Background: Consuming mealtime whey protein supplementation increases daily time in euglycemic range [TIR] in adults with type 2 diabetes [T2D] with inter-individual responses. The present post-hoc analysis aimed to identify metabolic predictors to the effectiveness of pre-meal whey protein. Methods: In a randomized-crossover design, 16 individuals with T2D [HbA1c 57±9 mmol/mol) underwent two 7d free-living periods where they consumed a whey protein (15g) or placebo beverage before each main meal. Glucose control was captured by blinded continuous glucose monitoring. Patient anthropometric and fasting markers of liver health and glucose metabolism were obtained at baseline. β-cell function was determined by the ratio of the incremental changes in insulin secretion to glucose during a feeding test. The relationship between TIR and clinical markers were analyzed by correlational analysis, and predictors of TIR were determined by multiple regression. Results: β-cell function was a strong determinant to TIR during both the whey (rs=0.615; p=0.011) and placebo (rs=0.598; p=0.019) weeks. Around 76% of the variance in TIR during the whey week was accounted by β-cell function, and fasting insulin and alanine aminotransferase concentrations (adj R2=0.760; p<0.001). During the whey intervention, TIR was inversely associated with aspartate aminotransferase (rs=−0.506; p=0.046) and tended to be related to fasting glucagon (rs=−0.482; p=0.058), whereas there were no associations between liver health or fasting hormonal markers with TIR during placebo (p>0.05). Conclusions: In a small cohort of people with T2D, our data indicates that those with compromised liver health and reduced β-cell function may experience a reduction in TIR when consuming mealtime protein supplementation. This is possibly due to disruptions in the liver-α-cell axis, which may be further aggravated by increasing plasma amino acid availability from protein supplementation. Disclosure K.Smith: None. G.Taylor: None. M.Walker: None. K.A.Bowden davies: None. E.J.Stevenson: None. D.J.West: None. Funding Francis James Bell Endowment Fund; County Durham Community Foundation