Exercise improves glucose tolerance in obese rodent models and humans; however effects with respect to mechanisms of -cell compensation remain unexplained. We examined exercise effects during the progression of hyperglycemia in male ZDF rats until 19-weeks of age. At 6-weeks old, rats were assigned to: 1) basal-euthanized for baseline values; 2) exercise-swam individually for 1h/day, 5d/week; and 3) controls (n=8-10/group). Thirteen weeks of exercise resulted in maintenance of fasted hyperinsulinemia and prevented increases in fed and fasted glucose (P<0.05) compared with sham-exercised and sedentary controls (P<0.05). -cell function calculations indicate prolonged -cell adaptation in exercised animals alone. During an intraperitoneal glucose tolerance test (IPGTT) exercised rats had lower 2h-glucose (P<0.05) versus controls. Area-under-the-curve analyses from baseline for IPGTT glucose and insulin indicate improved glucose tolerance with exercise was associated with increased insulin production and/or secretion. -cell mass increased in exercised versus basal animals however, mass expansion was absent at 19 weeks in controls (P<0.05). Hypertrophy and replication contributed to expansion of -cell mass; exercised animals had increased -cell size and BrdU incorporation rates versus controls (P<0.05). The relative area of GLUT2 and Akt/PKB was significantly elevated in exercised versus sedentary controls (P<0.05). Lastly, we show formation of ubiquitinated protein aggregates, a response to cellular/oxidative stress, occurred in non-exercised 19 week-old ZDF rats but not in lean, 6 week-old basal, or exercised rats. In conclusion, improved -cell compensation through increased -cell function and mass occurs in exercised but not sedentary ZDF rats and may be in part responsible for improved glucoregulation.