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Kidney Med
Kidney Med
Kidney Medicine
2590-0595
Elsevier

S2590-0595(24)00099-2
10.1016/j.xkme.2024.100888
100888
Correspondence
Letter to the Editor
Role of Glucagon in the Effects of SGLT2 Inhibition on Potassium and Magnesium Homeostasis
Shah Chintan V. MD shahc@ufl.edu
∗
Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, FL
∗ Address for Correspondence: Chintan V. Shah, Assistant Professor of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida – College of Medicine, 1600 SW Archer Road, Room CG-98, Gainesville, FL 32610. shahc@ufl.edu
13 8 2024
9 2024
13 8 2024
6 9 100888© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcTo the Editor:

We have reported that initiation of sodium-glucose cotransporter 2 (SGLT2) inhibitors can dramatically improve severe hypomagnesemia in patients with or without diabetes.1,2 As noted in a recent review, meta-analyses of randomized clinical trials have reinforced that SGLT2 inhibitors decrease the risk of hyperkalemia and correct hypomagnesemia.3 Palmer et al4 recently summarized a variety of possible mechanisms to explain the long-term impact of SGLT2 inhibitors on potassium homeostasis. Similarly, we have elaborated on the possible links to explain the effect of SGLT2 inhibitors on magnesium homeostasis.3 However, one must not ignore the potential mechanism that could explain both effects.

SGLT2 inhibitors directly and indirectly increase glucagon levels. The direct effect is via inhibition of SGLT2 on pancreatic alpha cells, which decreases sodium influx, improves intracellular pH, and increases glucagon secretion.5 A group of investigators noticed that SGLT2 inhibition using dapagliflozin mimics the glucagon response of human donor islet cells, similar to the effect of lowering glucose levels.6 The indirect effect occurs when the obligatory loss of glucose with SGLT2 inhibitors shifts metabolism to fatty substrate utilization via increased glucagon and decreased insulin levels in patients with or without diabetes.7 Increased glucagon levels can, in turn, increase TRPM6 activity, resulting in increased magnesium reabsorption in distal convoluted tubule cells.8 Similarly, data from animal and human studies suggest a kaliuretic effect of glucagon.9 Thus, the impact of SGLT2 inhibitors on glucagon could potentially explain its effect on potassium and magnesium homeostasis (Fig 1). Further studies are necessary to examine this direct link.Figure 1 Glucagon in the effects of sodium-glucose cotransporter 2 inhibition on potassium and magnesium homeostasis. Abbreviations: SGLT2i, Sodium-glucose cotransporter 2 inhibitors.

Article Information

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Financial Disclosure

The author declares that he has no relevant financial interests.

Peer Review

Received March 20, 2024. Accepted April 3, 2024 after editorial review by the Editor-in-Chief.
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References

1 Shah C.V. Robbins T.S. Sparks M.A. Sodium-glucose cotransporter 2 inhibitors and management of refractory hypomagnesemia without overt urinary magnesium wasting: a report of 2 cases Kidney Med 4 10 2022 100533 10.1016/j.xkme.2022.100533
2 Shah C.V. Hammad N. Bhasin-Chhabra B. Rashidi A. SGLT2 inhibitors in management of severe hypomagnesemia in patients without diabetes: a report of 4 cases Kidney Med 5 9 2023 Jul 1 100697 10.1016/j.xkme.2023.100697
3 Shah C.V. Sparks M.A. Lee C.T. Sodium/glucose cotransporter 2 inhibitors and magnesium homeostasis Am J Kidney Dis 83 5 2024 648 658 10.1053/j.ajkd.2023.11.006 38372686
4 Palmer B.F. Clegg D.J. SGLT2 inhibition and kidney potassium homeostasis Clin J Am Soc Nephrol 19 3 2024 399 405 10.2215/CJN.0000000000000300 37639260
5 Hodson D.J. Rorsman P. A variation on the theme: SGLT2 inhibition and glucagon secretion in human islets Diabetes 69 5 2020 864 866 10.2337/dbi19-0035 32312904
6 Saponaro C. Mühlemann M. Acosta-Montalvo A. Interindividual heterogeneity of SGLT2 expression and function in human pancreatic islets Diabetes 69 5 2020 902 914 10.2337/db19-0888 31896553
7 Ferrannini E. Baldi S. Frascerra S. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes Diabetes 65 5 2016 1190 1195 10.2337/db15-1356 26861783
8 Dai L.J. Bapty B. Ritchie G. Quamme G.A. Glucagon and arginine vasopressin stimulate Mg2+ uptake in mouse distal convoluted tubule cells Am J Physiol 274 2 1998 F328 F335 10.1152/ajprenal.1998.274.2.F328 9486227
9 Bankir L. Bouby N. Blondeau B. Crambert G. Glucagon actions on the kidney revisited: possible role in potassium homeostasis Am J Physiol Renal Physiol 311 2 2016 F469 F486 10.1152/ajprenal.00560.2015 27194722
