Troglitazone (CS-045) normalizes hypertriglyceridemia and restores the altered patterns of glucose-stimulated insulin secretion in dyslipidemic rats

Chicco, Adriana; Basabe, J. C.; Karabatas, Liliana; Ferraris, Norma; Fortino, Alejandra; Lombardo, Yolanda B.

doi:10.1053/meta.2000.9506

Cited by 24 publications

(20 citation statements)

References 18 publications

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“…This is consistent with our observation that treatment with rosiglitazone resulted in a non-significant reduction in fasting plasma TG levels in the fructose-fed hamster, an animal model of mild hypertriglyceridemia associated with VLDL oversecretion. A marked reduction of plasma TG levels after treatment with thiazolidinediones has been more consistently shown in various mouse and rat models of insulin resistance and type 2 diabetes, animal models that display a much more pronounced fasting hypertriglyceridemia than the one usually found in insulin-resistant humans (23,34,35) and in our hamster model. In the present study, the reduction of VLDL secretion in the fructose-fed hamster accounted for the reduction of plasma TG levels associated with rosiglitazone treatment, since VLDL-TG clearance was not different with rosiglitazone treatment.…”

Section: Discussionmentioning

confidence: 52%

“…Reduction of TG secretion with thiazolidinedione treatment has also been found in sucrose-fed and obese Zucker rats by other investigators (22,23). Nevertheless, most published studies in rats or mice did not show an inhibitory effect of thiazolidinediones on VLDL secretion, thereby concluding that the lowering of plasma TG resulted in total or in part from increased VLDL clearance (22,24,25).…”

Section: Discussionmentioning

confidence: 80%

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Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Carpentier¹,

Taghibiglou²,

Leung³

et al. 2002

Journal of Biological Chemistry

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To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulinmediated suppression of the glucose production rate and to a ϳ2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001). Rosiglitazone ameliorated the defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine phosphatase 1B levels were increased with fructose feeding and were markedly reduced by rosiglitazone. Rosiglitazone treatment led to a ϳ50% reduction of VLDL secretion rates (p < 0.05) in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR (fructose-fed ؉ rosiglitazone-treated) versus F (fructose-fed ؉ placebo-treated) hamsters, although there was a trend toward a lower clearance with rosiglitazone. Enhanced stability of nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was evident, and rosiglitazone treatment resulted in a significant reduction in apoB stability. The increase in intracellular mass of microsomal triglyceride transfer protein seen with fructose feeding was reduced by treatment with rosiglitazone. In conclusion, improvement of hepatic insulin signaling with rosiglitazone, a peroxisome proliferator-activated receptor ␥ agonist, is associated with reduced hepatic VLDL assembly and secretion due to reduced intracellular apoB stability.The typical dyslipidemia of insulin-resistant states and Type 2 diabetes consists of hypertriglyceridemia due to VLDL 1 overproduction, low high density lipoprotein cholesterol, and small dense low density lipoprotein particles (1). Elevated plasma free fatty acid (FFA) flux from peripheral and intra-abdominal adipose tissue depots due to resistance to the insulin antilipolytic and esterification effect in adipose tissue is felt to play an important role in driving VLDL assembly and secretion in insulin resistant states (2-4). Nevertheless, previous studies in humans suggest that insulin also has an important direct effect on the liver in controlling VLDL secretion (5-7).Rat and mouse models of insulin resistance and type 2 diabetes have provided important insights into the molecular mechanisms of insulin resistance. These animal models may not, however, be ideal for the study of human lipoprotein disorders because, unlike humans, their livers secrete both apoB48 and apoB100-containing VLDL, and they do not necessarily develop VLDL oversecretion as the basis for their hypertriglyceridemia (8, 9). Unlike livers from rat or mouse, the liver of the golden Syrian hamster secretes only apoB100-containing VLDL, and its lipoprotein metabolism more closely resembles that of humans (10). We have shown that insulin resistance in the fru...

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 80%

Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Carpentier¹,

Taghibiglou²,

Leung³

et al. 2002

Journal of Biological Chemistry

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“…However, our WT and Munc18c Ϫ/ϩ mice fed the HF diet had insulin contents similar to those of the ND-fed mice. Alternatively, consumption of the HF diet may have induced loss of first-phase insulin secretion, as has been previously described (51). Further experiments will be required to establish the role of Munc18c protein in biphasic insulin secretion.…”

Section: Discussionmentioning

confidence: 84%

Munc18c Heterozygous Knockout Mice Display Increased Susceptibility for Severe Glucose Intolerance

