Iron: the hard player in diabetes pathophysiology

Hansen, Jakob Bondo; Moen, Ingrid Wahl; Mandrup-Poulsen, Thomas

doi:10.1111/apha.12256

Cited by 117 publications

(107 citation statements)

References 102 publications

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“…This NFκB activation was primarily dependent on IL-1β, which is in line with a corresponding observation in human islets [24]. The weak cytokine-mediated activation of NFκB in EndoC-βH1 beta cells, as in human islets, failed to induce the iNOS pathway [22,24,33], which is at variance to rodent beta cells [7,13,19,21,[34][35][36][37][38][39]. Our results confirm recent studies in EndoC-βH1 beta cells that reported virtually no expression of iNOS [4,40].…”

Section: Discussionsupporting

confidence: 91%

“…Type 1 diabetes is an autoimmune disease characterised by a loss of pancreatic beta cells caused by proinflammatory cytokine-mediated toxicity [13,[17][18][19]. In the current study, maximal toxicity was observed with a mixture of three cytokines, IL-1β, TNF-α and IFN-γ, which has been shown to simulate the proinflammatory cytokine pattern in the infiltrating immune cells in the islets of Langerhans in patients with type 1 diabetes [13,16,20,21].…”

Section: Discussionmentioning

confidence: 65%

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Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

et al. 2016

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Aims/hypothesis The aim of this study was to perform a detailed analysis of cytokine toxicity in the new human EndoC-βH1 beta cell line. Methods The expression profile of the antioxidative enzymes in the new human EndoC-βH1 beta cells was characterised and compared with that of primary beta cells in the human pancreas. The effects of proinflammatory cytokines on reactive oxygen species formation, insulin secretory responsiveness and apoptosis of EndoC-βH1 beta cells were determined. Results EndoC-βH1 beta cells were sensitive to the toxic action of proinflammatory cytokines. Glucose-dependent stimulation of insulin secretion and an increase in the ATP/ADP ratio was abolished by proinflammatory cytokines without induction of IL-1β expression. Cytokine-mediated caspase-3 activation was accompanied by reactive oxygen species formation and developed more slowly than in rodent beta cells. Cytokines transiently increased the expression of unfolded protein response genes, without inducing endoplasmic reticulum stress-marker genes. Cytokine-mediated NFκB activation was too weak to induce inducible nitric oxide synthase expression. The resultant lack of nitric oxide generation in EndoC-βH1 cells, in contrast to rodent beta cells, makes these cells dependent on exogenously generated nitric oxide, which is released from infiltrating immune cells in human type 1 diabetes, for full expression of proinflammatory cytokine toxicity. Conclusions/interpretation EndoC-βH1 beta cells are characterised by an imbalance between H 2 O 2 -generating and -inactivating enzymes, and react to cytokine exposure in a similar manner to primary human beta cells. They are a suitable beta cell surrogate for cytokine-toxicity studies.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 65%

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

et al. 2016

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“…Iron mediates oxidative stress [38], and oxidative stress has many deleterious effects [1][2][3]. Studies in mouse models of the genetic disorder haemochromatosis have shown that pancreatic beta cells have an extreme susceptibility to oxidative damage that translates into increased apoptosis and a desensitisation of glucose-induced insulin secretion, which together result in decreased insulin secretory capacity [39].…”

Section: Discussionmentioning

confidence: 99%

“…The reference interval for serum ferritin is wide, comprising levels between approximately 20 and 300 μg/l among men and 15 and 200 μg/l among women. Biologically, iron is essential for the utilisation of oxygen; however, it is also a strong pro-oxidant known to catalyse the formation of reactive oxygen species, potentially causing severe damage to the insulin-producing pancreatic beta cells, muscle cells and liver cells [1][2][3]. Moreover, ferritin not only reflects iron stores, but is also an acute-phase reactant, commonly elevated in individuals with low-grade inflammation such as is seen in obesity, the metabolic syndrome and type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Fasting serum levels of ferritin are associated with impaired pancreatic beta cell function and decreased insulin sensitivity: a population-based study

