Abstract. The present study aimed at 1) investigating the effect of a combined insulin + glipizide treatment on the metabolic control (HbA1c levels) and insulin requirements (Biostator® assessment) in ten non-obese Type-II diabetic patients with recent secondary failure to sulfonylureas; and 2) characterizing the relative contributions of changes in endogenous insulin secretion (C-peptide response) and insulin sensitivity (insulin-induced glucose disposal in clamped conditions) to this effect. The patients were treated in a randomized cross-over order with either insulin alone or insulin + glipizide (3 × 10 mg/day) during two periods averaging 6 weeks each. Mean HbA1c levels were similar in both experimental conditions (8.2 ± 0.6 vs 7.9 ± 0.6%, NS). In fact, during the combined therapy, HbA1c levels decreased in five subjects (from 8.6 ± 0.7 to 7.1 ± 0.5%; 'responders'), but not in the five others ('non-responders'); the 20-h Biostator insulin infusion was significantly decreased in the responders (29%; P < 0.05), but not in the non-responders. Basal (0.271 ± 0.086 vs 0.086 ± 0.017 nmol/l; P < 0.05) and post-glucagon (0.468 ± 0.121 vs 0.180 ± 0.060 nmol/l; P < 0.05) C-peptide plasma levels were significantly higher in the responders than in the non-responders; in addition, glipizide significantly increased basal C-peptide concentrations in the responders only (+ 68%; P < 0.05). The insulininduced glucose disposal was significantly increased by glipizide in the responders (+ 23%; P < 0.05), but not in the non-responders; however, this difference could be due to higher plasma free insulin levels (+ 37%; P < 0.02) during the clamp with glipizide in the responders who showed persistent C-peptide stimulation. Thus, combining glipizide with insulin seems to be useful only in Type-II diabetic patients who still have a significant endogenous insulin secretion capable of being stimulated by this compound.