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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A class of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM), but family studies have failed to demonstrate linkage. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequence were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases.
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PMID:Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. 194 95

Parental genomic imprinting is the phenomenon in which the behavior of a gene is modified, depending on the sex of the transmitting parent [Peterson and Sapienza (1993): Annu Rev Genet 27:7-31]. Recent observations have revealed that the inheritance patterns, age-of-onset, severity, and etiology of certain human diseases can be explained by aberrations in the establishment or the maintenance of the imprint. Examples include the Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes [Nicholls (1994): Am J Hum Genet 54:733-740], malignancy [Sapienza (1990): Biochim Biophys Acta 1072:51-61; Feinberg (1993): Nat Genet 4:110-113], and insulin-dependent diabetes mellitus (IDDM) [Julier et al. (1994) Nature 354:155-159; Bennett et al. (1995) Nat Genet 9:284-292]. We review the evidence that implicates an imprinted gene in the INS-IGF2 region of chromosome 11p15 in the etiology of IDDM (referred to as the IDDM2 locus) and show that in human fetal pancreas, INS is not imprinted, thus providing an argument against INS as the candidate gene. We also examine imprinting effects on the expression of IGF2 in components of the human immune system believed to be important in IDDM and show imprinted expression in fetal thymus as early as 15 weeks gestation. We demonstrate further that in the circulating mononuclear cells of two individuals, lectin-stimulated IGF2 transcription was biallelic, indicating relaxation of imprinting, whereas in one individual, transcription was monoallelic. Finally, we review the current available data supporting a role for insulin-like growth factor-II (IGF-II) in the immune system and, more specifically, discuss the evidence supporting a role for the IGFs in the prevention of apoptosis. These data have led us to formulate a novel hypothesis that could mechanistically explain the involvement of the IDDM2 locus in the pathogenesis of IDDM.
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PMID:Imprinting of IGF2, insulin-dependent diabetes, immune function, and apoptosis: a hypothesis. 856 31

One of the loci encoding susceptibility to insulin-dependent diabetes mellitus (IDDM) is IDDM2, mapped to a variable number of tandem repeats (VNTR) polymorphism situated 596 bp upstream of the insulin gene (INS). The shorter alleles (class I) predispose to IDDM, while the longer class III alleles are protective. Besides INS, it is possible that transcription levels of IGF2, the nearby gene encoding the insulin-like growth factor II, may be modulated by allelic forms of the VNTR. In an effort to define the pathophysiologic mechanism of the IDDM2 effect, we examined the effect, in cis, of VNTR genotype on steady-state mRNA levels of INS in samples of human fetal pancreas, and of IGF2 in leucocytes of diabetic children. Relative levels of mRNA transcripts derived from each chromosome carrying a defined VNTR allele were measured by RT-PCR, taking advantage of transcribed polymorphisms at the 3' untranslated region of each gene. In 10 samples of human fetal pancreas, INS transcripts from chromosomes carrying a class III VNTR were slightly but significantly (P = 0.015) lower than those from class I (13% lower, 95% confidence limits 3-21%). In 10 leucocyte samples, mRNA from both IGF2 alleles was seen, indicating relaxation of the parental imprinting of IGF2 in these cells. However, this relaxation was incomplete as maternal allele mRNA was systematically at a lower level than paternal. The paternal/maternal ratio varied widely among individual subjects. Two of the most extreme cases, demonstrating almost complete repression of the maternal allele, were identical twins, suggesting that this variable relaxation of imprinting is genotype-dependent. However, this genotype-dependence cannot be accounted for by the maternal VNTR, as the mean ratios of paternal/maternal IGF2 mRNA levels were not statistically different in individuals with a maternal VNTR of class I vs. class III (3.2 +/- 1.5 vs. 3.89 +/- 0.94). Thus, we present evidence that: (a) class III VNTR alleles are associated with lower INS mRNA in fetal pancreas than class I alleles. The biologic importance of this difference remains to be determined; and (b) the variable relaxation of IGF2 imprinting seen in human leucocytes is not dependent on the presence of a class I vs. a class III VNTR.
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PMID:Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. 881 77

