Nateglinide prevents fatty liver through up-regulation of lipid oxidation pathway in Goto-Kakizaki rats on a high-fat diet

Mine, Tomoyuki; Miura, Kyoko; Kajioka, Toshifumi; Kitahara, Yoshiro

doi:10.1016/j.metabol.2007.08.017

Cited by 7 publications

(9 citation statements)

References 31 publications

(31 reference statements)

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“…Excessive dietary fat intake is also involved in the occurrence of non-alcoholic fatty liver disease [38,39]. Surprisingly liver size and weights of rapamycin-treated mice Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging epidemics of non-alcoholic fatty liver disease and hepatic steatosis are serious consequences of obesity [37]. Excessive dietary fat intake is also involved in the occurrence of non-alcoholic fatty liver disease [38,39]. Surprisingly liver size and weights of rapamycin-treated mice were lower than those of control mice, despite the significant increase in food intake by rapamycin-treated mice.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Long‐term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High‐Fat Diet‐fed KK/HlJ Mice

Chang

Chiu

et al. 2009

Basic Clin Pharma Tox

106

116

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Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients. In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance.The mammalian target of the rapamycin (mTOR) signalling pathway performs an important function in the regulation of cell growth, proliferation and nutrient signals [1,2]. Recent studies have demonstrated that mTOR is involved in specific pathological responses including obesity, diabetes, and cancer [2,3]. Consistent with the development of these diseases, the activation of the mTOR pathway is evident in insulin-resistant obese rats maintained on a high-fat diet [4].Rapamycin (also known as sirolimus), an anti-fungal macrolide, is a uniquely specific mTOR kinase inhibitor [5]. Rapamycin blocks mTOR Complex1 (mTORC1) function by forming a gain-of-function inhibitory complex with the immunophilin FK506 binding protein 1A (FKBP12) that inhibits progression through involvement in the G1 phase of the cell cycle [6]. Subsequently, rapamycin was shown to have potent immunosuppressive and antiproliferative effects [7]. As an immunosuppressant drug, it is used to prevent organ rejection following kidney, liver, and heart transplants [8,9]. In addition, because of its antiproliferative effects, rapamycin and its analogues have been shown to be effective and novel anticancer agents [10,11]. Moreover, rapamycin has recently been used to coat cardiac stents, preventing stenosis [12,13].However, despite evidence suggesting a role by mTOR in regulating metabolic syndromes [14,15], the extent of its role has not been fully explored. In this study, we aimed to clarify how rapamycin administration inhibition of the mTOR pathway affects the relationship between metabolic syndrome and diabetes. We planned to achieve this by examining the effect of ra...

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“…Excessive dietary fat intake is also involved in the occurrence of non-alcoholic fatty liver disease [38,39]. Surprisingly liver size and weights of rapamycin-treated mice Fig.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long‐term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High‐Fat Diet‐fed KK/HlJ Mice

Chang

Chiu

et al. 2009

Basic Clin Pharma Tox

106

116

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“…Nateglinide was effective in attenuating experimental hepatic steatosis [Mine et al 2008]. There was upregulation of hepatic PPAR-a and adiponectin receptor R2 mRNA expression [Mine et al 2008].…”

Section: Combination Of Metformin With Rosiglitazonementioning

confidence: 99%

Review: Treatment options for nonalcoholic fatty liver disease

Chitturi

2008

Therap Adv Gastroenterol

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Nonalcoholic fatty liver disease comprises a range of disorders from steatosis and steatohepatitis through to cirrhosis. Nonalcoholic steatohepatitis can progress to cirrhosis and liver-related death. Therefore, managing this common disorder is becoming an important public health issue. Lifestyle measures are commonly suggested but robust data are lacking. Trials with antioxidants (vitamin E, betaine) as well as cytoprotectants (ursodeoxycholic acid) have been disappointing. While data for insulin sensitizers such as metformin are less conclusive, thiazolidinediones appear promising. However, not all patients respond to thiazolidinediones. Moreover, issues related to weight gain, cardiovascular risk need to be addressed. The use of endocannabinoid antagonists and insulin secretagogues are novel strategies to combat this disorder.

