Associations Between Shift Work and Insulin Resistance Markers in 53,053 Spanish Workers: A Sex-Stratified Cross-Sectional Analysis Using TyG, TyG-BMI, METS-IR, and SPISE-IR Indices

<b>Background/Objective</b>: Shift work has been increasingly associated with adverse metabolic outcomes, including insulin resistance (IR), a key contributor to cardiometabolic diseases. However, few large-scale studies have explored the association between shift work and validated IR indices across sociodemographic and lifestyle variables, stratified by sex. To investigate the relationship between shift work and four surrogate markers of insulin resistance-TyG índex, TyG-BMI, METS-IR (Metabolic score for insulin resistance), and SPISE-IR (Single-Point insulin Sensitivity estimator)-in a large Spanish working population and to assess how sociodemographic and behavioral factors modify these associations. <b>Methods</b>: This cross-sectional study included 53,053 employed adults (31,753 men and 21,300 women) across various regions and labor sectors in Spain. Participants were classified as shift or non-shift workers based on their work schedules. Data were collected during routine occupational health assessments and included anthropometric, clinical, biochemical, and behavioral variables. IR indices were calculated using standard formulas. Statistical analyses included <i>t</i>-tests, chi-square tests, and multivariable logistic regression, with stratification by sex. <b>Results</b>: Shift workers exhibited significantly higher levels of TyG, TyG-BMI, and METS-IR, and lower SPISE values compared to non-shift workers (all <i>p</i> < 0.001). These differences persisted after stratification by sex, age, education, and lifestyle factors. Logistic regression analyses confirmed that shift work independently predicted high IR risk across all indices, with adjusted ORs ranging from 1.49 to 1.89. Physical inactivity, low adherence to the Mediterranean diet, and alcohol consumption were the strongest modifiable predictors. Men exhibited a higher burden of IR than women across all indices. <b>Conclusions</b>: Shift work is independently associated with elevated insulin resistance in both men and women. These findings emphasize the importance of workplace health interventions targeting physical activity, diet, and substance use, particularly in populations engaged in non-standard work schedules.