title: Troglitazone can prevent development of type 1 diabetes induced by multiple low-dose streptozotocin in mice.
abstract: Recent investigations suggest that cytotoxic cytokines such as tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta or free radicals play an essential role in destruction of pancreatic beta cells in Type 1 diabetes and that, therefore, anti-oxidant or anti-TNF alpha and IL-1beta therapy could prevent the development of Type I diabetes. Troglitazone belongs to a novel class of antidiabetic agent possessing the ability to enhance insulin action provably through activating PPAR gamma and to scavenge free radicals. In the present study, we examined whether troglitazone can prevent the development of Type 1 diabetes in multiple, low-dose streptozotocin (MLDSTZ)-injected mice. In addition, effects of troglitazone on cytokine-induced pancreatic beta cell damage were examined in vitro. Type 1 diabetes was induced by MLDSTZ injection to DBA/2 mice (40 mg/kg/day for 5 days). Troglitazone was administered as a 0.2% food admixture (240 mg/kg/day) for 4 weeks from the start of or immediately after STZ injection. MLDSTZ injection elevated plasma glucose to 615 +/- 8 mg/dl 4 weeks after final STZ injection and was accompanied by infiltration of leukocytes to pancreatic islets (insulitis). Troglitazone treatment with MLDSTZ injection prevented hyperglycemia (230 +/- 30 mg/dl) and, suppressed insulitis and TNF alpha production from intraperitoneal exudate cells. TNF alpha (10 pg/ml) and IL-1beta (1 pg/ml) addition to hamster insulinoma cell line HIT-T15 for 7 days in vitro decreased insulin secretion and cell viability. Simultaneous troglitazone addition (0.03 to approximately 3 microM) significantly improved cytokine-induced decrease in insulin secretion and in cell viability. These findings suggest that troglitazone prevents the development of Type 1 diabetes in the MLDSTZ model by suppressing insulitis associated with decreasing TNF alpha production from intraperitoneal exudate cells and the subsequent TNF alpha and IL-1beta-induced beta cell damage.
authors.affiliation: Pharmacology & Molecular Biology, Research Laboratories, Sankyo Co, Ltd., Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: J
authors.initials: J
authors.lastname: Fukushige
authors.forename: T
authors.initials: T
authors.lastname: Hosokawa
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.forename: S
authors.initials: S
authors.lastname: Kurakata
authors.forename: H
authors.initials: H
authors.lastname: Horikoshi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002839:Chromans / Q000627:therapeutic use*; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D013311:Streptozocin; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D002839:Chromans; D016166:Free Radical Scavengers; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000077288:Troglitazone