Potent antihyperglycaemic property of a new imidazoline derivative S-22068 (PMS 847) in a rat model of NIDDM

Abstract

Recent data suggest that some imidazoline derivatives can lower plasma glucose in experimental animal models of diabetes. We studied the activity of an imidazoline S-22068, in rat model of non-insulin-dependent diabetes mellitus (NIDDM) produced with a low dose of streptozotocin (35 mg kg(-1), i.v.) in the adult. The respective increase over basal value in glucose (deltaG) and insulin (deltaI), and the rate of glucose disappearance (K), were measured during a 30 min intravenous glucose tolerance test. After an intraperitoneal injection of S-22068 (24 mg kg(-1)), deltaG (mM min(-1)) was decreased (91.67+/-5.83 vs 120.5+/-3.65; P<0.001), whereas K was increased (1.74+/-0.09 vs 1.18+/-0.05; P<0.001). Although insulinaemia was increased at time-point 0 of the test, deltaI was unchanged. During oral glucose tolerance tests (OGTT), S-22068 (24 mg kg(-1), p.o.) improved glucose tolerance, and its efficiency was potentiated after chronic treatment (15 days). Basal glycaemia was unaffected by the treatment. Under the same conditions, a higher dose of S-22068 (40 mg kg(-1)) further improved glucose tolerance without causing hypoglycaemia. Binding experiments revealed that S-22068 displays no affinity for either adrenoceptors or the two imidazoline receptors I1 or I2. These results demonstrate that S-22068 improves glucose tolerance without causing hypoglycaemia. Thus S-22068 represents a new potential option in the treatment of NIDDM.