Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression.
OBJECTIVE
Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity.


METHODS
We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis.


METHODS
MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity.


RESULTS
Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis.


CONCLUSIONS
Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.
Department of Clinical LaboratoryYixing People's Hospital, Yixing, Wuxi, Jiangsu, China.
Xuhua
X
Mao
Department of Nuclear MedicineNanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China.
Hucheng
H
Chen
Department of Clinical LaboratoryYixing People's Hospital, Yixing, Wuxi, Jiangsu, China.
Junmin
J
Tang
Department of NeurologyYixing People's Hospital Affiliated to Jiangsu University, Yixing, Wuxi, Jiangsu, China.
Liangliang
L
Wang
Department of Central LaboratoryJiangsu Province Official Hospital, Nanjing, Jiangsu, China flora7227@hotmail.com.
Tingting
T
Shu
Pdx-1; gluco-toxicity; glucose-stimulated insulin secretion; hepcidin; type 2 diabetes