To identify predictors of favorable changes to postprandial insulin and glucose levels in response to interrupting prolonged sitting time with standing or light-intensity physical activity.Data were combined from four similarly designed randomized acute cross-over trials (n = 129; body mass index [BMI] range, 19.6-44.6 kg·m; South Asian = 31.0%; dysglycemia = 27.1%). Treatments included: prolonged sitting (6.5 h) or prolonged sitting broken-up with either standing or light-intensity physical activity (5 min every 30 min). Time-averaged postprandial responses for insulin and glucose were calculated for each treatment (mean ± 95% confidence interval). Mutually adjusted interaction terms were used to examine whether anthropometric (BMI), demographic (age, sex, ethnicity [white European vs South Asian]) and a cardiometabolic variable (Homeostatic Model Assessment of Insulin Resistance)-modified responses.Postprandial insulin and glucose were reduced when individuals interrupted prolonged sitting with bouts of light physical activity, but not with standing. Reductions in time-averaged postprandial insulin were more pronounced if individuals were South Asian compared with white European (-18.9 mU·L [-23.5%] vs -8.2 mU·L [-9.3%]), female compared with male (-15.0 mU·L [-21.2%] vs -12.1 mU·L [-17.6%]) or had a BMI ≥27.2 kg·m (-20.9 mU·L [-22.9%] vs -8.7 mU·L [-18.2%]). Similarly, being female (-0.4 mmol·L [-0.6 mmol·L, -0.2 mmol·L], -6.8% vs -0.1 mmol·L [-0.3 mmol·L, 1 mmol·L], -1.7%) or having a BMI ≥27.2 kg·m (-0.4 mmol·L [-0.6 mmol·L, -0.2 mmol·L], -6.7% vs -0.2 mmol·L [-0.4 mmol·L, 0.0 mmol·L], -3.4%) modified the postprandial glucose response. No significant interactions were found for Homeostatic Model Assessment of Insulin Resistance or age.Being female, South Asian, or having a higher BMI, all predicted greater reductions in postprandial insulin, whereas being female and having a higher BMI predicted greater reductions in postprandial glucose when sitting was interrupted with light physical activity. These results could help to guide personalized interventions in high-risk participants for whom breaking prolonged sitting time with light activity may yield the greatest therapeutic potential.