Kidney Week

Abstract: TH-PO0026

Sodium-Glucose Cotransporter-2 Inhibition Enhances Magnesium Reabsorption in the Thick Ascending Limb in Patients with Type 2 Diabetes

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Swanekamp, Emily, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Emily Swanekamp

• Schaub, Jennifer A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Jennifer A. Schaub, MD

• Chakraborty, Saroj, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Saroj Chakraborty, PhD

• Choi, Ye Ji, University of Washington, Seattle, Washington, United States

Ye Ji Choi, MPH

• Pyle, Laura, University of Washington, Seattle, Washington, United States

Laura Pyle, MS, PhD

• Bjornstad, Petter, University of Washington, Seattle, Washington, United States

Petter Bjornstad, MD

• Pennathur, Subramaniam, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Subramaniam Pennathur, MD

• Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Wolf, Matthias Tilmann, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Matthias Tilmann Wolf, MD, PhD, FASN

Background

Type 2 Diabetes (T2D) incidence is increasing among youth worldwide, and kidney disease is a common comorbidity that improves with glucose- lowering interventions. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been effective in reducing hyperglycemia in patients with T2D and have also been associated with higher serum Mg²⁺ concentrations, suggesting a potential therapeutic role in treating hypomagnesemia. Several different hypotheses have been proposed to explain how SGLT2i elevate serum Mg²⁺ concentrations, but the underlying mechanism remains elusive. We aim to investigate whether alterations in tubular ion transport in the thick ascending limb (TAL) and distal convoluted tubule (DCT) could explain this phenomenon.

Methods

We performed single cell (sc)-RNA seq on kidney biopsies obtained from six healthy controls, six participants with T2D, and ten participants with T2D treated with SGLT2i. In parallel, qPCR was conducted on kidney tissue from db/db mice and db/db mice treated with 5mg/mL empagliflozin in the drinking water for 8 weeks starting at 28 weeks old.

Results

NKCC2, ROMK, and CLDN16 gene expressions are significantly elevated after SGLT2i treatment in both mice and humans. CLDN 19 gene expression is significantly elevated after SGLT2i treatment in humans but remains unchanged in mice. In the distal convoluted tubule (DCT) of human patients, TRPM6, TRPM7, NCC, and WNK4 expression are all significantly upregulated in humans after treatment with SGLT2i. The expression level of these magnesiotropic genes in the DCT remained unchanged in mice.

Conclusion

This data supports the hypothesis that SGLT2i augment the lumen-positive potential in the TAL driving Mg²⁺ reabsorption through the paracellular space in both human and mice. However, magnesiotropic genes in the DCT that stimulate TRPM6/TRPM7 channel may further increases Mg²⁺ reabsorption in only human kidneys.

Funding

• NIDDK Support