Oxidative stress impairs insulin internalization in endothelial cells in vitro

Bertelsen, Mads F.; Änggård, Erik; Carrier, Martin

doi:10.1007/s001250051667

Cited by 87 publications

(53 citation statements)

References 30 publications

(43 reference statements)

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“…Advanced glycation end products themselves bind transition metals (20), potentiating their toxic effects, including insulin resistance. Reactive oxygen species interfere with insulin signaling at various levels, impairing insulin uptake through a direct effect on insulin receptor function (21) and inhibiting the translocation of GLUT4 in the plasma membrane (22). Decreasing iron stores would ameliorate insulin resistance by reducing this cascade of events.…”

Section: Discussionmentioning

confidence: 99%

Blood Letting in High-Ferritin Type 2 Diabetes

Fernández‐Real¹,

Peñarroja²,

Castro³

et al. 2002

Diabetes

311

199

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Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had highferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 ؎ 0.9% vs. 6.39 ؎ 1.2%), insulin sensitivity (2.75 ؎ 1.8 vs. 3.2 ؎ 2.1 mg ⅐ dl ؊1 ⅐ min ؊1 ), and area under the curve for C-peptide (AUC C-peptide ; 38.7 ؎ 11.6 vs. 37.6 ؎ 14.1 ng ⅐ ml ؊1 ⅐ min ؊1 ) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA 1c decreased significantly only in group 1 subjects (mean differences, ؊0.61; 95% CI, ؊0.17 to ؊1.048; P ‫؍‬ 0.01). AUC C-peptide decreased by ؊10.2 ؎ 6.3% after blood letting. In contrast, a 10.4 ؎ 6.4% increase in AUC C-peptide was noted in group 2 subjects at 4 months (P ‫؍‬ 0.032). At 12 months, AUC C-peptide returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 ؎ 43.2% vs. ؊8.6 ؎ 9.9% in groups 1 and 2, respectively, P ‫؍‬ 0.049). At 12 months, the differences between the two groups were even more marked (55.5 ؎ 24.8% vs. ؊26.8 ؎ 9.9%; P ‫؍‬ 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 ؎ 1.81 to 3.08 ؎ 2.55 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 3.16 ؎ 1.85 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months; P ‫؍‬ 0,045) in contrast with group 2 subjects (from 3.24 ؎ 1.9 to 3.26 ؎ 2.05 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 2.31 ؎ 1.35 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months). In summary, blood letting led simultaneously to decreased blood HbA 1c levels and to changes in insulin secretion and insulin resistance that were significantly different from those observed in a matched observational group of subjects with high-ferritin type 2 diabetes. The mechanisms for improvement in peripheral insulin sensitivity after blood letting should be investigated further.

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Section: Discussionmentioning

confidence: 99%

Blood Letting in High-Ferritin Type 2 Diabetes

Fernández‐Real¹,

Peñarroja²,

Castro³

et al. 2002

Diabetes

311

199

View full text Add to dashboard Cite

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“…Oxidative stress induces both insulin resistance, by decreasing internalization of insulin (34), and increased ferritin synthesis. Factors related to hyperglycemia or oxidative stress can mediate in part the association between visfatin and parameters of iron metabolism (sTfR and prohepcidin) in subjects with altered glucose tolerance.…”

Section: Methodsmentioning

confidence: 99%

Circulating Visfatin Is Associated With Parameters of Iron Metabolism in Subjects With Altered Glucose Tolerance

