Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats

Takayanagi, Kaori; Shimizu, Taisuke; Tayama, Yosuke; Ikari, Akira; Anzai, Naohiko; Iwashita, Takatsugu; Asakura, Juko; Hayashi, Keitaro; Mitarai, Tetsuya; Hasegawa, Hajime

doi:10.1152/ajprenal.00593.2013

Cited by 29 publications

(22 citation statements)

References 62 publications

(70 reference statements)

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“…Moreover, in kidneys of the LowMg-HFD mice, a lower mRNA expression of other DCT-specific genes, such as Slc12a3, Pvalb, and Klk1, was observed (24). These findings are in line with a study that observed reduced renal Trpm6 and Slc12a3 mRNA and protein levels in diabetic (Otsuka Long-Evans Tokushima fatty) rats (27). It is, however, not clear from this study if the reduced Trpm6 levels are a direct consequence of the lower Slc12a3 expression or if the DCT itself is affected.…”

Section: Discussionsupporting

confidence: 88%

Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

et al. 2019

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Hypomagnesemia (blood Mg2+ concentration <0.7 mM) is a common electrolyte disorder in patients with type 2 diabetes (T2D), but the etiology remains largely unknown. In patients with T2D, reduced blood Mg2+ levels are associated with an increased decline in renal function, independent of glycemic control and hypertension. To study the underlying mechanism of this phenomenon, we investigated the renal effects of hypomagnesemia in high‐fat‐diet (HFD)‐fed mice. In mice fed a low dietary Mg2+, the HFD resulted in severe hypomagnesemia within 4 wk. Renal or intestinal Mg2+ wasting was not observed after 16 wk on the diets. Despite the absence of urinary or fecal Mg2+ loss, the HFD induced a reduction in the mRNA expression transient receptor potential melastatin type 6 in both the kidney and colon. mRNA expression of distal convoluted tubule (DCT)‐specific genes was down‐regulated by the LowMg‐HFD, indicating atrophy of the DCT. The low dietary Mg2+ resulted in severe HFD‐induced proximal tubule phospholipidosis, which was absent in mice on a NormalMg‐HFD. This was accompanied by albuminuria, moderate renal damage, and alterations in renal energy metabolism, including enhanced gluconeo‐genesis and cholesterol synthesis. In conclusion, this study shows that hypomagnesemia is a consequence of diet‐induced obesity and insulin resistance. Moreover, hypomagnesemia induces major structural changes in the diabetic kidney, including proximal tubular phospholipidosis, providing a novel mechanism for the increased renal decline in patients with hypomagnesemic T2D.—Kurstjens, S., Smeets, B., Overmars‐Bos, C., Dijkman, H. B., den Braanker, D. J. W., de Bel, T., Bindels, R. J. M., Tack, C. J. J., Hoenderop, J. G. J., de Baaij, J. H. F. Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice. FASEB J. 33, 7192–7201 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 88%

Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

et al. 2019

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“…The mRNA expression of TRPM6 is changed in diabetic rats, although results are contradictory and may depend on the experimental model used (96,97). 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: 95%

“…However, these differences may be explained by the dietary Mg 2+ intake of the subjects, since patients in the original study showed reduced Mg 2+ intake (,250 mg/day) (71). The mRNA expression of TRPM6 is changed in diabetic rats, although results are contradictory and may depend on the experimental model used (96,97). Whereas some report increased TRPM6 expression (96), others show that TRPM6 is downregulated (97).…”

Section: Trpm6mentioning

confidence: 99%

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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“…Magnesiuria is likely caused by the reduced activity of the transient receptor potential melastatin 6 (TRPM6) ion channel in the distal convoluted tubules and is possibly related to insulin resistance . In fact, a downregulation of TRPM6 channels, hypermagnesiuria, and hypomagnesemia were observed in obese T2D rats . Hence, the improvement of insulin resistance observed after SGLT2i administration may be associated with reduced magnesium excretion through TRPM6.…”

Section: Clinical and Preclinical Studies On Electrolytes Imbalancesmentioning

confidence: 99%

Mineral and Electrolyte Disorders With SGLT2i Therapy

et al. 2019

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The newly developed sodium‐glucose cotransporter 2 inhibitors (SGLT2is) effectively modulate glucose metabolism in diabetes. Although clinical data suggest that SGLT2is (empagliflozin, dapagliflozin, ertugliflozin, canagliflozin, ipragliflozin) are safe and protect against renal and cardiovascular events, very little attention has been dedicated to the effects of these compounds on different electrolytes. As with other antidiabetic compounds, some effects on water and electrolytes balance have been documented. Although the natriuretic effect and osmotic diuresis are expected with SGLT2is, these compounds may also modulate urinary potassium, magnesium, phosphate, and calcium excretion. Notably, they have had no effect on plasma sodium levels and promoted only small increases in serum potassium and magnesium concentrations in clinical trials. Moreover, SGLT2is may induce an increase in serum phosphate, FGF‐23, and PTH; reduce 1,25‐dihydroxyvitamin D; and generate normal serum calcium. Some published and preliminary reports, as well as unconfirmed reports have suggested an association with bone fractures. Some homeostasis perturbations are transient, whereas others may persist, suggesting that the administration of SGLT2is may affect electrolyte balances in exposed subjects. Although current evidence supports their safety, additional efforts are needed to elucidate the long‐term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited follow‐up studies and the heterogeneity of the case‐mix of different randomized controlled trials preclude a definitive answer on the impact of these compounds on long‐term outcomes such as the risk of bone fracture. Here we review the current understanding of the mechanisms involved in electrolyte handling and the available data on the clinical implications of electrolytes and mineral metabolism perturbations induced by SGLT2i administration. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats

Cited by 29 publications

References 62 publications

Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

Hypomagnesemia in Type 2 Diabetes: A Vicious Circle?

Mineral and Electrolyte Disorders With SGLT2i Therapy

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