High glucose stimulates early response gene c-Myc expression in rat pancreatic beta cells.
Glucose-induced insulin secretion from hyperglycemic 90% pancreatectomized rats is markedly impaired, possibly because of loss of beta cell differentiation. Association of these changes with beta cell hypertrophy, increased mRNA levels of the transcription factor c-Myc, and their complete normalization by phlorizin treatment suggested a link between chronic hyperglycemia, increased c-Myc expression, and altered beta cell function. In this study, we tested the effect of hyperglycemia on rat pancreatic islet c-Myc expression both in vivo and in vitro. Elevation of plasma glucose for 1-4 days (glucose infusion/clamp) was followed by parallel increases in islet mRNA levels (relative to TATA-binding protein) of c-Myc and two of its target genes, ornithine decarboxylase and lactate dehydrogenase A. Similar changes were observed in vitro upon stimulation of cultured islets or purified beta cells with 20 and 30 mmol.liter(-1) glucose for 18 h. These effects of high glucose were reproduced by high potassium-induced depolarization or dibutyryl-cAMP and were inhibited by agents decreasing cytosolic Ca(2+) or cAMP concentrations. In conclusion, the expression of the early response gene c-Myc in rat pancreatic beta cells is stimulated by high glucose in a Ca(2+)-dependent manner and by cAMP. c-Myc could therefore participate to the regulation of beta cell growth, apoptosis, and differentiation under physiological or pathophysiological conditions.
Jonas
J C
JC
Unit of Endocrinology and Metabolism, University of Louvain, Brussels, Belgium. jonas@endo.ucl.ac.be
Laybutt
D R
DR
Steil
G M
GM
Trivedi
N
N
Pertusa
J G
JG
Van de Casteele
M
M
Weir
G C
GC
Henquin
J C
JC
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects*; D016259:Genes, myc; D005947:Glucose / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D017931:DNA Primers; D012333:RNA, Messenger; D000242:Cyclic AMP; D005947:Glucose; D003000:Clonidine; D002118:Calcium