POTENT ANTIHYPERGLYCEMIC PROPERTY OF A NEW IMIDAZOLINE DERIVATIVE S-22068 (PMS-847) IN A RAT MODEL OF NIDDM

1 Recent data suggest that some imidazoline derivatives can lower plas ma glucose in experimental animal models of diabetes. We studied the a ctivity of an imidazoline S-22068, in rat model of noninsulin-dependen t diabetes mellitus (NIDDM) produced with a low dose of streptozotocin (35 mg kg(-1), i.v.) in the adult. 2 The respective increase: over ba sal value in glucose (Delta G) and insulin (Delta I), and the rate of glucose disappearance (K), were measured during a 30 min intravenous g lucose tolerance test. After an intraperitoneal injection of S-22068 ( 24 mg kg(-1)), Delta G (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 t he test, Delta I was unchanged. 3 During oral glucose tolerance tests (OGTT), S-22068 (24 mg kg(-1), p.o.) improved glucose tolerance, and i ts 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 tole rance without causing hypoglycaemia. 4 Binding experiments revealed th at S-22068 displays no affinity for either adrenoceptors or the two im idazoline receptors I-1 or I-2. 5 These results demonstrate that S-220 68 improves glucose tolerance without causing hypoglycaemia. Thus S-22 068 represents a new potential option in the treatment of NIDDM.