Pluronic L81 ameliorates diabetic symptoms in db/db mice through transcriptional regulation of microsomal triglyceride transfer protein

Au, Wo‐Shing; Lu, Liwei; Tam, S; Ko, Otis King Hung; Chow, Billy K. C.; He, Ming; Ng, Stephanie; Yeung, Chung-Man; Liu, Ching-Chiu; Kung, Hsiang-Fu; Lin, Marie C.

doi:10.3748/wjg.15.2987

Cited by 5 publications

(3 citation statements)

References 33 publications

(45 reference statements)

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“…However, this remains to be determined and warrants further investigation, although MTP inhibition in lean mice reveals unaltered lipid and glucose homeostasis. 41 In conclusion, we report that inhibition of the critical step of VLDL and chylomicron synthesis with a small molecule inhibitor of MTP significantly improves insulin sensitivity. In addition to improvements in serum lipid profiles, MTP inhibition produced beneficial effects on other metabolic risk factors, such as oxidative stress and obesity.…”

Section: Discussionmentioning

confidence: 66%

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Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats

Dhote¹,

Joharapurkar²,

Kshirsagar³

et al. 2011

Clin Exp Pharma Physio

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1. Insulin-resistant states are commonly associated with a significantly higher risk of atherosclerosis. Insulin resistance has also been correlated with enhanced very low-density lipoprotein (VLDL) production, which is exacerbated by increased intestinal lipid synthesis and insulin-stimulated de novo lipogenesis. Microsomal triglyceride transfer protein (MTP) catalyses the critical step in the synthesis and secretion of VLDL and chylomicrons. The purpose of the present study was to test the hypothesis that chronic inhibition of MTP with a small molecule inhibitor would improve insulin sensitivity and reduce atherogenic risk in a genetic model of diabetic dyslipidaemia. 2. The in vivo activity of BMS-201038, a potent inhibitor of MTP, was evaluated in a model of hypertriglyceridemia induced by Triton WR1339 and corn oil in Zucker fatty rats. Triglyceride secretion rate was significantly reduced by a single dose of BMS-201038 by 35% at 0.3 mg/kg and 47% at 1 mg/kg, respectively. 3. Another group of Zucker fatty rats was dosed orally with BMS-201038 (0.3 and 1 mg/kg) for 14 days. Serum levels of triglycerides were reduced by 71% and 87%, non-esterified free fatty acids were reduced by 33% and 40%, and low-density lipoproteins by 26% and 29%, by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. These serum lipid changes were accompanied by significant improvements in glucose tolerance and insulin sensitivity. In addition, lipid peroxidation in liver was reduced by 59% and 61%, and superoxide dismutase activity was increased by 11% and 45% by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. Similar beneficial changes were found in aorta as well. 4. The present study provides evidence that inhibition of MTP with a small molecule inhibitor significantly improves dyslipidaemia associated with insulin resistance and reduces the atherosclerotic risk.

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Section: Discussionmentioning

confidence: 66%

“…Therefore, it is appealing to speculate that the chronic modulation of appetite and fat metabolism produced by MTP inhibition here will improve insulin sensitivity. However, this remains to be determined and warrants further investigation, although MTP inhibition in lean mice reveals unaltered lipid and glucose homeostasis 41 …”

Section: Discussionmentioning

confidence: 99%

Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats

Dhote¹,

Joharapurkar²,

Kshirsagar³

et al. 2011

Clin Exp Pharma Physio

View full text Add to dashboard Cite

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“…Total ketone bodies (KB) and cholesterol concentrations were significantly increased in the SA 15% group. Plasma ALT values were not different between groups, although AST concentrations were slightly increased in the SA 15% , it was still in the normal range [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Six weeks' sebacic acid supplementation improves fasting plasma glucose, HbA1c and glucose tolerance in db/db mice

Membrez

Chou

Raymond

et al. 2010

Diabetes Obesity Metabolism

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Aim: To investigate the impact of chronic ingestion of sebacic acid (SA), a 10-carbon medium-chain dicarboxylic acid, on glycaemic control in a mouse model of type 2 diabetes (T2D).Methods: Three groups of 15 db/db mice were fed for 6 weeks either a chow diet (Ctrl) or a chow diet supplemented with 1.5 or 15% (SA1.5% and SA15%, respectively) energy from SA. Fasting glycaemia was measured once a week and HbA1c before and after supplementation. An oral glucose tolerance test (OGTT) was performed at the end of the supplementation. Gene expression was determined by transcriptomic analysis on the liver of the Ctrl and SA15% groups.Results: After 42 days of supplementation, fasting glycaemia and HbA1c were ∼70 and 25% lower in the SA15% group compared with the other groups showing a beneficial effect of SA on hyperglycaemia. During OGTT, plasma glucose area under the curve was reduced after SA15% compared with the other groups. This effect was associated with a tendency for an improved insulin response. In the liver, Pck1 and FBP mRNA were statistically decreased in the SA15% compared with Ctrl suggesting a reduced hepatic glucose output induced by SA.Conclusion: Dietary supplementation of SA largely improves glycaemic control in a mouse model of T2D. This beneficial effect may be due to (i) an improved glucose-induced insulin secretion and (ii) a reduced hepatic glucose output.

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New Insights Into How the Intestine Can Regulate Lipid Homeostasis and Impact Vascular Disease: Frontiers for New Pharmaceutical Therapies to Lower Cardiovascular Disease Risk

Warnakula

Hsieh

Adeli

et al. 2011

Canadian Journal of Cardiology

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Pluronic L81 ameliorates diabetic symptoms in db/db mice through transcriptional regulation of microsomal triglyceride transfer protein

Cited by 5 publications

References 33 publications

Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats

Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats

Six weeks' sebacic acid supplementation improves fasting plasma glucose, HbA1c and glucose tolerance in db/db mice

New Insights Into How the Intestine Can Regulate Lipid Homeostasis and Impact Vascular Disease: Frontiers for New Pharmaceutical Therapies to Lower Cardiovascular Disease Risk

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