Dose-related effects of ferric citrate supplementation on endoplasmic reticular stress responses and insulin signalling pathways in streptozotocin-nicotinamide-induced diabetes

Kai Li Liu, Pei Yin Chen, Chi Mei Wang, Wei-Yu Chen, Chia Wen Chen, E. E. Owaga, Jung-Su Chang

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)194-201
Number of pages8
JournalFood and Function
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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nicotinamide
Niacinamide
streptozotocin
Streptozocin
citrates
diabetes
stress response
insulin
Iron
Insulin
iron
dosage
Diet
diet
rats
ferric citrate
Pharmacology
Hepcidins
Glycogen Synthase Kinase 3
Insulin Receptor Substrate Proteins

ASJC Scopus subject areas

  • Food Science

Cite this

Dose-related effects of ferric citrate supplementation on endoplasmic reticular stress responses and insulin signalling pathways in streptozotocin-nicotinamide-induced diabetes. / Liu, Kai Li; Chen, Pei Yin; Wang, Chi Mei; Chen, Wei-Yu; Chen, Chia Wen; Owaga, E. E.; Chang, Jung-Su.

In: Food and Function, Vol. 7, No. 1, 01.01.2016, p. 194-201.

Research output: Contribution to journalArticle

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