To study the effect of time and different forms of hyperketonemia, with or without puerperal metritis, on insulin and glucose responses, 31 Holstein cows were subjected to glucose (GTT) and insulin tolerance tests (1717) between 18 and 22 d before, and on days 7 and 60-70 after calving. Plasma concentrations of beta-hydroxybutyrate (BHB), nonesterified fatty acids, glucose, insulin, insulin-like growth factor I and leptin were measured from 18 d before until 70 d after calving. The revised quick insulin sensitivity index (RQUICKI) was calculated at each time point. First postpartum (PP) ovulation was monitored by milk progesterone. Based on BHB patterns and clinical findings, animals were classified as 1) Normoketonernic (NK, n = 9); 2) Transiently hyperketonernic (tHK, n = 7); 3) Continuously HK (cHK, n = 7); and 4) Continuously HK, with signs of puerperal metritis (cHK + PM, n = 6). Insulin area under the curve (AUC) and insulin response to glucose were significantly lower in the early PP period than in late-pregnancy (P < 0.001), and on day 7 after calving in cHK and cHK + PM groups compared to NK and tHK groups (P < 0.001). On day 7, insulin stimulated a decrease in plasma glucose in cHK, cHK + PMthan NK, and tHK groups. Normoketonemic cows (group 1) ovulated earlier than all other groups (P = 0.002). There was no correlation between GTT and ITT variables and the RQUICKI. Time had a significant effect on RQUICKI. Long-term hyperketonemia, especially combined with puerperal metritis, interacts with secretion of insulin and whole-body IR, and results in a significant delay in PP ovarian activity in dairy cows.