Abstract: TH-PO0355
Bioenergetic Shifts in Plasma Amino Acids and Related Metabolites in Response to SGLT2 Inhibition and Hyperglycemia in Type 1 Diabetes
Session Information
- Diabetic Kidney Disease: From Early Biomarkers to Novel Therapeutic Targets
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 702 Diabetic Kidney Disease: Clinical
Authors
- Kugathasan, Luxcia, University Health Network, Toronto, Ontario, Canada
- Ragi, Nagarjunachary, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Debnath, Subrata, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Sridhar, Vikas, The University of British Columbia, Vancouver, British Columbia, Canada
- Maity, Soumya, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Feng, Tianqing, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Trevino, Esmeralda, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Perkins, Bruce A., Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
- Cherney, David, University Health Network, Toronto, Ontario, Canada
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background
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).
Methods
The ATIRMA trial, a single-arm study, evaluated the effects of 8 weeks of oral empagliflozin (25 mg/day) in 40 young adults with type 1 diabetes (T1D). Plasma samples were tested for 28 metabolites during euglycemia and hyperglycemia, both pre- and post-treatment. Principal component analysis was performed on key amino acid pathways identified using MetaboAnalyst 5.0.
Results
Acute, ambient hyperglycemia altered seven of the 28 available plasma metabolites, including increases in methionine, serine, threonine, proline, and asparagine, and decreases in alanine. Acute hyperglycemia induced changes to eight metabolic pathways, including but not limited to, increases in cysteine and methionine metabolism (0.57-fold, p<0.0001), valine, leucine and isoleucine biosynthesis (0.31-fold, p=0.002); and nitrogen metabolism (0.11-fold, p=0.003). Introduction of empagliflozin was associated with a decrease in adenine (–0.02, p=0.04), cysteine and methionine metabolism (–0.29-fold, p=0.02) when maintained under euglycemia and an increase in nitrogen metabolism under hyperglycemia (0.07-fold, p=0.04) (Figure 1).
Conclusion
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 bioenergetic effects. This adaptive metabolic shift may offer protection against cardiovascular and kidney complications in T1D, highlighting the need for further long-term studies.
Figure 1. Plasma metabolite pathways at baseline and 8 weeks post-treatment are reflected as a Z-score of mean ± SD under both clamped euglycemic (blue) and hyperglycemia (red).
Funding
- Commercial Support – Boehringer Ingelheim and Eli Lilly and Company