be a novel subtype of type I diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Lernmark (2000) argued that, despite the unusual features, these patients had autoimmune type I diabetes. Since the patients described by Imagawa et al. (2000) had features of genetic susceptibility to autoimmune type I diabetes, Lernmark (2000) found it tempting to speculate that diabetes resulted from accelerated beta-cell destruction due to some environmental factor that had such a rapid effect that the autoimmune response characteristic of autoimmune type I diabetes was precluded. Along the same lines, Honeyman et al. (2000) suggested that rotavirus, which is not infectious until it is activated by trypsin (a product of the exocrine pancreas that can infect islets in tissue culture), may have been a cause of clinically silent pancreatic infection in the patients reported by Imagawa et al. (2000) and may have led to T cell-mediated loss of beta cells before islet-cell antibodies could develop. The incidence of IDDM in Korea is less than one-tenth of that in the United States, and it has been suggested that HLA alleles of Asian patients associated with diabetes differ from those of Caucasians. Park et al. (2000) analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with IDDM. They performed HLA DR and DQ typing of 158 IDDM patients in a case control study, 140 nondiabetic subjects from the same geographic area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the 2 populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families. The authors concluded that, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of IDDM.