Fernández-Real¹,

Moreno²,

Chico³

et al. 2007

Diabetes Care

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OBJECTIVE -Visfatin is a novel adipokine that is predominantly secreted by visceral adipose tissue. Accumulation of visceral adipose tissue is also associated with iron metabolism. Despite the coincidence of visfatin expression in iron-rich tissues, no study has investigated the possible interaction of visfatin with parameters of iron metabolism.RESEARCH DESIGN AND METHODS -We evaluated insulin sensitivity and parameters of iron metabolism in 95 men with normal glucose tolerance (NGT) and 43 men with altered glucose tolerance.RESULTS -Men with newly diagnosed type 2 diabetes had significantly increased serum visfatin in parallel with increased serum prohepcidin and serum ferritin compared with the other groups. In all subjects as a whole, circulating visfatin was not found to be significantly linked to insulin sensitivity (r ϭ 0.07, P ϭ 0.4) but was significantly associated with serum prohepcidin concentration (r ϭ 0.40, P Ͻ 0.0001). Obesity status and glucose tolerance status influenced the relationships among visfatin, insulin sensitivity, and parameters of iron metabolism. Among men with altered glucose tolerance, serum visfatin was strongly associated with serum prohepcidin (r ϭ 0.61, P Ͻ 0.0001) and serum soluble transferrin receptor (sTfR) (r ϭ Ϫ0.51, P Ͻ 0.0001). In nonobese subjects, sTfR (P ϭ 0.02) and prohepcidin (P ϭ 0.04) contributed independently to visfatin variance after controlling for age and BMI. When insulin sensitivity was added to the model, only the latter (P ϭ 0.006) contributed to 17% of visfatin variance. In obese men, however, only sTfR (P ϭ 0.04) contributed independently to visfatin variance in this latter model.CONCLUSIONS -Serum visfatin concentration is significantly associated with parameters of iron metabolism, especially in subjects with altered glucose tolerance. Diabetes Care 30:616 -621, 2007V isfatin, also known as pre-␤-cell colony-enhancing factor (1), is a novel adipokine that is predominantly secreted by visceral adipose tissue (2), although controversy exists over the contribution of this fat depot to serum visfatin in humans (2,3). The protein exerts adipogenic effects in vitro and therefore is a good candidate to explain the accumulation of visceral adipose tissue that is associated with insulin resistance (2). Accumulation of visceral adipose tissue is also associated with iron metabolism. Serum ferritin is linked to centrally distributed body fatness. Studies in Norwegian (4) and Mexican-American men (5) demonstrated independent associations between serum ferritin concentrations and the waist-to-thigh ratio (4) or the waist-to-hip ratio (5). Serum ferritin concentration was also significantly associated with the computed tomographyestimated visceral fat area, hepatic fat content, and the degree of insulin resistance (6).The maximum level of visfatin mRNA was found in the liver tissue and the next highest amount was found in muscle tissue (1). These tissues are classically insulin sensitive but are also characterized as central in iron metabolism. High expression of ...

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“…It has been shown that AM deficiency induces insulin resistance in mice (35) and that acute hyperinsulinemia increases circulating AM levels in diabetic patients (36) or in uncomplicated obese subjects (37). In obese and/or diabetic patients, AM may, in turn, interact with the regulation of insulinemia (37)(38)(39)(40).…”

Section: Lean Population (Nz9)mentioning

confidence: 99%

Expression of adrenomedullin in adipose tissue of lean and obese women

et al. 2006

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Objective: Adrenomedullin (AM), a potent vasodilatator and antioxidative peptide, was shown recently to be expressed by adipose tissue. The aim of our study was to investigate the precise localization of AM within human adipose tissue, and to examine AM regulation in obesity. Design: Subcutaneous (SC) and omental (OM) adipose tissues from 9 lean and 13 obese women were profiled for AM expression changes. Preadipocytes from human adipose tissue were isolated and differentiated under defined adipogenic conditions. Methods: AM expression was analyzed by immunohistochemistry, in situ hybridization and quantitative RT-PCR. Results: A strong AM expression was observed in vessel walls, stromal cell clusters and isolated stromal cells, some of them being CD 68 positive, whereas mature adipocytes were not labeled. Calcitonin receptor-like receptor and receptor activity-modifying proteins (RAMP) 2 and RAMP 3 were expressed in vessel walls. In vitro, preadipocytes of early differentiation stages spontaneously secreted AM. No difference in AM localization was found between SC and OM adipose tissue. AM levels in SC tissue did not differ between lean and obese subjects. By contrast, AM levels in OM tissue were significantly higher in obese as compared with lean women. Moreover, we found a positive relationship between OM AM and tumor necrosis factor a mRNA levels and AM-immunoreactive area in OM tissue followed the features of the metabolic syndrome. Conclusion: Stromal cells from human adipose tissue, including macrophages, produce AM. Its synthesis increased in the OM territory during obesity and paralleled the features of the metabolic syndrome. Therefore, AM should be considered as a new member of the adipokine family.

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Oxidative stress impairs insulin internalization in endothelial cells in vitro

Cited by 87 publications

References 30 publications

Blood Letting in High-Ferritin Type 2 Diabetes

Blood Letting in High-Ferritin Type 2 Diabetes

Circulating Visfatin Is Associated With Parameters of Iron Metabolism in Subjects With Altered Glucose Tolerance

Expression of adrenomedullin in adipose tissue of lean and obese women

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