Study of iron metabolism disturbances in an animal model of insulin resistance

Guenno, G. Le; Chanséaume, Emilie; Ruivard, M.; Morio, Béatrice; Mazur, Andrzej

doi:10.1016/j.diabres.2007.02.004

Cited by 60 publications

(48 citation statements)

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“…As the authors comment, hepatic fat accumulation might be induced by mechanisms different from increased lipogenesis, such as the reduction of lipid and lipoprotein output from the liver, according to previous evidence in humans. (4) Data from our group are consistent with this hypothesis. Indeed, we detected a beneficial effect of cholic acid feeding in the choline-deficient dietary model (in which hepatic lipid export is reduced) but not in the highfat model.…”

Section: To the Editorsupporting

confidence: 83%

“…(2) As expected, we found an inverse correlation between intestinal iron absorption and plasma hepcidin (r 5 20.61, P < 0.001), ultrasensitive C-reactive protein levels (r 5 20.52, P < 0.001), and serum ferritin (r 5 20.51, P < 0.001). These results indicate that regulation of iron absorption through hepcidin is preserved in DIOS.The study of Hoki et al(1) raises several issues: (1) the time elapsed between the oral absorption test and the duodenal biopsy was not indicated (a long time could explain the lack of correlation between the oral iron absorption test, serum hepcidin, and expression of ferroportin); (2) the authors did not compare results of the iron absorption test according to the absence or presence of hepatic iron accumulation; (3) the expression of DMT1 in duodenal cells depending on local hypoxia through induction of hypoxia inducible factor2a, (3) the hypothesis of a serum factor regulating DMT1 expression needs further investigation; and (4) the results are difficult to reconcile with the demonstration that a 6-week regimen of a high-fat/highenergy diet (4) induced hepcidin down-regulation in an animal model.It is likely that iron metabolism varies along the long story of the metabolic syndrome: in the constitutive phase of overweight, hepcidin down-regulation allows iron accumulation, probably to supply the increase of erythropoiesis, as has been demonstrated in rats (4) ; and in the steady overweight phase, hepcidin is upregulated, which is related to iron excess. Interpretation of future studies of iron metabolism in DIOS or/and NASH should take such a dynamic view into account.…”

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confidence: 98%

“…It is likely that iron metabolism varies along the long story of the metabolic syndrome: in the constitutive phase of overweight, hepcidin down-regulation allows iron accumulation, probably to supply the increase of erythropoiesis, as has been demonstrated in rats (4) ; and in the steady overweight phase, hepcidin is upregulated, which is related to iron excess. Interpretation of future studies of iron metabolism in DIOS or/and NASH should take such a dynamic view into account.…”

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without iron overload (Fig. 1). (2) As expected, we found an inverse correlation between intestinal iron absorption and plasma hepcidin (r 5 20.61, P < 0.001), ultrasensitive C-reactive protein levels (r 5 20.52, P < 0.001), and serum ferritin (r 5 20.51, P < 0.001). These results indicate that regulation of iron absorption through hepcidin is preserved in DIOS.The study of Hoki et al.(1) raises several issues: (1) the time elapsed between the oral absorption test and the duodenal biopsy was not indicated (a long time could explain the lack of correlation between the oral iron absorption test, serum hepcidin, and expression of ferroportin); (2) the authors did not compare results of the iron absorption test according to the absence or presence of hepatic iron accumulation; (3) the expression of DMT1 in duodenal cells depending on local hypoxia through induction of hypoxia inducible factor2a, (3) the hypothesis of a serum factor regulating DMT1 expression needs further investigation; and (4) the results are difficult to reconcile with the demonstration that a 6-week regimen of a high-fat/highenergy diet (4) induced hepcidin down-regulation in an animal model.It is likely that iron metabolism varies along the long story of the metabolic syndrome: in the constitutive phase of overweight, hepcidin down-regulation allows iron accumulation, probably to supply the increase of erythropoiesis, as has been demonstrated in rats (4) ; and in the steady overweight phase, hepcidin is upregulated, which is related to iron excess. Interpretation of future studies of iron metabolism in DIOS or/and NASH should take such a dynamic view into account. REPLY:The study reported by Ruivard et al.(1) differed markedly from our own, (2) the major difference being the study subjects. Patients with dysmetabolic iron FIG. 1. Intestinal iron absorption evaluated by the area under the curve of 58 Fe given orally in patients with insulin-resistance iron overload (DIOS), overweight controls, and lean controls. Results are expressed in mean 6 standard deviation. Differences between DIOS patients and controls were significant (P < 0.01 for DIOS versus lean controls and P < 0.05 for DIOS versus overweight controls). Abbreviations: AUC, area under the curve; L, lean controls; OW, overweight controls. (Adapted from Ruivard et al.,

