Iron Regulation of Pancreatic Beta-Cell Functions and Oxidative Stress

Backe, Marie Balslev; Moen, Ingrid Wahl; Ellervik, Christina; Hansen, Jakob Bondo; Mandrup-Poulsen, Thomas

doi:10.1146/annurev-nutr-071715-050939

Cited by 87 publications

(95 citation statements)

References 208 publications

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“…It is well established that iron and copper, among other trace metals, are essential to maintaining many cellular processes. Numerous studies have pointed to iron overload (Swaminathan et al 2007; Simcox & McClain 2013; Backe et al 2016) and copper overload (Walter et al 1991; Tanaka et al 2009; Qiu et al 2016) as contributing factors to insulin resistance and beta-cell dysfunction. With such obvious links, it is somewhat surprising that STEAP4’s function as a metalloreductase has not been examined in the context of metabolic diseases.…”

Section: Resultsmentioning

confidence: 99%

“…Several excellent reviews detail cellular iron regulation and the relationship between iron and diabetes (Swaminathan et al 2007; Simcox & McClain 2013; Backe et al 2016). Further, iron regulation is governed by multiple processes involving heme vs. non-heme dietary iron intake, iron absorption, inflammation, and cellular iron regulation that are more complex than we can address within the scope of this review.…”

Section: Steap4 In Metabolic Disordersmentioning

confidence: 99%

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STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

Scarl

Lawrence

Gordon

et al. 2017

Journal of Endocrinology

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Preserving energy homeostasis in the presence of stressors such as proinflammatory cytokines and nutrient overload is crucial to maintaining normal cellular function. Six-transmembrane epithelial antigen of the prostate 4 (STEAP4), a metalloreductase involved in iron and copper homeostasis, is thought to play a potentially important role in the cellular response to inflammatory stress. Genome-wide association studies have linked various mutations in STEAP4 with the development of metabolic disorders such as obesity, metabolic syndrome, and type 2 diabetes. Several studies have shown that expression of Steap4 is modulated by inflammatory cytokines, hormones, and other indicators of cellular stress, and that STEAP4 may protect cells from damage, helping to maintain normal metabolic function. STEAP4 appears to be particularly relevant in metabolically oriented cells, such as adipocytes, hepatocytes, and pancreatic islet cells. These cells struggle to maintain their function in iron or copper overloaded states, presumably due to increased oxidative stress, suggesting STEAP4’s role in metal homeostasisis critical to the maintenance of cellular homeostasis in general, and in preventing the onset of metabolic disease. In this review, we explore genetic associations of STEAP4 with metabolic disorders, and we examine STEAP4 tissue expression, subcellular localization, regulation, structure, and function as it relates to metabolic diseases. We then examine how STEAP4’s role as a regulator of cellular iron and copper may relate to type 2 diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Steap4 In Metabolic Disordersmentioning

confidence: 99%

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

Scarl

Lawrence

Gordon

et al. 2017

Journal of Endocrinology

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“…100,101 Recently, ferroptosis was identified as one form of regulated cell death that depends on iron and reactive oxygen species. 103 Insulin resistance associated with overnutrition pressures ER to meet increased demand for insulin production. 103 Insulin resistance associated with overnutrition pressures ER to meet increased demand for insulin production.…”

Section: Stress Pathways That Contribute To Beta Cell Dysfunction Undmentioning

confidence: 99%

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Imai

Cousins

Liu

et al. 2019

Annals of the New York Academy of Sciences

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Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans. To better understand the two‐sided relationship between lipids and beta cells, we present a current view of acute and chronic handling of lipids by beta cells and implications for beta cell function and health. We also discuss an emerging role for lipid droplets (LD) in the dynamic regulation of lipid metabolism in beta cells and insulin secretion, along with a potential role for LD under nutritional stress in beta cells, and incorporate recent advancement in the field of lipid droplet biology.

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“…However, oxidative stress seems to play an important role in the induction of IR . Notably, iron is a potent pro‐oxidant as it is a major catalyst in several cellular reactions that result in the production of highly reactive oxygen species . An imbalance in iron homeostasis can therefore affect major tissues such as the muscle, liver, and adipose tissue.…”

Section: Introductionmentioning

confidence: 99%

“…An imbalance in iron homeostasis can therefore affect major tissues such as the muscle, liver, and adipose tissue. In fact, excess iron (even within the “normal” range) can have lipotoxic effects, inducing pancreatic β‐cell and liver cell dysfunction and contribute to liver‐mediated IR . It also increases proinflammatory cytokines .…”

Section: Introductionmentioning

confidence: 99%

Plasma Phospholipids with Long‐Chain Polyunsaturated Fatty Acids and Dihydroceramides at the Crossroads of Iron Stores and Insulin Resistance

Mayneris‐Perxachs

Mousa

Naderpoor

et al. 2020

Molecular Nutrition Food Res

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Scope Iron plays an important role in the pathogenesis of insulin resistance (IR) and type 2 diabetes. Recent studies suggest a role of specific lipids in the induction of IR, but the potential relationships between iron and lipid metabolites in relation to IR have not been explored. Therefore, the aim of the study is to evaluate the association among iron, IR, and the lipidome. Methods and results The plasma lipidome, IR, parameters of iron metabolism, and several cytokines and adipokines in 65 overweight/obese participants are measured. Measurements of IR correlate positively with ferritin, a measure of iron storage (r = 0.35, p = 0.005), and negatively with adiponectin (r = −0.30, p = 0.02). The serum ferritin/adiponectin ratio has a stronger association with IR (r = 0.41, p < 0.001). From multivariate analyses adjusted for age, sex, and BMI, several phospholipids containing long chain polyunsaturated fatty acids (PUFA) with 20–22 carbons (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, and a phosphatidylserine), are positively associated with ferritin and the ferritin/adiponectin ratio. Two dihydroceramides (Cer(18:0/22:0), Cer(18:0/24:0)) and several diglycerides and triglycerides, mainly comprised of C14:0, C16:0, C18:0, C18:1, and C18:2, also have positive correlations with ferritin and the ferritin/adiponectin ratio. Conclusions The positive associations between these lipid species and ferritin or the ferritin/adiponectin ratio suggest a potential crosstalk between iron and lipid metabolism in obesity and IR.

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Iron Regulation of Pancreatic Beta-Cell Functions and Oxidative Stress

Cited by 87 publications

References 208 publications

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Plasma Phospholipids with Long‐Chain Polyunsaturated Fatty Acids and Dihydroceramides at the Crossroads of Iron Stores and Insulin Resistance

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