Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.

Abstract

Prolonged poor glycemic control in non-insulin-dependent diabetes mellitus patients often leads to a decline in insulin secretion from pancreatic ␤ cells, accompanied by a decrease in the insulin content of the cells. As a step toward elucidating the pathophysiological background of the socalled glucose toxicity to pancreatic ␤ cells, we induced glycation in HIT-T15 cells using a sugar with strong deoxidizing activity, D -ribose, and examined the effects on insulin gene transcription. The results of reporter gene analyses revealed that the insulin gene promoter is more sensitive to glycation than the control ␤ -actin gene promoter; ‫ف‬ 50 and 80% of the insulin gene promoter activity was lost when the cells were kept for 3 d in the presence of 40 and 60 mM D -ribose, respectively. In agreement with this, decrease in the insulin mRNA and insulin content was observed in the glycationinduced cells. Also, gel mobility shift analyses using specific antiserum revealed decrease in the DNA-binding activity of an insulin gene transcription factor, PDX-1/IPF1/STF-1. These effects of D -ribose seemed almost irreversible but could be prevented by addition of 1 mM aminoguanidine or 10 mM N-acetylcysteine, thus suggesting that glycation and reactive oxygen species, generated through the glycation reaction, serve as mediators of the phenomena. These observations suggest that protein glycation in pancreatic ␤ cells, which occurs in vivo under chronic hyperglycemia, suppresses insulin gene transcription and thus can explain part of the ␤ cell glucose toxicity. ( J. Clin. Invest. 1997. 99:144-150.)

Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status

“…Under diabetic conditions, reactive oxygen species (ROS) (19) are produced in various tissues (20 -23) and are involved in the development of insulin resistance (24 -26) as well as the progression of ␤-cell deterioration (18,(27)(28)(29)(30)(31)(32). FFAs and TNF-␣ are also likely to be involved in the development of insulin resistance; levels of FFAs and TNF-␣ are increased under obese diabetic conditions with insulin resistance, which leads to a further increase in insulin resistance.…”

The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death

“…23,24 This molecule belongs to a group of reducing sugars that trigger apoptosis, generating an increase in the levels of intracellular peroxide and carbonil radicals, as well as a decrease in intracellular GSH, all phenomena that can be abrogated by NAcetyl-Cysteine. [25][26][27][28] dRib is in fact a relevant source for in vivo oxidative stress 29,30 being synthesised by thymidine phosphorylase, an enzyme whose expression is induced by hypoxia and chronic inflammation, two conditions that share in the pathogenesis of atherosclerosis and its complications. 31, 32 Since we noted that the difference in in vitro apoptosis susceptibility of the p53 codon 72 genotypes was evident predominately in old people (sexagenarians and centenarians), we investigated the in vivo relevance of the phenomenon in old subjects.…”

High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NF?B

“…These V-shaped glucose concentration response curves for changes in islet c-Myc and HO1 expression with a minimum at G10 are similar to that of beta cell death [29]. Whereas the stimulation of beta cell apoptosis by prolonged culture in low glucose may be due to activation of AMP-dependent protein kinase and stimulation of c-Myc expression under these conditions [23,30], it has been suggested that the deleterious effects of supraphysiological glucose concentrations on the beta cell phenotype result from NFκB activation by oxidative stress [12,[31][32][33][34] or by induction of production and autocrine actions of IL-1β [35].…”