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 differenti ation. Association of these changes with beta cell hypertrophy, increased m RNA levels of the transcription factor c-Myc, and their complete normalizat ion 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 express ion both in vivo and in vitro. Elevation of plasma glucose for 1-4 days (gl ucose infusion/clamp) was followed by parallel increases in islet mRNA leve ls (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 cell s with 20 and 30 mmol(.)liter(-1) glucose for 18 h. These effects of high g lucose were reproduced by high potassium-induced depolarization or dibutyry l-cAMP and were inhibited by agents decreasing cytosolic Ca2+ or cAMP conce ntrations. In conclusion, the expression of the early response gene c-Myc i n rat pancreatic beta cells is stimulated by high glucose in a Ca2+ -depend ent manner and by cAMP. c-Myc could therefore participate to the regulation of beta cell growth, apoptosis, and differentiation under physiological or pathophysiological conditions.