Low Hepatic Mg2+ Content promotes Liver dysmetabolism: Implications for the Metabolic Syndrome

Abstract

Metabolic Syndrome, a pathological condition affecting approximately 35% of the USA population, is characterized by obesity, insulin resistance, and hypertension. Metabolic syndrome is considered the single most common condition predisposing to the development of various chronic diseases including diabetes and hypertension. Hypomagnesaemia has been consistently observed in association with metabolic syndrome, but it is unclear whether reduced Mg2+ levels are the consequence or a possible cause for the development of the metabolic syndrome and/or its associated pathologies. Research performed in our laboratory showed that rats exposed for 2 weeks to a Mg2+ deficient diet presented decreased glucose accumulation into the hepatocytes together with low Mg2+ level in the circulation and within the liver cells. To better investigate the changes in glucose metabolism, HepG2 were used to mimic in vitro Mg2+ deficiency conditions. HepG2 cells cultured in low extracellular Mg2+ presented a 20% decrease in total cellular Mg2+ content, reduced glucose accumulation, and enhanced glucose 6-phosphate (G6P) transport into the endoplasmic reticulum (ER). The increased G6P transport was associated with its enhanced hydrolysis by the glucose 6-phosphatase, but also conversion to 6-phosphogluconolactone by the glucose 6-phosphate dehydrogenase. The latter process resulted in the increased generation of NADPH within the ER and the increased conversion of cortisone to cortisol by the 11-β-hydroxysteroid dehydrogenase type-1 (11-β-OHSD1). Taken together, our results provide compelling evidence that Mg2+ deficiency precedes and actually promotes some of the hepatic dysmetabolisms typical of the metabolic syndrome. The decrease in intrahepatic Mg2+ content up-regulates G6P entry into the hepatic endoplasmic reticulum and its routing into the pentose shunt pathway for energetic purposes. The associated increased in NADPH production within the ER then stimulates cortisol production, setting the conditions for hepatic insulin resistance and further altering liver metabolism.

Telomere Homeostasis: Interplay with Magnesium

“…Furthermore, N -methyl- d -aspartate receptors (NMDARs) within the SCN, which orchestrate light-induced phase resetting of the circadian rhythm [ 148 ], are Mg 2+ -dependent [ 149 ]. An indirect effect of cellular Mg 2+ homeostasis that may be mediated through hepatocyte activation of cortisone remains relatively unexplored from a circadian perspective [ 150 , 151 ]. The increased cortisol activity may cause further Mg 2+ loss and aggravate the circadian disruption [ 152 ].…”

Metabolic Syndrome Features: Is There a Modulation Role by Mineral Water Consumption? A Review

“…Interestingly, due to its magnesium content, sulphurous mineral water may combat the state of hypomagnesaemia often found in diabetes [9,74]. Magnesium is needed for β-cell function, is crucial for insulin signalling (is essential for the insulin-insulin receptor interaction, the affinity of the insulin receptor tyrosine kinase for ATP and the autophosphorylation of the β-subunits of the insulin receptor), has anti-inflammatory and anti-oxidant properties, plays a role in the regulation of glucocorticoid production and is a co-factor in intra- and extracellular lipid metabolism [9,28,91,99,159,160,161,162,163]. Bicarbonate, through correction of metabolic acidosis/counteraction of diet-induced acid load, improves insulin sensitivity and decreases glucocorticoid production [9,20,22,25,75,162].…”