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

Beales, P. E.; Liddi, Roberto; Giorgini, Angela; Signore, Alberto; Procaccini, Enrica; Batchelor, Kenneth W.; Pozzilli, Paolo

doi:10.1016/s0014-2999(98)00574-3

Cited by 46 publications

(29 citation statements)

References 18 publications

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“…Antibodies against IL-1 (Cailleau et al, 1997) and TNF-␣ (Yang et al, 1994) have both been shown to prevent diabetes in the NOD mouse. Inhibitors of TNF-␣ transcription, such as MDL 201,449A (Holstad and Sandler, 2001), or secretion, such as troglitazone (Beales et al, 1998), have both prevented diabetes in the MLDS and NOD mouse models of diabetes, respectively.…”

Section: Discussionmentioning

confidence: 99%

Nicotine Reduces the Incidence of Type I Diabetes in Mice

Mabley

Pacher

Southan

et al. 2002

J Pharmacol Exp Ther

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Nicotine has been previously shown to have immunosuppressive actions. Type I diabetes is an autoimmune disease resulting from the specific destruction of the insulin-producing pancreatic ␤-cells. Thus, we hypothesized that nicotine may exert protective effects against type I diabetes. The multiple lowdose streptozotocin (MLDS)-induced model and spontaneous nonobese diabetic (NOD) mouse model of type I diabetes were used to assess whether nicotine could prevent this autoimmune disease. Blood glucose levels, diabetes incidence, pancreas insulin content, and cytokine levels were measured in both models of diabetes, both to asses the level of protection exerted by nicotine and to further investigate its mechanism of action. Nicotine treatment reduced the hyperglycemia and incidence of disease in both the MLDS and NOD mouse models of diabetes. Nicotine also protected against the diabetes-induced decrease in pancreatic insulin content observed in both animal models. The pancreatic levels of the Th1 cytokines interleukin (IL)-12, IL-1, tumor necrosis factor (TNF)-␣, and interferon (IFN)-␥ were increased in both MLDS-induced and spontaneous NOD diabetes, an effect prevented by nicotine treatment. Nicotine treatment increased the pancreatic levels of the Th2 cytokines IL-4 and IL-10. Nicotine treatment reduces the incidence of type I diabetes in two animal models by changing the profile of pancreatic cytokine expression from Th1 to Th2.Type I diabetes is a disease characterized by the specific destruction of the insulin-producing ␤-cells of the pancreatic islets of Langerhans by the immune system (Bottazzo and Bonifacio, 1991;Noorchashm et al., 1997). The islet is invaded by immune cells, particularly T-cells that are CD4 ϩ and CD8 ϩ (Rabinovitch, 1994), forming a pancreatic inflammation termed insulitis, with the resulting production of immune cell mediators, such as cytokines and free radicals (including nitric oxide and related radicals such as peroxynitrite), inhibiting ␤-cell function and ultimately inducing ␤-cell death (Rabinovitch and Suarez-Pinzon, 1998). The induction of nitric oxide synthase (iNOS) and the subsequent formation of nitric oxide and related free radicals have been implicated in the destruction of the ␤-cells in diabetes.A variety of cytokines have been found expressed in the insulitis lesion of the animal models of diabetes and in the pancreata of humans with type I diabetes. It has been proposed that the insulitis lesion is ␤-cell destructive when Th1 cytokines (IL-12, IFN-␥, IL-1, and TNF-␣), produced by isletinfiltrating T-cells, dominate over Th2 cytokines (Rabinovitch, 1998). Agents that suppress the immune system, including cyclosporine (Baquerizo et al., 1989) and glucocorticoids (Like et al., 1983), have been shown to reduce the disease incidence in animal models of type I diabetes.There are two murine models of autoimmune diabetes: the multiple low-dose streptozotocin (MLDS) model and the spontaneous NOD mouse model. The MLDS model of diabetes is characterized by progressive hy...

