Grape pomace polyphenols inhibit Type 2 Diabetes Mellitus (T2DM)-related enzymes, reinforcing their sustainable recovery to be used as an alternative to the synthetic drug acarbose. Protic co-solvents (ethanol 15% and glycerol 15%) were evaluated in the hot pressurized liquid extraction (HPLE) of Carmenere pomace at 90, 120, and 150 degrees C in order to obtain extracts rich in monomers and oligomers of procyanidins with high antioxidant capacities and inhibitory effects on alpha-amylase and alpha-glucosidase. The higher the HPLE temperature (from 90 degrees C to 150 degrees C) the higher the total polyphenol content (similar to 79%, similar to 83%, and similar to 143% for water-ethanol, water-glycerol and pure water, respectively) and antioxidant capacity of the extracts (Oxygen Radical Absorbance Capacity, ORAC), increased by similar to 26%, 27% and 13%, while the half maximal inhibitory concentration (IC50) decreased by similar to 65%, 67%, and 59% for water-ethanol, water-glycerol, and pure water extracts, respectively). Water-glycerol HPLE at 150 and 120 degrees C recovered the highest amounts of monomers (99, 421, and 112 mu g/g dw of phenolic acids, flavanols, and flavonols, respectively) and dimers of procyanidins (65 and 87 mu g/g dw of B1 and B2, respectively). At 90 degrees C, the water-ethanol mixture extracted the highest amounts of procyanidin trimers (13 and 49 mu g/g dw of C1 and B2, respectively) and procyanidin tetramers of B2 di-O-gallate (13 mu g/g dw). Among the Carmenere pomace extracts analyzed in this study, 1000 mu g/mL of the water-ethanol extract obtained, at 90 degrees C, reduced differentially the alpha-amylase (56%) and alpha-glucosidase (98%) activities. At the same concentration, acarbose inhibited 56% of alpha-amylase and 73% of alpha-glucosidase activities; thus, our grape HPLE extracts can be considered a good inhibitor compared to the synthetic drug.