Involvement of Protein Kinase C β2 in c-mycInduction by High Glucose in Pancreatic β-Cells

Abstract

The expression of the basic helix-loop-helix transcription factor c-Myc is induced in pancreatic islets of several different diabetic model animals and is possibly involved in suppression of the insulin gene transcription. In this study, we found that activity of protein kinase C is increased by high glucose, preceding the induction of c-myc expression and that PKC ␤2 specifically regulates c-myc expression in pancreatic ␤-cells. Since PKC ␣, ␤2, ␦, ⑀, and were expressed in rat pancreatic islets, we prepared each wild type (WT) and dominant negative type (DN) PKC isoform (␣, ␤2, ␦, ⑀, and )-expressing adenovirus to examine the effect of each PKC isoform on c-myc expression. In isolated rat pancreatic islets, adenovirus-mediated overexpression of WT PKC ␤2, but not other PKC isoforms, markedly increased c-myc expression. Moreover, c-myc induction by high glucose was suppressed by adenovirus-mediated overexpression of DN PKC ␤2 but not by other DN PKC isoforms. Finally, adenovirus-mediated overexpression of WT PKC ␤2, but not of other PKC isoforms, leads to suppression of the insulin gene transcription in pancreatic islets. These results suggest that at least some of the reduction of insulin gene transcription found in the diabetic state is mediated by PKC ␤2 regulation of c-myc expression.

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

“…[45,46]. In this regard, while the stimulation of c-Myc expression by high glucose could result from the activation of PKCβ 2 [47], our preliminary results indicate that the stimulation of islet HO1 expression may involve glucose activation of both p38MAPK and ERK [48].…”

Induction of c-Myc Expression Suppresses Insulin Gene Transcription by Inhibiting NeuroD/BETA2-mediated Transcriptional Activation

“…Additionally, c-myc gene transcription is directly regulated by high glucose per se (13,52) and oxidative stress (53), which is provoked in islets under diabetic conditions (54) and is thought to be involved in the pathogenesis of ␤-cell dysfunction in diabetes (50,55,56). Finally, as shown in this study, increased expression of c-Myc in ␤-cells exerts a deleterious effect on the insulin gene transcription, probably at least in part by inhibiting NeuroD-mediated transcriptional activation.…”

Fetal programming of glucose–insulin metabolism

“…Any defects in ATP production within the beta cell would therefore have large detrimental effects on the function of the beta cell. Indeed, increased levels of ROS lead to decreased levels of glucose mediated insulin secretion (86)(87)(88), decreased beta cell proliferation (86) and decreased expression of genes vital for beta cell function, including insulin (89)(90)(91)(92)(93)(94)(95). Ultimately the viability of beta cells is at risk (96,97).…”