Spurlin

Pessin

et al. 2005

Diabetes

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The disruption of Munc18c binding to syntaxin 4 impairs insulin-stimulated GLUT4 vesicle translocation in 3T3L1 adipocytes. To investigate the physiological function and requirement for Munc18c in the regulation of GLUT4 translocation and glucose homeostasis in vivo, we used homologous recombination to generate Munc18c-knockout (KO) mice. Homozygotic disruption of the Munc18c gene resulted in early embryonic lethality, whereas heterozygous KO mice (Munc18c ؊/؉ ) had normal viability. Munc18c ؊/؉ mice displayed significantly decreased insulin sensitivity in an insulin tolerance test and a >50% reduction in skeletal muscle insulinstimulated GLUT4 translocation when compared with wild-type (WT) mice. Furthermore, glucose-stimulated insulin secretion was significantly reduced in islets isolated from Munc18c ؊/؉ mice compared with those from WT mice. Despite the defects in insulin action and secretion, Munc18c ؊/؉ mice demonstrated the ability to clear glucose to the same level as WT mice in a glucose tolerance test when fed a normal diet. However, after consuming a high-fat diet for only 5 weeks, the Munc18c ؊/؉ mice manifested severely impaired glucose tolerance compared with high-fat؊fed WT mice. Taken together, these data suggest that the reduction of Munc18c protein in the Munc18c ؊/؉ mice results in impaired insulin sensitivity with a latent increased susceptibility for developing severe glucose intolerance in response to environmental perturbations such as intake of a high-calorie diet rich in fat and carbohydrate. Diabetes 54:638 -647, 2005 G lucose homeostasis is maintained by a series of regulated vesicle exocytosis events in several cell types and tissues. Vesicle exocytosis entails the pairing of a vesicle-associated membrane protein (VAMP) v-SNARE (soluble N-ethylmaleimide sensitive factor attachment protein [SNAP] receptor) with a binary cognate receptor complex at the target membrane composed of SNAP-25/23 and syntaxin proteins (t-SNAREs) to form the SNARE core complex. Multiple isoforms of each SNARE protein have been identified and it is hypothesized that by specific pairing and compartmentalization of these proteins, specificity of vesicle targeting can be achieved (rev. in 1,2). On the basis of these studies, investigators from diabetes-related fields have discovered that SNARE protein core complexes are also responsible for regulating the secretion of insulin from islet ␤-cells in response to increased blood glucose (3-6), as well as facilitating the downstream action of insulin on peripheral glucose disposal via the translocation to and integration of intracellular glucose transporter (GLUT4) vesicles into the cell surface membranes of adipocytes and skeletal muscle (rev. in 7-9).Concurrent with the discovery of SNARE proteins has come evidence from yeast genetics suggesting that other proteins also participate in exocytosis and play a role in the regulation of the SNARE complex; this has led to the discovery of the Sec1 secretory proteins. Yeast Sec1 interacts directly with the t-SNARE syntaxin,...

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“…This model, studied carefully by Lombardo's group over 20 years, similar to genetic models, evokes glucose intolerance associated with hyperinsulinemia, increased plasma nonesterified fatty acid (NEFA) and hypertriglyceridemia and mild obesity through the high-fructose content of the diet [29]. A three-step metabolic syndrome has been recognized depending on the time of administration of the sucrose-rich diet:…”

Section: Rat Model Evoked By 63% Sucrose-rich Diet Time Dependencementioning

confidence: 99%

Antagonism between Type 1 and Type 2 diabetes in unsaturated fatty acid biosynthesis

Brenner

2006

Future Lipidology

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Type 1 diabetes mellitus, which is characterized by a series of carbohydrate and lipid metabolism alterations due to the absence of insulin, differs in many aspects from Type 2 diabetes mellitus, in which, although insulinemia is normal or increased, insulin is ineffective, provoking what is termed insulin resistance. One of the differences observed regards the biosynthesis of unsaturated fatty acids, which play a variety of roles in human health. Type 1 diabetes depresses the biosynthesis of all unsaturated acids of the n-9, -6 and -3 series by depressing the mRNAs and activities of stearoyl-CoA desaturase-1 and Δ6 and Δ5 desaturases. Insulin indirectly promotes mRNA transcription of the desaturases through sterol response element-binding protein-1c expression and activation, a process in which liver X receptors are also involved. Desaturases are also modulated by nuclear receptors, peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors, which are activated by unsaturated fatty acids. By contrast, Type 2 diabetes mellitus, investigated using a rat sucrose-rich diet model and a spontaneous genetic rat model, evokes an increase in hepatic desaturase mRNA transcription. This effect is found together with increased triglyceridemia, nonesterified fatty acids and insulinemia, however, insulin enhancement is not the cause of the desaturase increase. Troglitazone, a thiazolidinedione agonist of PPARγ1, depresses the mRNA of hepatic desaturases, apparently by an indirect depression of hepatic PPARα evoked by a decrease of the free fatty acid flux to the liver. Therefore, both types of diabetes mellitus evoke antagonistic effects on the biosynthesis of unsaturated fatty acids by the modification of enzymes actively modulated by the interaction of a complex system of mechanisms in which insulin, nuclear receptors and transcription factors are involved.

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Troglitazone (CS-045) normalizes hypertriglyceridemia and restores the altered patterns of glucose-stimulated insulin secretion in dyslipidemic rats

Cited by 24 publications

References 18 publications

Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Munc18c Heterozygous Knockout Mice Display Increased Susceptibility for Severe Glucose Intolerance

Antagonism between Type 1 and Type 2 diabetes in unsaturated fatty acid biosynthesis

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