<b>Interactive effects of Empagliflozin and Hyperglycemia on Urinary Amino Acids in Individuals with Type 1 Diabetes</b>

Abstract

<p dir="ltr"><b>Abstract</b></p><p dir="ltr">Optimizing energy utilization in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter-2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of oral empagliflozin 25 mg/day in 40 normotensive, normoalbuminuric young adults with T1D. A consecutive two-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and post-treatment visit. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways – aminoacyl-tRNA, valine, leucine and isoleucine, arginine, as well as phenylalanine, tyrosine, and tryptophan. Under acute hyperglycemia, empagliflozin significantly attenuated the increases to aminoacyl-tRNA biosynthesis and valine, leucine and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism.</p><p><br></p><p dir="ltr"><b>Article highlights:</b></p><p><br></p><p dir="ltr">1. Altered amino acid metabolism in the kidney mitochondria is a key metabolomic signature of diabetes mellitus.</p><p dir="ltr">2. In young adults with type 1 diabetes (T1D), acute hyperglycemia is associated with the induction of four biosynthetic amino acid pathways – aminoacyl-tRNA, valine, leucine and isoleucine, arginine, and phenylalanine, tyrosine, and tryptophan.</p><p dir="ltr">3. Sodium glucose cotransporter 2 (SGLT2) inhibition with empagliflozin attenuates the effects on amino acids by acute hyperglycemia.</p><p dir="ltr">4. An advantageous shift towards ‘pseudo-fasting state’ with SGLT2 inhibition may optimize energy use and contribute to kidney protection in T1D.</p>