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Section: Discussionmentioning

confidence: 99%

Nicotine Reduces the Incidence of Type I Diabetes in Mice

Mabley

Pacher

Southan

et al. 2002

J Pharmacol Exp Ther

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“…In addition to its hypoglycemic effect, troglitazone has been shown to possess in vitro anti-inflammatory properties, as shown by the reduction of cytokines such as tumor necrosis factor-␣ and ␥-interferon (61). The latter mechanism could explain why, in the experimental model of the NOD mouse, troglitazone protects animals from diabetes development (62). Also, another compound of the same family of drugs-rosiglitazone-has been shown to possess similar effects in reducing diabetes incidence of autoimmune diabetes (63).…”

Section: Glitazonesmentioning

confidence: 99%

Autoimmune Diabetes Not Requiring Insulin at Diagnosis (Latent Autoimmune Diabetes of the Adult)

2001

Self Cite

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Type 1 diabetes is caused by the immune-mediated destruction of islet insulin-secreting β-cells. This chronic destructive process is associated with both cellular and humoral immune changes in the peripheral blood that can be detected months or even years before the onset of clinical diabetes. Throughout this prediabetic period, metabolic changes, including altered glucose tolerance and reduced insulin secretion, deteriorate at variable rates and eventually result in clinical diabetes. A fraction of individuals with humoral immunological changes have clinical diabetes that initially is not insulin-requiring. The onset of diabetes in these patients is usually in adult life, and because their diabetes is at least initially not insulin-requiring, they appear clinically to be affected by type 2 diabetes. Such patients probably have the same disease process as patients with type 1 diabetes in that they have similar HLA genetic susceptibility as well as autoantibodies to islet antigens, low insulin secretion, and a higher rate of progression to insulin dependency. These patients are defined as being affected by an autoimmune type of diabetes not requiring insulin at diagnosis, which is also named latent autoimmune diabetes of the adult (LADA). Special attention should be paid to diagnose such patients because therapy may influence the speed of progression toward insulin dependency, and in this respect, efforts should be made to protect residual C-peptide secretion. LADA can serve as a model for designing new strategies for prevention of type 1 diabetes but also as a target group for prevention in its own right.

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“…Although the precise mechanism of action of TRO is still not fully understood, the insulin-sensitizing effects of TRO are believed to be mediated through the activation of PPAR␥. This notion is supported by the fact that the binding affinity of TRO analogs to PPAR␥ corresponds to the potency of their anti-diabetic action (Wilson et al, 1996;Beales et al, 1998;Day, 1999;Lebovitz et al, 2002).…”

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confidence: 96%

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Bae

Song²

2003

Mol Pharmacol

125

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The peroxisome proliferator-activated receptor agonist troglitazone (TRO) was used for treatment of non-insulin-dependent diabetes until its removal from the market because of its severe hepatotoxicity. However, the mechanism for its hepatotoxicity is still poorly understood. In this study, we investigated whether TRO caused cell death by altering signaling pathways associated with cell damage and survival in human hepatoma cells. Our data reveal that TRO caused time-and concentrationdependent apoptosis of HepG2 and Chang liver human hepatoma cells, as evidenced by DNA fragmentation and staining with Hoechst 33342. In contrast, 50 or 100 M rosiglitazone, a structural analog of TRO, did not cause apoptosis in these hepatoma cells. TRO activated both c-Jun N-terminal protein kinase (JNK) and p38 kinase about 5-fold between 0.5 and 8 h before they returned to control levels at 16 h in HepG2 cells. In contrast, TRO failed to activate the extracellular signal-regulated kinase. Furthermore, TRO increased the levels of proapoptotic proteins, Bad, Bax, release of cytochrome c, and cleavage of Bid in a time-dependent manner. The antiapoptotic Bcl-2 protein level decreased in hepatoma cells treated with TRO. Pretreatment of hepatoma cells with a selective JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), significantly reduced the rate of TRO-induced cell death, whereas 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), an inhibitor of p38 kinase, had little effect on apoptosis. Pretreatment with SP600125 also prevented JNK activation and c-Jun phosphorylation. In addition, rosiglitazone, which is not as toxic to hepatoma cells as TRO, did not stimulate JNK activity. Transfection of cDNA for the dominant-negative mutant JNK-KR (Lys3 Arg) or SEK1-KR (Lys3 Arg), an immediate upstream kinase of JNK, significantly reduced TRO-induced JNK activation and cell death rate. Furthermore, SP600125 pretreatment effectively prevented the TRO-mediated changes in Bad, Bax, Bid cleavage, and cytochrome c release. These data strongly suggest that hepatotoxic TRO causes apoptosis by activating the JNK-dependent cell death pathway accompanied by increased Bid cleavage and elevation of proapoptotic proteins.

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

Cited by 46 publications

References 18 publications

Nicotine Reduces the Incidence of Type I Diabetes in Mice

Nicotine Reduces the Incidence of Type I Diabetes in Mice

Autoimmune Diabetes Not Requiring Insulin at Diagnosis (Latent Autoimmune Diabetes of the Adult)

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

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