EXPERIMENTAL NIDDM - DEVELOPMENT OF A NEW MODEL IN ADULT RATS ADMINISTERED STREPTOZOTOCIN AND NICOTINAMIDE

We took advantage of the partial protect on exerted by suitable dosage s of nicotinamide against the beta-cytotoxic effect of streptozotocin (STZ) to create a new experimental diabetic syndrome in adult rats tha t appears closer to NIDDM than other available animal models with rega rd to insulin responsiveness to glucose and sulfonylureas, Among the v arious dosages of nicotinamide tested in 3-month-old Wistar rats (100- 350 mg/kg body wt), the dosage of 230 mg/kg, given intraperitoneally 1 5 min before STZ administration (65 mg/kg i.v.) yielded a maximum of a nimals with moderate and stable nonfasting hyperglycemia (155 +/- 3 vs , 121 +/- 3 mg/dl in controls; P < 0.05) and 40% preservation of pancr eatic insulin stors. We also evaluated beta-cell function both in vitr o and in vivo 4-9 weeks after inducing diabetes. In the isolated perfu sed pancreas, insulin response to glucose elevation (5-11 mmol/l) was clearly present, although significantly reduced with respect to contro ls (P < 0.01), Moreover, the insulin response to tolbutamide (0.19 mol /l) was similar to that observed in normal pancreases, Perfused pancre ases from diabetic animals also exhibited a striking hypersensitivity to arginine infusion (7 mmol/l), In rats;administered STZ pins nicotin amide, intravenous glucose tolerance tests revealed clear abnormalitie s in glucosc tolerance and insulin responsiveness, which were interest ingly reversed by tolbutamide administration (40 mg/kg i.v.). In concl usion, this novel NIDDM syndrome with reduced pancreatic insulin store s, which is similar to human NIDDM in that it has a. significant respo nse to glucose (although abnormal in kinetics) and preserved sensitivi ty to tolbutamide, may provide a particularly advantageous tool fur ph armacological investigations of new insulinotropic agents.