Abstract MP58: A Plasma Metabolite Score Related to Psychological Distress and Future Diabetes Risk: A Nested Case-Control Study in US Women
Authors: Huang Tianyi , Zhu Yiwen , Shutta Katherine , Balasubramanian Raji , Zeleznik Oana , Rexrode Kathryn M , Clish Clary , Sun Qi , Hu Frank , Kubzansky Laura , Hankinson Susan 
Published: March 2023

Introduction:
Various forms of psychological distress, such as depression and anxiety, have been identified as risk factors for diabetes. However, there is limited evidence from population-based, epidemiologic studies investigating potential molecular mechanisms (e.g., metabolic dysregulation) linking psychological distress and diabetes development.

Hypothesis:
We assessed the hypothesis that a metabolite score reflecting psychological distress-related metabolic dysregulation is predictive of future diabetes risk in women.

Methods:
We conducted a nested case-control study of plasma metabolomics and diabetes risk in the Nurses’ Health Study, including 728 women (mean age: 55.2 years) with incident diabetes and 728 controls matched on age, race, fasting status, and time/date of blood collection. Blood samples were collected between 1989-1990 and incident diabetes was diagnosed between 1990-2012. Based on the metabolomic signature of chronic psychological distress we previously identified and validated in women (including coefficient estimates for individual metabolite associations), we calculated a weighted plasma metabolomic score of psychological distress comprised of 19 metabolites (e.g., serotonin, threonine, hippurate, biliverdin, glutamine, etc.). We used conditional logistic regression accounting for matching factors and other diabetes risk factors to estimate odds ratios (OR) and 95% CI for diabetes risk across quintiles of the distress-related metabolite score.

Results:
After adjusting for sociodemographic factors, family history of diabetes and health behaviors, the OR (95% CI) for diabetes risk across quintiles of the distress-related metabolite score was 1.00 (reference) for Q1, 1.11 (0.77, 1.61) for Q2, 1.64 (1.14, 2.35) for Q3, 2.07 (1.42, 3.01) for Q4, and 2.35 (1.60, 3.47) for Q5. Each 1-unit increase in the score was associated with 26% higher diabetes risk (95% CI: 1.15, 1.38; p-trend<0.0001). This association was moderately attenuated after additional adjustment for baseline body mass index (OR per 1-unit increase: 1.13; 95% CI: 1.02, 1.25; p-trend=0.02). Further, psychological distress assessed via self-report (defined as presence of depression or anxiety) was associated with modestly increased diabetes risk in the same sample (OR: 1.25; 95% CI: 1.01, 1.55). The metabolite score mediated 20.7% (95% CI: 5.1, 56.1) of the association between psychological distress and diabetes risk (p=0.0065).

Conclusions:
Our results suggest that the distress-related metabolite score was significantly associated with diabetes risk in women and partly mediated the association between self-reported psychological distress and diabetes risk. These findings provide supporting evidence that metabolic dysregulation may be an important mechanism underlying the observed association between psychological distress and diabetes risk.