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Induction of glycation suppresses glucokinase gene expression in HIT-T15 cells.

Abstract：

AIMS/HYPOTHESIS:Chronic hyperglycaemia in patients with Type II (non-insulin-dependent) diabetes mellitus often leads to a decline in glucose-responsive insulin secretion from pancreatic beta cells, a phenomenon called glucose toxicity. Upon hyperglycaemia, glycation reaction occurs in the beta cells and induces oxidative stress. To understand the molecular basis of the beta-cell glucose toxicity, we investigated the possible effects of glycation on the expression and enzymatic activity of glucokinase, which plays a crucial part in glucose-responsive insulin secretion. METHODS:Glycation and reactive oxygen species were induced in HIT-T15 cells by treatment with D-ribose and effects on glucokinase gene transcription, glucokinase protein amount, glucose phosphorylation activity, and DNA-binding activities of putative glucokinase gene transcription factors were evaluated. RESULTS:When glycation was induced in HIT-T15 cells, the activity of the human glucokinase gene beta-cell-type promoter was suppressed substantially (83% reduction at 60 mmol/l D-ribose). Also, similar reductions in mRNA and protein amounts of glucokinase and in the Vmax of its enzymatic activity were observed. In agreement with the reduction in the promoter activity, the two major transcription factors of the glucokinase gene, the Pal-binding factor and PDX-1, reduced their binding to their target sequences in the glucokinase gene promoter in glycation-induced HIT cells. Because these effects of D-ribose were counteracted by aminoguanidine or N-acetylcysteine, reactive oxygen species, generated by the glycation reaction, appears to be involved in the phenomena. CONCLUSION/INTERPRETATION:The induction of the glycation reaction, which is known to occur in pancreatic beta cells in chronic hyperglycaemia, suppresses the glucokinase gene transcription and its enzymatic activity. Thus, hyperglycaemia-dependent inhibition of glucokinase activity could in part explain beta-cell glucose toxicity.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Kajimoto Y,Matsuoka T,Kaneto H,Watada H,Fujitani Y,Kishimoto M,Sakamoto K,Matsuhisa M,Kawamori R,Yamasaki Y,Hori M

doi

10.1007/s001250051313

subject

Has Abstract

pub_date

1999-12-01 00:00:00

pages

1417-24

issue

eissn

0012-186X

issn

1432-0428

journal_volume

pub_type

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Induction of glycation suppresses glucokinase gene expression in HIT-T15 cells.