2. Academic Validation
  3. Metabolic shifts in plasma amino acids and related metabolites in response to SGLT2 inhibition and hyperglycemia in type 1 diabetes

Metabolic shifts in plasma amino acids and related metabolites in response to SGLT2 inhibition and hyperglycemia in type 1 diabetes

  • Physiol Rep. 2025 Aug;13(16):e70465. doi: 10.14814/phy2.70465.
Luxcia Kugathasan 1 2 3,  Nagarjunachary Ragi 4 5,  Subrata Debnath 4 5,  Vikas S Sridhar 6,  Soumya Maity 4 5,  Tianqing Feng 4 5,  Esmeralda Treviño 4 5,  Bruce A Perkins 7 8,  David Z I Cherney 1 2 3,  Kumar Sharma 4 5
Affiliations

Affiliations

  • 1 Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.
  • 2 Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
  • 3 Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Ontario, Canada.
  • 4 Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas, USA.
  • 5 Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, Texas, USA.
  • 6 Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
  • 7 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
  • 8 Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
PMID: 40842430 DOI: 10.14814/phy2.70465
Abstract

Regulated kidney function is dependent on maintaining efficient energy utilization. Our aim in this study was to determine the effects of acute, ambient hyperglycemia and sodium-glucose cotransporter-2 (SGLT2) inhibition on plasma amino acid metabolism in patients with type 1 diabetes (T1D). The ATIRMA trial, a single-arm study, evaluated the effects of 8 weeks of oral empagliflozin (25 mg/day) in 40 young adults with T1D. The study involved consecutive two-day assessments of clamped euglycemia and hyperglycemia at both baseline and post-treatment. MetaboAnalyst 6.0 categorized 35 metabolites into significant pathways, which were statistically compared using principal component analysis. Acute hyperglycemia induced changes to 10 metabolic pathways, including but not limited to increases in cysteine and methionine metabolism (0.52 ± 0.12, p < 0.0001), valine, leucine, and isoleucine biosynthesis (0.31 ± 0.10, p = 0.002); and nitrogen metabolism (0.11 ± 0.03, p = 0.003). Introduction of empagliflozin was associated with a decrease in adenine, and an increase in cysteine and methionine metabolism (0.31 ± 0.13, p = 0.02) when maintained under euglycemia and a decrease in nitrogen metabolism under hyperglycemia (-0.07 ± 0.04, p = 0.04). Our findings show that SGLT2 inhibition counteracts the hyperglycemia-induced changes in plasma amino acid metabolism, potentially improving energy efficiency and metabolic health, though more research is needed to confirm these metabolic effects.

Keywords

SGLT2 inhibition; amino acids; empagliflozin; hyperglycemia; metabolites; type 1 diabetes.

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