title: Dose-related effects of ferric citrate supplementation on endoplasmic reticular stress responses and insulin signalling pathways in streptozotocin-nicotinamide-induced diabetes.
abstract: Diabetic patients are at high risk of developing anemia; however, pharmacological doses of iron supplementation may vary greatly depending on diabetes-related complications. The aim of this study was to investigate the dose-dependent effect of iron on glucose disposal with a special focus on endoplasmic reticular (ER) stress, iron metabolism, and insulin signalling pathways. Diabetes was induced in overnight fasted rats by intraperitoneal (i.p.) injections of 40 mg kg(-1) streptozotocin (STZ) and 100 mg kg(-1) nicotinamide. Diabetic rats were fed a standard diet (36.7 mg ferric iron per kg diet) or pharmacological doses of ferric citrate (0.5, 1, 2, and 3 g ferric iron per kg diet). Ferric citrate supplementation showed a dose-related effect on hepatic ER stress responses and total iron levels, which were associated with increased hepcidin and decreased ferroportin expressions. Iron-fed rats had increased sizes of their pancreatic islets and hyperinsulinemia compared to rats fed a standard diet. A western blot analysis revealed that iron feeding decreased total insulin receptor substrate 1 (IRS1), phosphorylated IRS1ser307, and AS160 but increased phosphorylated GSK-3β. Iron supplementation inhibited the nuclear translocation of AKT but promoted FOXO1 translocation to nuclei. Ferric citrate supplementation showed a dose-related effect on ER stress responses, hepatic iron, and the insulin signaling pathway. Adverse effects were more evident at high iron doses (>1 g ferric iron per kg diet), which is equivalent to a 60 kg human male consuming >500 mg elemental iron per day.
authors.affiliation: Department of Nutrition, Chung Shan Medical University, Taichung 40203, Taiwan, Republic of China and Department of Dietitian, Chung Shan Medical University Hospital, Taichung 40203, Taiwan, Republic of China.
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.affiliation: Department of Nutrition, Chung Shan Medical University, Taichung 40203, Taiwan, Republic of China.
authors.forename: Pei-Yin
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Department of Nutrition, MacKay Memorial Hospital, Hsinchu Branch, Taiwan, Republic of China.
authors.forename: Chi-Mei
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan, Republic of China and Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taiwan, Republic of China.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan, Republic of China. susanchang@tmu.edu.tw.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Institute of Food and Bioresources Technology, Dedan Kimathi University of Technology, Nyeri, Kenya.
authors.forename: Eddy
authors.initials: E
authors.lastname: Owaga
authors.affiliation: School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan, Republic of China. susanchang@tmu.edu.tw.
authors.forename: Jung-Su
authors.initials: JS
authors.lastname: Chang
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D064451:Hepcidins / Q000235:genetics; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D007501:Iron / Q000032:analysis / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D005290:Ferric Compounds; D064451:Hepcidins; D007328:Insulin; D000098742:Ferroportin; C025314:ferric citrate; D007501:Iron