The IDDM2 component of the genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) has been mapped to chromosome 11p15.5. The exact identity of IDDM2 remains uncertain. It has been suggested that IDDM2 maps within the 5' VNTR (variable number tandem repeat) polymorphism upstream of the insulin gene (INS). This has not been confirmed and a contribution from other INS gene region polymorphisms cannot be excluded. We present INS region genotype data from four racial groups: the Japanese, Hong Kong Chinese, North Indian Asians and Afro-Caribbeans (two groups; one born and resident in the UK, one in Jamaica). These races have not been previously studied with the range of INS region polymorphisms included here. No INS polymorphism was associated with IDDM across all races. These data from this study thus do not identify any INS polymorphism as IDDM2. The Afro-Caribbean race showed a very different distribution of INS genotypes from the other races and novel race-specific INS haplotypes were identified. Analysis of these excluded a contribution to susceptibility to IDDM from the- 23HphI INS polymorphism. An Afro-Caribbean INS haplotype which differed only at the VNTR from the very protective INS haplotype (VPH) identified in white Caucasians was detected. Population analysis of this haplotype will allow direct assessment of the role of the VNTR in susceptibility to IDDM. In conclusion, the diverse Afro-Caribbean TH/INS/IGF2 haplotypes identified in this study will be valuable in mapping IDDM2 more precisely.
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PMID:The insulin gene region and susceptibility to insulin-dependent diabetes mellitus in four races; new insights from Afro-Caribbean race-specific haplotypes. 955 51

Body mass index (BMI) is an established epidemiological predictor of coronary disease, diabetes and hypertension. In a previous study of 2560 healthy British Caucasoid males aged 50-61 years (Northwick Park Heart Study II; NPHSII), we showed that IGF2 ApaI AA homozygotes display a mean body weight 3.3 kg lower than GG homozygotes (P = 0.0002) independent of height. Two RFLPs in the insulin (INS) gene, +1127/PstI shown previously and -23/HphI in this study, both of which are in strong linkage disequilibrium with class I/III alleles of the INS 5' variable number tandem repeat (VNTR), are not associated with weight or BMI. The IGF2 ApaI polymorphism therefore appears to mark an effect independent of INS VNTR class I vs class III. We now show by regression that there is a positive correlation of BMI with INS VNTR class I allele size, with an average 0.33% (95% CI = 0.13%, 0.50%) increase in BMI per extra tandem repeat (P < 0.0001) representing variation of 4.8% over the allele size range. However, an alternative interpretation is of 'step' rather than 'slope', the small class I subclass allele group (mode 669 bp) being lighter than the large subclass group (mode 814 bp). This small effect would not be evident as an association between INS VNTR class I/I1 genotype and BMI. The IGF2 ApaI association and INS VNTR class I subclass regression association account for at least 1.1% of population BMI variance. Neither, both, or a third site may be aetiological.
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PMID:Associations of IGF2 ApaI RFLP and INS VNTR class I allele size with obesity. 1057 16

Wound healing, including re-epithelialization, is delayed in diabetes. Growth factors influence the healing process and amongst these, insulin-like growth factor (IGF) has been shown to stimulate keratinocyte proliferation in vitro. Monoclonal antibodies to insulin-like growth factors 1 and 2 (IGF1 and IGF2) were used to investigate their distribution in diabetic foot ulcers and surrounding tissues by immunohistochemistry, compared with diabetic and non-diabetic uninjured skin. IGF2 was found throughout the epidermis (stratum granulosum, spinosum, and basale) in all three groups. Staining for IGF2 was intense in both normal and diabetic skin as well as in diabetic foot ulcers, being greatest at the ulcer edge. IGF1, in comparison, was found throughout the epidermis of non-diabetic skin; expression was restricted to the stratum granulosum and spinosum of uninjured diabetic skin and was absent in the basal layer at the ulcer edge. A similar absence of IGF1 in dermal fibroblasts was found in tissue sections from diabetic patients. This lack of expression of IGF1 within the basal layer and fibroblasts may contribute to retarded wound healing in diabetes mellitus.
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PMID:Lack of insulin-like growth factor 1 (IGF1) in the basal keratinocyte layer of diabetic skin and diabetic foot ulcers. 1072 85

Allelic variation in the size of the insulin (INS) variable number tandem repeat (VNTR) correlates with the expression of both INS in the pancreas and thymus and IGF2 (the gene downstream of INS) in the placenta. In addition, the shorter, class I alleles are associated with type 1 diabetes, whereas the longer, class III alleles are associated with type 2 diabetes, polycystic ovary syndrome (PCOS), and size at birth. Parent-of-origin effects have been reported for type 2 diabetes and PCOS, thus implicating a role for genomic imprinting in these phenotypes. In mice, Ins2 is imprinted and paternally expressed in the yolk sac. In humans, evidence for the imprinting of INS is circumstantial, with occasional monoallelic expression in the thymus. In the present study, we found evidence for the imprinted paternal expression of INS in the human yolk sac. Two other imprinted genes from the same cluster are also expressed monoallelically in the human yolk sac. IGF2 was expressed solely from the paternal allele, and H19 was expressed solely from the maternal allele. These data suggest not only further functional roles for the human yolk sac in early fetal growth, but also evidence for a potential causal link between the control of insulin expression during development and insulin/growth-related diseases in later life.
Diabetes 2001 Jan
PMID:Evidence that insulin is imprinted in the human yolk sac. 1114 88

