ORF42-03 - Amino Acids Influence Type 2 Diabetes Risk through Changes in Insulin Sensitivity, Secretion, and Clearance

Background: Type 2 diabetes (T2D) is driven by multiple factors, including circulating amino acids, particularly branched-chain amino acids (BCAA). However, the exact mechanisms by which the amino acids contribute to diabetes are not well understood. We investigated the relationships between 20 amino acids and early indicators of T2D including insulin sensitivity, secretion, and clearance.

Methods: This study was conducted in a cohort of 353 participants enrolled in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Insulin homeostasis was evaluated via oral glucose tolerance testing. Amino acid levels were acquired from global metabolomic analysis (Metabolon). Statistical analysis with multiple linear regression was used to assess the associations among the 20 amino acid levels with baseline participant characteristics and calculated measures of insulin sensitivity, insulin secretion, and insulin clearance.

Results: The cohort consisted of 62% females and 37% non-Hispanic Black participants; mean age was 59.4 (SD 9.0) years. Fifteen amino acids were significantly associated with at least one insulin homeostasis trait in multivariable analysis. Cysteine was correlated with all 3 traits: decreased sensitivity (p < 0.001), increased secretion (p = 0.042), and increased clearance (p < 0.001). Among the BCAA, leucine and valine were linked to both decreased insulin sensitivity (p = 0.004 and 0.001, resp.) and decreased clearance (p = 0.014 and 0.005, resp.), while isoleucine was associated with decreased insulin sensitivity only (p < 0.001). Methionine and glutamate were significantly associated with both insulin secretion and clearance while serine was associated with both insulin sensitivity and clearance. Eight amino acids were associated with one insulin trait and five had no associations.

Discussion: These results clarify the underlying insulin changes by which amino acids may influence the development of T2D. Cysteine is correlated with decreased insulin sensitivity and increases in both insulin secretion and clearance. Considering T2D develops when a decrease in insulin sensitivity occurs followed by failure of compensatory hyperinsulinemia, cysteine’s associations may be indicative of a multifaced impact on aspects of insulin homeostasis. The BCAA were similarly associated with a significant decrease in insulin sensitivity, pointing to insulin resistance as the possible primary mechanism by which BCAA contribute to T2D risk. In contrast, the amino acids glycine, serine, and threonine were associated with increased insulin sensitivity, suggestive of a potential protective effect against T2D development. These findings provide insight into how amino acids may modulate insulin action in glucose metabolism.

Conclusion: The mechanisms by which amino acids influence T2D risk may occur via changes in insulin sensitivity, secretion, and clearance.