PROLONGED EFFECT OF TROGLITAZONE (CS-045) ON XENOGRAFT SURVIVAL OF HYBRID ARTIFICIAL PANCREAS

Troglitazone (CS-045), a thiazolidinedione derivative, is a new oral a ntidiabetic agent that enhances insulin sensitivity and improves insul in responsiveness, In this study we examined the effects of CS-045 on the survival of xenografted bioartificial pancreas, Isolated rat islet s were microencapsulated with three-layer agarose microcapsules (polyb rene, carboxymethyl cellulose, and an agarose-polystyrene sulfonic aci d mixture), Diabetes was induced by intraperitoneal injection of strep tozotocin 220 mg/kg, Recipient diabetic mice were separated into two g roups, In the CS-045 treated group, the recipient mice were given feed mixed with CS-045 (0.2% w/w) starting from 1 wk before transplantatio n up to graft failure. The mice in the control group had feed without CS-045. Three hundred microencapsulated rat islets were xenotransplant ed into the intraperitoneal cavity of each recipient mouse in both gro ups. One month after xenotransplantation, IVGTT was performed for all recipients, Xenotransplantation of 300 rat islets in microcapsules dec reased the nonfasting blood glucose levels of both groups within 2 day s, In the CS-045-treated group (n = 3), the normoglycemic period laste d for more than 1 mo without administration of immunosuppressive drugs (45 +/- 4.3 days), However, in the control group (n = 4), the blood g lucose levels of all recipients were already elevated on day 4, In the IVGTT study, the glucose assimilation was markedly and significantly better in the CS-045-treated group than in the control group (K = 1.7 +/- 0.1 vs, 0.7 +/- 0.28 respectively, p < 0.01), This study demonstra tes that a newly developed oral antidiabetic agent, CS-045 could favor ably ameliorate the diabetic state of the recipients xenotransplanted with the bioartificial pancreas, leading to an improved glucose tolera nce and longer xenograft survival. (C) 1997 Elsevier Science Inc.