Endocrinology

Biography

Biography: Andrea Romani

Abstract

Tissue and serum Mg2+ deficiency have been observed in several endocrine pathologies including diabetes and metabolic syndrome, but it is still undefined to which extent an altered Mg2+ homeostasis contributes to the onset of these pathologies and/or their complications. In the present study, we report that Mg2+ deficient hepatocyte exhibit an increased entry of G6P into the endoplasmic reticulum, where the substrate is oxidized by the H6PD to generate NADPH. As H6PD operates in conjunction with 11β-HSD1, the increased level of NADPH is utilized by the latter enzyme to convert inactive cortisone to active cortisol. Administration of cortisone to Mg2+ deficient hepatocytes results in a marked production of cortisol, which in turn enhances gluconeogenesis and alters intrahepatic fatty acid synthesis, thus increasing intrahepatic triglyceride levels. Protein and mRNA expression of H6PD and 11β-HSD1 are both increased 3-4 fold in Mg2+ deficient cells. Mg2+ deficient hepatocytes also exhibit decreased insulin responsiveness, which is further compromised by cortisol production. Returning cellular Mg2+ content to its physiological levels, results in a dramatic decrease in cortisol production, and in the progressive renormalization of expression and activity of H6P, 11β-HSD1, and cortisol-responsive genes. Investigation into the underlying mechanism of action suggest that under Mg2+ deficient conditions 11β-HSD1 expression and activity increase as a consequence of increased nuclear translocation of NF-kB and increased expression of inflammatory cytokines (namely IL-1β and/or TNFα). Taken together, our results suggest that by increasing H6PD and 11β-HSD1 activity and expression, Mg2+ deficiency sets the conditions for an increased intrahepatic production of cortisol and decreased insulin responsiveness. This altered hormonal balance can play a major role in the onset and progression of the metabolic syndrome and its associated complications.