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“…The significant inverse correlation that we found between the degree of steatosis and the amount of iron removed by phlebotomies provides the strongest evidence that the higher the percentage of hepatocytes involved by steatosis, the lower the amount of iron accumulation. Recent studies in severely obese patients [26] and in an animal model of insulin resistance [27] suggest that obesity or hyperinsulinemia favour the development of iron deficiency. Increased adipocyte hepcidin production has been reported in morbid obesity that could result in reduced intestinal iron absorption, macrophage iron release and eventually in low iron stores [26] .…”

Section: Discussionmentioning

confidence: 99%

Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome

Riva¹,

Trombini²,

Mariani³

et al. 2008

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AIM:To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical, biochemical and histopathological findings. METHODS:We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes. The metabolic syndrome (MS) was defined according to ATPⅢ criteria. Iron overload was assessed by liver biopsy. Liver histology was evaluated by Ishak's score and iron accumulation by Deugnier's score; steatosis was diagnosed when present in ≥ 5% of hepatocytes. RESULTS: According to transferrin saturation levels, we observed significant differences in the amount of hepatic iron overload and iron distribution, as well as the number of metabolic abnormalities. Using Receiving Operating Curve analysis, we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload (P < 0.0001). Patients with ≥ 2 metabolic alterations and steatosis had lower amount of hepatic iron, lower transferrin saturation and higher sinusoidal iron than patients with < 2 MS components and absence of steatosis. CONCLUSION: In our patients, the presence of ≥ 2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome. By contrast, patients with transferrin saturation ≥ 60% had more severe iron overload, few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload.

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“…We hypothesized that genetic factors, the absence of a regular menstrual blood loss, or even hyperinsulinemia resulting from insulin resistance, considering that insulin might stimulate intestinal iron absorption by upregulating the activity of hypoxia-inducible factor-1 ␣ and downregulating hepcidin expression (15,16), may have contributed to the increased body iron stores and serum ferritin levels observed in PCOS patients.…”

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Increased Body Iron Stores of Obese Women With Polycystic Ovary Syndrome Are a Consequence of Insulin Resistance and Hyperinsulinism and Are Not a Result of Reduced Menstrual Losses

et al. 2007

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OBJECTIVE -Increased serum ferritin levels, indicating increased body iron stores, have been found in overweight and obese women with polycystic ovary syndrome (PCOS). This finding might result from reduced menstrual losses secondary to oligo-or amenorrhea or from hyperinsulinism secondary to insulin resistance, because insulin favors the intestinal absorption and the tissue deposition of iron. To explore which of these mechanisms is responsible for the increase in body iron stores in women with PCOS, we have monitored the changes in serum ferritin levels during treatment with an antiandrogenic oral contraceptive or an insulin sensitizer.RESEARCH DESIGN AND METHODS -Thirty-four consecutive PCOS patients were randomized to an oral contraceptive containing 35 g ethinyl-estradiol plus 2 mg cyproterone acetate (Diane 35 Diario) or metformin (850 mg twice daily), and their serum ferritin levels were evaluated at baseline and after 12 and 24 weeks of treatment. RESULTS -Despite the fact that treatment with Diane35 Diario restored regular menstrual cycles in all the patients, whereas metformin only did so in 50% of them, serum ferritin levels decreased at 12 and 24 weeks of treatment only with metformin, in association with a marked increase in insulin sensitivity. On the contrary, no changes in ferritin and insulin sensitivity were observed with Diane 35 Diario.CONCLUSIONS -Our present results suggest that insulin resistance and hyperinsulinism, and not the reduced menstrual losses secondary to from oligo-or amenorrhea, are responsible of the increased ferritin levels and body iron stores found in overweight and obese women with PCOS. Diabetes Care 30:2309-2313, 2007P olycystic ovary syndrome (PCOS) is a predominantly hyperandrogenic disorder (1) that affects 6 -7% of premenopausal women (2-5). Aside from the hyperandrogenic features and ovarian dysfunction characteristic of the syndrome, obesity and insulin resistance are frequently associated with PCOS (6,7).We have reported previously (8) that overweight and obese women with PCOS have increased serum ferritin levels that do not relate to chronic inflammation, indicating that body iron stores are increased in these women in agreement with what has been published for other insulin-resistant conditions (9). The increase in body iron stores might contribute to the insulin resistance and ␤-cell dysfunction frequently found in PCOS patients (10), as has been previously proposed for insulin resistance (11), the metabolic syndrome (12), and type 2 diabetes (13,14).We hypothesized that genetic factors, the absence of a regular menstrual blood loss, or even hyperinsulinemia resulting from insulin resistance, considering that insulin might stimulate intestinal iron absorption by upregulating the activity of hypoxia-inducible factor-1 ␣ and downregulating hepcidin expression (15,16), may have contributed to the increased body iron stores and serum ferritin levels observed in PCOS patients.Our recent results suggest that mutations in the hereditary hemochromatosis gene do not p...

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Study of iron metabolism disturbances in an animal model of insulin resistance

Cited by 60 publications

References 29 publications

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Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome

Increased Body Iron Stores of Obese Women With Polycystic Ovary Syndrome Are a Consequence of Insulin Resistance and Hyperinsulinism and Are Not a Result of Reduced Menstrual Losses

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