The Epithelial Mg2+ Channel Transient Receptor Potential Melastatin 6 Is Regulated by Dietary Mg2+ Content and Estrogens

Groenestege, Wouter M. Tiel; Hoenderop, Joost G. J.; Heuvel, Lambertus van den; Knoers, Nine V A M; Bindels, René J. M.

doi:10.1681/asn.2005070700

Cited by 214 publications

(230 citation statements)

References 46 publications

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“…In addition, one would expect an increased TRPM6 expression in the colon during conditions of lowered serum Mg 2ϩ , an effect that is not observed here and elsewhere. 3 It is currently unclear how colonic Mg 2ϩ absorption is regulated. An increase was found in the renal EGFR mRNA expression, whereas in the colon no such change could be detected.…”

Section: Discussionmentioning

confidence: 99%

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Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

Dimke¹,

Wijst²,

Alexander³

et al. 2010

Journal of the American Society of Nephrology

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A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg 2ϩ transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg 2ϩ homeostasis, however, remains unknown. Here, we injected C57BL/6 mice with erlotinib for 23 days and observed a small but significant decrease in serum Mg handling but its effect on the systemic Mg 2ϩ concentration seems less potent than that observed with antibody-based EGFR inhibitors. These data suggest that typical human dosages of erlotinib are unlikely to severely affect serum Mg 2ϩ concentrations.

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Section: Discussionmentioning

confidence: 99%

“…The transient receptor potential melastatin subtype 6 (TRPM6) was originally identified as the causative gene for the rare autosomal recessive disorder: hypomagnesemia with secondary hypocalcemia. 1,2 TRPM6, which is expressed in the kidney and colon, 1,3,4 constitutes the gatekeeper and postulated rate-limiting entry step for active Mg 2ϩ (re-)absorption.…”

mentioning

confidence: 99%

Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

Dimke¹,

Wijst²,

Alexander³

et al. 2010

Journal of the American Society of Nephrology

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“…Whereas some report increased TRPM6 expression (96), others show that TRPM6 is downregulated (97). Given that hypomagnesemia itself also stimulates TRPM6 expression (77,98), it is difficult to distinguish between the effect of hypomagnesemia and T2DM in these studies.…”

Section: Trpm6mentioning

confidence: 93%

Hypomagnesemia in Type 2 Diabetes: A Vicious Circle?

et al. 2015

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Over the past decades, hypomagnesemia (serum Mg 2+ <0.7 mmol/L) has been strongly associated with type 2 diabetes mellitus (T2DM concentrations. This Perspective provides a systematic overview of the molecular mechanisms underlying the effects of Mg 2+ on insulin secretion and insulin signaling. In addition to providing a review of current knowledge, we provide novel directions for future research and identify previously neglected contributors to hypomagnesemia in T2DM.Globally, over 300 million people suffer from type 2 diabetes mellitus (T2DM), and the prevalence is predicted to rise to over 600 million over the next decades (1). T2DM is characterized by a combination of insulin deficiency and insulin resistance. The general pathophysiological concept is that hyperglycemia emerges when endogenous insulin secretion can no longer match the increased demand owing to insulin resistance (2).Since the 1940s, it has been reported that T2DM is associated with hypomagnesemia (3,4). Low serum magnesium (Mg 2+ ) levels have been reported in large cohorts of patients with T2DM (5). In T2DM, the prevalence of hypomagnesemia ranges between 14 and 48% compared with between 2.5 and 15% in healthy control subjects (4). Hypomagnesemia is associated with a more rapid, and permanent, decline in renal function in patients with T2DM (6). In addition, epidemiological studies consistently show an inverse relationship between dietary Mg 2+ intake and risk of developing T2DM (7). Several patient studies have shown beneficial effects of Mg 2+ supplementation on glucose metabolism and insulin sensitivity (8-10). Recently, Rodríguez-Morán et al. (11) published an excellent overview of the clinical studies addressing the role of Mg 2+ in T2DM. In our review, we will focus on the molecular mechanisms underlying these clinical observations. Mg 2+ is an essential ion for human health, as it is involved in virtually every mechanism in the cell, including energy homeostasis, protein synthesis, and DNA stability (12). Considering these divergent functions, it can be appreciated that serum Mg 2+ levels are tightly regulated between 0.7 and 1.05 mmol/L in healthy individuals. However, impaired intestinal Mg 2+ absorption or renal Mg 2+ wasting can lead to hypomagnesemia. A wide range of genetic and environmental factors can affect the Mg 2+ -deficient state, which have previously been extensively reviewed (12).In this review, we address the following questions that are central to the role of hypomagnesemia in T2DM: 1) Does Mg 2+ regulate insulin secretion? 2) How does Mg 2+ affect insulin resistance? 3) How does insulin regulate Mg 2+ homeostasis? Taken together, these questions will aid the understanding of whether hypomagnesemia is a causative factor for or a consequence of T2DM.

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“…TRPM6 plays a key role in the absorption of Mg ( Fig. 1) (8,9). TRPM6 expression in the intestine is regulated by dietary Mg.…”

Section: Trpm6mentioning

confidence: 99%

“…TRPM6 expression in the intestine is regulated by dietary Mg. This suggests that TRPM6 functions as a gatekeeper of Mg absorption (9). Loss-of-function mutations in the TRPM6 gene were identified in patients with the rare autosomal-recessive disease, hypomagnesemia (10).…”

Section: Trpm6mentioning

confidence: 99%