Role of Hemochromatosis C282Y and H63D Mutations in <i>HFE</i> Gene in Development of Type 2 Diabetes and Diabetic Nephropathy

Moczulski, Dariusz; Grzeszczak, W; B, Gawlik

doi:10.2337/diacare.24.7.1187

Cited by 94 publications

(65 citation statements)

References 28 publications

(29 reference statements)

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“…There have been reports of significant increases in the frequency of HFE mutations in diabetes clinic populations [26,27], although other studies have failed to see such increases [28][29][30][31][32]. If the frequency of haemochromatosis subjects in white populations is 0.5% [1,2] and 20% of those adults have diabetes, then the frequency of adult diabetic individuals with haemochromatosis in the population will be approximately 0.1%.…”

Section: Discussionmentioning

confidence: 99%

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

et al. 2006

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Aims/hypothesis: The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis.Subjects and methods: Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. Results: The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both.Conclusions/interpretation: Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

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Section: Discussionmentioning

confidence: 99%

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

et al. 2006

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“…In 1994, it was reported (Nankivell et al 1994) that iron overload might cause diabetic nephropathy through accumulation in tubular lysosomes. Moreover, Moczulski et al (2001) have recently reported that hemochromatosis-causing mutation H63D, but not C282Y, predisposes to diabetic nephropathy. It has been demonstrated that the C282 mutation alters the HFE protein structure and beta 2 -microglobulin association or cell-surface expression, whereas the H63D mutation, in contrast, does not appear to prevent beta 2 -microglobulin association or cell-surface expression, indicating that the C282 mutation results in a greater loss of protein function than does H63D , Lebron et al 1998.…”

Section: Discussionmentioning

confidence: 99%

A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes

et al. 2003

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Iron metabolism might be involved in the pathogenesis of type 2 diabetes and in the pathogenesis of diabetic retinopathy. C282Y and H63D mutations in the hemochromatosis (HFE) gene are associated with increased serum iron levels and consequently with hereditary hemochromatosis. In the present study, we searched for a relationship between C282Y and H63D gene mutations and the development of proliferative diabetic retinopathy in Caucasians with type 2 diabetes. For this purpose, 90 subjects with type 2 diabetes with proliferative diabetic retinopathy (PDR) were compared to 133 diabetic subjects without PDR. There was a significantly higher frequency of the C282Y heterozygotes in patients with PDR compared to subjects without it (OR=3.0, 95% CI=1.2-8.0; p=0.02), whereas no association was demonstrated between PDR and H63D genotypes (OR=1.1, 95% CI=0.6-2.2; p=0.7). Logistic regression analysis revealed that the C282Y mutation was a significant independent risk factor for the development of PDR (OR=6.1, 95% CI=1.2-30.5; p=0.027). These data suggest that heterozygosity for C282Y might be a novel risk factor for PDR in Caucasians with type 2 diabetes.

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“…Some studies suggest that the frequency of HFE mutations is increased in type 2 diabetes, probably in relationship with liver iron overload (11)(12)(13)(14)(15)(16). Nevertheless, the Rotterdam study has not found an increase of the frequency of HFE mutation in patients with glucose intolerance or type 2 diabetes by comparison with general population or in case control studies (9,17,18).…”

Section: Discussionmentioning

confidence: 86%

“…By contrast, only 43% of the control group had an abnormal HFE genotype, with no case of HH and the same prevalence of H63D heterozygosity than in the D group. When we compared our data to other genotype analyses according to diabetes status (11)(12)(13)(14)(15)(16)(17)(18)(19), we found a much higher frequency of HFE gene mutations (21% C282Y homozygote) in the Lille series. This can be explained by the fact that we did not perform genotyping systematically, but only when iron parameters were disturbed.…”

Section: Discussionmentioning

confidence: 90%

Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department

Vantyghem¹,

Fajardy²,

Dhondt³

et al. 2006

eur j endocrinol

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Objective: The aim of this study was to describe HFE genotype in a population of patients with altered iron markers recruited in an Endocrinology Department and to define the possible phenotypegenotype relationships. Methods: A total of 156 patients with high serum ferritin concentrations (O300 ng/ml) or transferrin saturation (O45%) (I group), and a control group of 106 healthy subjects (C group) underwent HFE genotyping (classical C282Y and H63D mutations). We also examined the main genetic features of subgroups in I according to the presence (D) or the absence (ND) of diabetes. Results: (1) The genotypes were significantly different in the I and C groups (P!0.001), with an increased frequency of major 282Y allele in the I group (35% vs 7.5%), but not of minor 63D allele (17 vs 18.5%). (2) The genotype of D and ND groups also differed (P!0.0001), with a lower frequency of C282 heterozygosity (P!0.0001) in the D group, and a higher prevalence of H63D heterozygosity in the D vs ND groups (P!0.01). (3) The phenotypic comparison of D and ND groups also showed a higher mean body mass index, age, and serum ferritin concentration, as well as an increased proportion of males with increased liver enzymes in the D group. Conclusion: This population harboring abnormal iron markers had a different HFE genotype and a higher 282Y allele frequency than the control population. This suggests that blood iron markers could be checked in etiological investigations of metabolic disturbances to identify patients who should undergo genotyping, since approximately 20% were diagnosed with C282Y homozygosity.European Journal of Endocrinology 154 835-841

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Role of Hemochromatosis C282Y and H63D Mutations in HFE Gene in Development of Type 2 Diabetes and Diabetic Nephropathy

Cited by 94 publications

References 28 publications

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes

Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department

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