Abdominal visceral fat (AVF), abdominal subcutaneous fat (ASF), and abdominal total fat (ATF) were measured using a computed tomography scan, both before (baseline) and after (post) a 20-week endurance exercise training protocol in the HERITAGE Family Study. Each of the baseline and response (post minus baseline) measures was adjusted for several covariates, including total fat mass, and responses to training were further adjusted for baseline levels. Multipoint variance components linkage analysis using a genomewide scan of 344 markers was conducted separately by race using race-specific allele frequencies. Several promising results (P < 0.0023) were obtained. For baseline AVF, the best evidence was on 2q22.1 and 2q33.2-q36.3 (including the IRS1 locus) in whites, with suggestive findings on 7q22.2-q31.3 (including the LEP locus) in blacks. Although several regions were indicated for baseline ASF, only 4q31.22-q32.2 and 11p15.4-p11.2 replicated the results of another study. For responses to training, promising results were limited to ASF and ATF primarily on 7q36.2 (including NOS3) in blacks, with suggestive regions (P < 0.01) on 1q21.2-q24.1 (S100A, ATP1A2, and ATP1B1), 10q25.2 (ADRA2A), and 11p15.5 (IGF2). In summary, the 4q and 11p regions have now been implicated in two independent studies for ASF; further research is warranted to identify the genes and mutations in these regions that are responsible for fat accumulation in the abdominal depot. Additional work in an independent sample is needed to verify the linkages for baseline AVF as well as the response measures.
Diabetes 2002 Mar
PMID:A genomewide linkage scan for abdominal subcutaneous and visceral fat in black and white families: The HERITAGE Family Study. 1187 90

The subtelomeric region of 11p harbours three closely linked genes, TH, INS and IGF2, that have been associated with obesity, size at birth, type I diabetes, polycystic ovary syndrome, overgrowth in Beckwith-Wiedemann syndrome and possibly hypertension. We have previously shown that the IGF2 ApaI single nucleotide polymorphism (SNP) associates with weight and body mass index in middle-aged Caucasian males but that there is no such association with the INS -23/ HphI site that marks INS 5' variable number of tandem repeats (VNTR) class I vs class III VNTR alleles. We report here the examination of three SNP markers in IGF2: 6815 A/T in the P1 promoter, AluI in exon 3 and ApaI in the 3' untranslated region (UTR), INS 5'VNTR class I alleles and the TH01 tetranucleotide microsatellite in a population sample. The analysis has taken into account the possibility that typing failure and the number of parameters required to model multiallelic loci could create spurious significance. We have exercised Hardy-Weinberg equilibrium tests, dichotomised multiallelic series to impose parsimony, and examined the data with failures modelled or excluded. Regression analysis infers that three markers, IGF2 ApaI, TH01 and subclasses of INS VNTR class I independently predict derived weight indices (combined P<10(-8) and accounting up to 2% of population weight variance), with no evidence of interaction. This establishes that there must be multiple causal sites impacting on weight in this genomic region.
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PMID:Evidence of multiple causal sites affecting weight in the IGF2-INS-TH region of human chromosome 11. 1193 24

Paternal mutation of ATP-sensitive K(+) (K(ATP)) channel genes and loss of heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8, IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic hypoglycemia of infancy (FoPHHI). We aimed to understand the actual nature of FoPHHI in comparison with insulinoma. In FoPHHI, the lesion consists in clusters of beta-cells surrounded by non-beta-cells. Compared with adjacent islets, proinsulin mRNA is similar and proinsulin production higher (P < or = 0.02), indicating regulation at a translational level, with slightly lower insulin stock and lower ABCC8 peptide labeling (P<0.05). Insulinomas, composed of beta-cell nests or cords, have similar proinsulin mRNA compared with adjacent islets, highly variable proinsulin production, lower insulin stock (P < or = 0.02), and higher ABCC8 peptide labeling (P<0.05). Proinsulin mRNA is lower than in FoPHHI (P<0.001). Islets adjacent to FoPHHI appear to be resting, in contrast to those adjacent to insulinomas, evidencing intrapancreatic regulation of islet beta-cell activity. IGF2 peptide is present inside and outside both lesions, but IGF2 mRNA is restricted to the lesions. The 11p15 LOH and absence of CDKN1C peptide staining are demonstrated in all FoPHHI but also in three of eight insulinomas. Despite some molecular similarities, FoPHHI is thus fundamentally different from insulinoma.
Diabetes 2003 Mar
PMID:The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. 1260 21


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