Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse.

Troglitazone has recently been introduced in the treatment of Type 2 diabetes. In addition to its anti-diabetic effects it acts as a perixosome proliferator activated receptor-gamma (PPAR-gamma) agonist and has anti-inflammatory properties by inhibiting macrophage tumour necrosis factor-alpha (TNF-alpha) secretion. It also inhibits the production of endothelial selectin (e-selectin). Troglitazone also reduces interleukin-1alpha induced nitric oxide production in pancreatic beta-cells, which may be relevant in preventing nitric oxide mediated damage to these cells in the Type 1 diabetes process. We tested troglitazone in the spontaneous model of autoimmune diabetes, the non-obese diabetic (NOD) mouse, to determine its effect on the disease process. When administered by gavage from weaning at a dose of 400 mg/kg body weight (n = 32), troglitazone reduced the incidence of diabetes by 16 weeks compared to controls (n = 32) in a pattern that was maintained up to the conclusion of the experiment at 31 weeks of age (p < 0.05). Insulitis was unaltered (index = 1.05 +/- 0.71 vs. 1.13 +/- 0.82, treated vs. controls, p = 0.78). The study was repeated using troglitazone in the diet of NOD mice (n = 24) to give a dose of approximately 200 mg/kg body weight in order to provide a more consistent level of troglitazone during the time course of the experiment. There was a reduction of diabetes incidence in this group but it did not reach significance. Insulin levels were reduced in gavage treated mice although such reduction did not reach significance (p < 0.07). We conclude that, in view of its effect on this model of autoimmune diabetes and because of its known function as an insulin sensitiser, troglitazone might be considered for potential use in those patients with Type 1 masquerading as Type 2 diabetes.

Troglitazone exhibits immunomodulatory activity on the cytokine production of activated human lymphocytes.

Troglitazone (TGL), a thiazolidinedione compound that improves the response of peripheral target tissue to insulin, also has anti-inflammatory properties, a potential means of protection from Type 1 (insulin dependent) diabetes. In order to test the ability of TGL to affect cytokine production, peripheral blood mononuclear cells from healthy donors were exposed to TGL in the presence or absence of a polyclonal activator (PHA) and the production of cytokines assayed. TGL enhanced PHA response, promoted secretion of the cytokines granulocyte and macrophage colony-stimulating factor and leukaemia inhibitory factor and inhibited tumour necrosis factor-alpha secretion, consistent with causing Th-2 differentiation in T-cells. These results suggest that TGL is capable of modulating cytokine production and could therefore influence Th1/Th2 differentiation.