Diabetes mellitus (DM) affects 30% to 60% of patients with hereditary hemochromatosis (HH). The underlying pathophysiology of DM in patients with hemochromatosis has not been fully elucidated. We studied both insulin secretion and insulin sensitivity in a cohort of patients with HH. We studied glucose metabolism in 53 newly diagnosed HH patients using a standard 75-g oral glucose tolerance test. Basal and stimulated insulin sensitivities were calculated using the quantitative insulin sensitivity check index and oral glucose insulin sensitivity index, respectively. beta-Cell function was assessed using C-peptide concentrations during the oral glucose tolerance test after adjusting for ambient insulin sensitivity. Twenty healthy subjects served as the control group. Fifteen subjects (28%) with HH had abnormal glucose tolerance (AGT). Seven (13%) had DM, and 8 (15%) had impaired glucose tolerance. As well as higher fasting glucose and glycated hemoglobin, those with AGT had a higher fasting insulin and C-peptide levels compared with those with normal glucose tolerance (NGT) (all Ps < .05). Insulin sensitivity measurements showed that the subjects in HH group with AGT were more insulin resistant than the subjects with NGT and controls subjects (P < .05). No significant changes were observed between the groups with NGT and AGT regarding hepatic insulin extraction and both indices related to insulin release in subjects with HH. Our cohort of patients with hemochromatosis and AGT had features similar to typical type 2 DM patients. These findings challenge the traditional view that DM in hemochromatosis is due primarily to iron-induced beta-cell failure.
"It has been shown that elevated iron stores are associated with increased oxidative stress and insulin resistance, which can be induced by high-fat feeding [25–27]. Iron overload is often associated with decreased insulin sensitivity [28, 29]. In the study of Wapnir and Devas , rats fed a 45% fat diet had increased hepatic Fe content. "
[Show abstract][Hide abstract] ABSTRACT: Although maternal, fetal, and placental mechanisms compensate for disturbances in the fetal environment, any nutritional inadequacies present during pregnancy may affect fetal metabolism, and their consequences may appear in later life. The aim of the present study is to investigate the influence of maternal diet during gestation on Fe, Zn, and Cu levels in the livers and kidneys of adult rats. The study was carried out on the offspring (n = 48) of mothers fed either a protein-balanced or a protein-restricted diet (18% vs. 9% casein) during pregnancy, with or without folic acid supplementation (0.005- vs. 0.002-g folic acid/kg diet). At 10 weeks of age, the offspring of each maternal group were randomly assigned to groups fed either the AIN-93G diet or a high-fat diet for 6 weeks, until the end of the experiment. The levels of Fe, Zn, and Cu in the livers and kidneys were determined by the F-AAS method. It was found that postnatal exposure to the high-fat diet was associated with increased hepatic Fe levels (p < 0.001), and with decreased liver Zn and Cu contents (p < 0.01 and p < 0.05, respectively), as well as with decreased renal Cu contents (p < 0.001). Moreover, the offspring's tissue mineral levels were also affected by protein and folic acid content in the maternal diet. Both prenatal protein restriction and folic acid supplementation increased the liver Zn content (p < 0.05) and the kidney Zn content (p < 0.001; p < 0.05, respectively), while folic acid supplementation resulted in a reduction in renal Cu level (p < 0.05). Summarizing, the results of this study show that maternal dietary folic acid and protein intake during pregnancy, as well as the type of postweaning diet, affect Fe, Zn, and Cu levels in the offspring of the rat. However, the mechanisms responsible for this phenomenon are unclear, and warrant further investigation.
Biological trace element research 04/2011; 144(1-3):885-93. DOI:10.1007/s12011-011-9048-3 · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excess tissue iron levels are a risk factor for diabetes, but the mechanisms underlying the association are incompletely understood. We previously published that mice and humans with a form of hereditary iron overload, hemochromatosis, exhibit loss of β-cell mass. This effect by itself is not sufficient, however, to fully explain the diabetes risk phenotype associated with all forms of iron overload.
We therefore examined glucose and fatty acid metabolism and hepatic glucose production in vivo and in vitro in a mouse model of hemochromatosis in which the gene most often mutated in the human disease, HFE, has been deleted (Hfe⁻(/)⁻).
Although Hfe⁻(/)⁻ mice exhibit increased glucose uptake in skeletal muscle, glucose oxidation is decreased and the ratio of fatty acid to glucose oxidation is increased. On a high-fat diet, the Hfe⁻(/)⁻ mice exhibit increased fatty acid oxidation and are hypermetabolic. The decreased glucose oxidation in skeletal muscle is due to decreased pyruvate dehydrogenase (PDH) enzyme activity related, in turn, to increased expression of PDH kinase 4 (pdk4). Increased substrate recycling to liver contributes to elevated hepatic glucose production in the Hfe⁻(/)⁻ mice.
Increased hepatic glucose production and metabolic inflexibility, both of which are characteristics of type 2 diabetes, may contribute to the risk of diabetes with excessive tissue iron.
[Show abstract][Hide abstract] ABSTRACT: Hereditary hemochromatosis (HH) is associated with abnormal glucose metabolism (AGM). We investigated the effect on glucose metabolism of normalization of the markers of iron overload by phlebotomy in subjects with HH. We prospectively studied 11 newly diagnosed subjects with HH and AGM using a standard 75-g oral glucose tolerance test. Basal quantitative insulin sensitivity check index (QUICKI) and stimulated oral glucose insulin sensitivity index (OGIS) insulin sensitivity was calculated from glucose and insulin data, whereas β-cell function was assessed using C-peptide concentration after adjusting for ambient insulin sensitivity. After normalization of ferritin and transferrin saturations by venesection for 12 (range, 8-16) months, subjects were studied again using the same methods. From 11 subjects with AGM at the time that HH was diagnosed, 7 had impaired glucose tolerance (IGT) and 4 had type 2 diabetes mellitus (T2DM). Normalization of the iron stores (ferritin and transferrin) improved the glucose tolerance status of 4 patients with IGT (to normal glucose tolerance), whereas 2 of those with IGT progressed to T2DM. In 5 patients, glucose tolerance status did not change (4 T2DM and 1 IGT). The area under the insulin and the C-peptide curve during the oral glucose tolerance test and the hepatic insulin extraction increased (P = .05), whereas no statistically significant changes occurred in insulin sensitivity. However, the disposition index, a measure of the ability of insulin release to compensate for insulin resistance, improved significantly (P = .02). Normalization of ferritin and transferrin saturation by venesection in subjects with HH and AGM led to improvements in some, but not all, measures of insulin secretion and action. Most patients with AGM had an improvement in glucose tolerance status, probably due to the augmented action of insulin in peripheral tissues.
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