Our primary objective was to determine whether administering the viscous and fermentable polysaccharide PolyGlycopleX (PGX) with metformin (MET) or sitagliptin/metformin (S/MET) reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than monotherapy of each. Glucose tolerance, adiposity, satiety hormones and mechanisms related to dipeptidyl peptidase 4 activity, gut microbiota and, hepatic and pancreatic histology were examined. Male ZDF rats (9–10 weeks of age) were randomized to: i) cellulose/vehicle (control, C); ii) PGX (5% wt/wt)/vehicle (PGX); iii) cellulose/metformin (200 mg/kg) (MET); iv) cellulose/S/MET (10 mg/kg+200 mg/kg) (S/MET); v) PGX (5%)+MET (200 mg/kg) (PGX+MET); vi) cellulose/sitagliptin/MET (5%)+(10 mg/kg+200 mg/kg) (PGX+S/MET) for 6 weeks. PGX+MET and PGX+S/MET reduced glycemia compared with C and singular treatments (P=0.001). Weekly fasted and fed blood glucose levels were lower in PGX+MET and PGX+S/MET compared with all other groups at weeks 4, 5, and 6 (P=0.001). HbA1c was lower in PGX+S/MET than C, MET, S/MET, and PGX at week 6 (P=0.001). Fat mass was lower and GLP1 was higher in PGX+S/MET compared with all other groups (P=0.001). β-cell mass was highest and islet degeneration lowest in PGX+S/MET. Hepatic lipidosis was significantly lower in PGX+S/MET compared with PGX or S/MET alone. When combined with PGX, both MET and S/MET markedly reduce glycemia; however, PGX+S/MET appears advantageous over PGX+MET in terms of increased β-cell mass and reduced adiposity. Both combination treatments attenuated diabetes in the obese Zucker rat.