Longitudinal analyses of iron-overloaded individuals have indicated that patients in the highest quartile of serum ferritin levels, a proxy for iron, have 3.5-fold greater risk of developing Type II Diabetes over a 6-year period. The exact mechanism is unclear but may be related to increased reactive oxygen species, particularly in the pancreatic β-cells which are responsible for insulin release. The hereditary blood disorder β-thalassemia results in chronic hemolytic anemia, causing iron overload. The prevalence of diabetes could be as high as 40% in β-thalassemia patients.
Given these observations, Dalina Tanyong of Mahidol University, Thailand, and colleagues, examined the combined effect of iron and cytokines on the human pancreatic β-cell lines. The results were published in the journal PeerJ.
Ferric ammonium citrate (FAC), which is a food additive, was used as an iron source for the experiments. FAC increased reactive oxygen species in pancreatic β-cells in a dose dependent response. Cell viability was reduced and apoptosis increased.
FAC decreased the ability of β-cells to secrete insulin. Furthermore, insulin secretion and INS gene expression was reduced by more when FAC was combined with IL-1β or TNF-ɑ. High glucose increased this effect further.
Insulin-secretion related genes including glucose kinase (GCK), proprotein convertase subtilisin/ kexin type 1 (PCSK1), and proprotein convertase subtilisin/ kexin type 2 (PCSK2) gene expressions were decreased by more than twice in both FAC treatment only and in combination with cytokines.
The study was limited by only performing experiments in human pancreatic β-cell lines, as a model, with no direct measurement of in vivo human pancreas and external validation. Organ-on-chip or organoid technologies could potentially address this limitation.
“This study suggests that FAC combined with cytokines, IL-1β and TNF-ɑ in high glucose condition could increase ROS production, ER stress and apoptosis induction. However, they reduce insulin secretion in human pancreatic β-cell lines. This information could be benefit for understanding the mechanism on development of [diabetes] in thalassemia patient,” concluded the authors.