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“…Nateglinide is a short-acting insulin secretagogue with a rapid effect, which restores early-phase insulin secretion in patients with type 2 diabetes by rapidly binding to SUR1 [26][27][28][29][30] and thus suppresses postprandial hyperglycemia. It has been unclear whether or not GLP-1 is involved in these effects of nateglinide.…”

Section: )mentioning

confidence: 99%

Nateglinide Stimulates Glucagon-Like Peptide-1 Release by Human Intestinal L Cells via a KATP Channel-Independent Mechanism

Kitahara

Miura

Yasuda

et al. 2011

Biological & Pharmaceutical Bulletin

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The incretin effect is markedly reduced in patients with type 2 diabetes, mainly due to defective glucagon-like peptide-1 (GLP-1) secretion from the intestinal L cells in response to stimulation by various nutrients. 1,2) This leads to impairment of early-phase insulin secretion after food intake and consequently results in postprandial hyperglycemia and hyperlipidemia. [3][4][5][6] GLP-1 is an incretin hormone that is released by intestinal L cells following their stimulation by nutrients, 7,8) and it promotes glucose-stimulated insulin secretion by pancreatic bcells. GLP-1 has also been reported to have various other beneficial effects, such as promoting b-cell proliferation, 9) suppressing glucagon release, 10) suppressing food intake, 11,12) slowing gastric emptying, 13,14) and cardiovascular protection.15) Therefore, restoration of GLP-1 secretion by intestinal L cells could be an important new therapeutic option for the management of metabolic syndrome. Although the exact mechanism of GLP-1 secretion by intestinal L cells remains to be elucidated, the sulfonylurea receptor 1 (SUR1)/K ATP channel, 16,17) Na ϩ /glucose co-transporter 1 (SGLT1), 18) glucose transporter 2 (GLUT2), 19) sweet taste receptor, 20)TGR5 21) and G-protein coupled receptors (GPRs) [22][23][24][25] have all been reported to be involved in this process. In the present study, we investigated the effect of nateglinide on GLP-1 secretion by human intestinal L cells.Nateglinide is a short-acting insulin secretagogue with a rapid effect, which restores early-phase insulin secretion in patients with type 2 diabetes by rapidly binding to SUR1 [26][27][28][29][30] and thus suppresses postprandial hyperglycemia. It has been unclear whether or not GLP-1 is involved in these effects of nateglinide. Recently, Duffy et al. reported that nateglinide increases the plasma GLP-1 level by inhibiting dipeptidyl peptidase IV (DPP IV), 31) but the influence of nateglinide on GLP-1 secretion is still unknown. Therefore, we investigated the effect of nateglinide on GLP-1 secretion in vivo by monitoring GLP-1 levels in the portal venous blood after oral administration of nateglinide to normal Wistar rats. We also conducted an in vitro study to assess the direct effect of nateglinide on GLP-1 secretion by human intestinal L cells (NCI-H716). MATERIALS AND METHODSAnimals Male Goto-Kakizaki (GK) rats and male Wistar rats (6 weeks old) were purchased from Japan SLC Inc. (Hamamatsu, Japan). The animals were housed in individual polycarbonate cages with woodchip bedding, and were provided with food and water ad libitum. The animal room was maintained on a 12-h light/dark cycle (7 a.m.-7 p.m.: dark; 7 p.m.-7 a.m.: light), with a temperature range of 22Ϯ1°C and a relative humidity of 55Ϯ5%, throughout the experimental period. These animal experiments were performed in accordance with the Guiding Principles for the care and use of laboratory animals approved by the Japanese Pharmacological Society. In addition, this study was approved by the Animal Care and Use Committ...

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Nateglinide prevents fatty liver through up-regulation of lipid oxidation pathway in Goto-Kakizaki rats on a high-fat diet

Cited by 7 publications

References 31 publications

Long‐term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High‐Fat Diet‐fed KK/HlJ Mice

Long‐term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High‐Fat Diet‐fed KK/HlJ Mice

Review: Treatment options for nonalcoholic fatty liver disease

Nateglinide Stimulates Glucagon-Like Peptide-1 Release by Human Intestinal L Cells via a KATP Channel-Independent Mechanism

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