We examined the influence of diabetes mellitus (DM) on the healing of HCl-induced gastric lesions and the healing promoting effect of polaprezinc [N-(3-aminopropionyl)-L-histidinato zinc] on these lesions. Studies were performed on rats injected intraperitoneally with streptozotocin (STZ, 70 mg/kg) five weeks prior to experiments. Diabetic rats had blood glucose levels (BGLs) higher than 350 mg/100 ml. Randomly chosen animals were treated subcutaneously with insulin (4 IU/day/rat) starting 1 week after STZ. Animals were given 1 ml of 0.6 N HCl by oral gavage (per os) following 18 hr of fasting; they were fed normally from 1 hr later and killed at various time points after HCl administration. Polaprezinc (3-30 mg/kg) or its components ZnSO4/7H2O and L-carnosine were given orally, twice daily for four days following HCl treatment. Gastric lesions induced by HCl healed macroscopically to quiescence within 10 days. DM and insulin did not affect the development of HCl-invoked gastric lesions, but the healing of such lesions was markedly impaired in animals with DM. Daily administration of insulin returned high BGLs to significantly lower ranges (190-208 mg/100 ml) and markedly antagonized the healing impairment. Polaprezinc (>10 mg/kg) significantly reversed the delay observed in diabetic rats without any notable effects on BGLs or acid secretion. Similar trends were observed with ZnSO4/7H2O or a mixture of ZnSO4/7H2O and L-carnosine, but not by L-carnosine alone. The mucosal expression of insulin-like growth factor-1 (IGF-I) mRNA was significantly lower in diabetic rats, a dysregulation partially corrected by insulin and polaprezinc. In addition, the delayed healing in diabetic rats was also significantly promoted by the repeated subcutaneous administration of rhIGF-I (>10 microg/kg, twice daily) without any notable effect on BGLs or acid secretion. These results suggest that DM exerted a deleterious influence on the healing of acute gastric lesions in both insulin- and zinc-sensitive manner. The salutary effects of polaprezinc on the impaired healing of gastric lesion in STZ-diabetic animals may at least be partly explained by enhancement of mucosal IGF-I mRNA expression in the stomach.