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Troglitazone can prevent development of type 1 diabetes induced by multiple low-dose streptozotocin in mice
J Ogawa1, S Takahashi, T Fujiwara
1Pharmacology & Molecular Biology, Research Laboratories, Sankyo Co, Ltd., Tokyo, Japan.
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.
Insights
Troglitazone, an antidiabetic agent, prevents Type 1 diabetes development in mice by reducing inflammation and protecting pancreatic beta cells. This antioxidant therapy also improves insulin secretion and cell viability in vitro.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Cytotoxic cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), along with free radicals, are implicated in pancreatic beta cell destruction in Type 1 diabetes.
- Antioxidant and anti-cytokine therapies are potential strategies for preventing Type 1 diabetes.
Purpose of the Study:
- To investigate the potential of troglitazone, a PPARγ activator and free radical scavenger, in preventing Type 1 diabetes development.
- To evaluate troglitazone's effects on cytokine-induced pancreatic beta cell damage in vitro.
Main Methods:
- Type 1 diabetes was induced in DBA/2 mice using multiple low-dose streptozotocin (MLDSTZ) injections.
- Troglitazone was administered orally for 4 weeks, starting before or after MLDSTZ injection.
- In vitro experiments assessed troglitazone's impact on cytokine-induced damage in a hamster insulinoma cell line (HIT-T15).
Main Results:
- MLDSTZ injection led to hyperglycemia and insulitis (leukocyte infiltration in islets).
- Troglitazone treatment prevented hyperglycemia, suppressed insulitis, and reduced TNF-α production.
- In vitro, troglitazone significantly improved cytokine-impaired insulin secretion and beta cell viability.
Conclusions:
- Troglitazone demonstrates preventative effects against Type 1 diabetes in the MLDSTZ mouse model.
- These protective effects are attributed to the suppression of insulitis and reduced TNF-α production.
- Troglitazone mitigates beta cell damage induced by TNF-α and IL-1β, suggesting therapeutic potential.