et al. 2014

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Aims/hypothesis Elevated serum ferritin levels are associated with an increased risk of type 2 diabetes, but the nature of this association remains elusive. The aim of this study was to test the hypothesis that an elevated fasting serum ferritin level is associated with an increased risk of type 2 diabetes due to its association with impaired beta cell function and decreased insulin sensitivity. Methods We investigated 6,392 individuals from the Danish general population. Surrogate measures of beta cell function and insulin sensitivity were calculated for approximately 6,100 individuals based on OGTT examinations. ResultsThe ORs for type 2 diabetes were 4.2 (95% CI 2.4, 7.2) for the highest vs the lowest quintile of serum ferritin, and 17 (95% CI 8.9, 33) for serum ferritin levels ≥97.5th percentile vs <20th percentile. Elevated serum ferritin levels were associated with elevated plasma glucose levels at 0, 30 and 120 min ( p<0.001), elevated serum insulin levels at 0 and 120 min ( p=0.02 and p<0.001), decreased beta cell function estimated as the insulinogenic index and corrected insulin response ( p<0.001), and decreased insulin sensitivity estimated by the Matsuda index of insulin sensitivity and HOMA-IR ( p<0.001). Whereas the association with impaired beta cell function was present in both men and women, the association Electronic supplementary material The online version of this article

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“…Together with an induction of iron import via Dmt1 through pro-inflammatory cytokines , this would support hydroxyl radical formation, promoting serious damage to many cellular structures (Mehmeti et al 2011b, Hansen et al 2014. We therefore characterized the influence of pro-inflammatory cytokines on the expression of the different Dmt1 isoforms and whether enhanced Dmt1 expression could be compensated, probably by increased expression of the iron-chelating protein Ft.…”

Section: Introductionmentioning

confidence: 99%

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Lortz

Schröter

Stückemann

et al. 2014

Journal of Molecular Endocrinology

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Free intracellular ferrous iron (Fe 2C ) is essential for the generation of the extremely toxic hydroxyl radicals, which contribute to b-cell destruction by cytokines. Therefore the expression of the different divalent metal transporter 1 (Dmt1) isoforms and ferritin (Ft) subunits, responsible for iron import and chelation, was analyzed under pro-inflammatory conditions (IL1b alone or together with TNFaCIFNg). The Dmt1 isoforms (1A/1B and CIRE/ KIRE) and the total Dmt1 expression in insulin-producing cells (RINm5F and INS-1E), in primary rat islets and, for comparison, in the neuroendocrine PC12 cell line were quantified by qRT-PCR. In addition, the expression of the light (L-Ft) and heavy Ft (H-Ft) subunits and the mitochondrial Ft isoform (Mtft) in insulin-producing cells under control conditions and after cytokine treatment was estimated. The 1B isoform was the predominant Dmt1 mRNA in all insulin-producing cells, accounting for almost 100% of the 1A/1B isoform expression. For the IRE variants, CIRE expression was higher than KIRE expression. Pro-inflammatory cytokines accelerated the expression of Dmt1 isoforms significantly with an overall 2.5-to 3-fold increase in the total Dmt1 expression. In contrast, the expression of the iron-buffering ferritin subunits L-and H-Ft was unaffected by IL1b and only slightly induced by the cytokine mixture. Mtft expression was also not increased. Dmt1 expression was significantly elevated through pro-inflammatory cytokines, whereas Ft expression was marginally increased. This imbalance between the increased iron transport capacity and the almost unaffected iron storage capacity can foster cytokine-mediated formation of hydroxyl radicals and thus pro-inflammatory cytokine toxicity through elevated free iron concentrations.

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Iron: the hard player in diabetes pathophysiology

Cited by 117 publications

References 102 publications

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

Fasting serum levels of ferritin are associated with impaired pancreatic beta cell function and decreased insulin sensitivity: a population-based study

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

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