Effects of Atorvastatin on Glucose Metabolism and Insulin Resistance in KK/Ay Mice

Suzuki, Michitaka; Kakuta, Hirotoshi; Takahashi, Akimitsu; Shimano, Hitoshi; Tada-Iida, Kaoruko; Yokoo, Tomotaka; Kihara, Rumi; Yamada, Nobuhiro

doi:10.5551/jat.12.77

Cited by 42 publications

(29 citation statements)

References 36 publications

(30 reference statements)

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“…Accordingly, we hypothesized that statins may improve the outcome of diabetic PAD by reducing p53 accumulation through activation of the Akt/MDM2 degradation pathway in diabetes. In addition, considering recent reports demonstrating that statins improve insulin resistance (IR) [14][15][16] , we observed the concomitant effect of ATR on IR in the present study.…”

Section: Introductionsupporting

confidence: 62%

Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53

Morimoto

Bando

Shigeta

et al. 2011

JAT

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Aim: Diabetic peripheral artery disease (PAD) is prone to be aggressive and recent reports have demonstrated that p53 accumulation may be responsible for impaired wound healing in diabetes. Statins has been demonstrated to facilitate p53 degradation by activating its specific ubiquitin ligase, MDM2. The aim of this study was to determine whether atorvastatin (ATR) improves the outcome of diabetic PAD through MDM2-mediated reduction of p53. Methods: Male KK/Ay mice (9 weeks old) were treated with ATR (2 mg/kg/day p.o.) or vehicle for 2 weeks and subjected to ischemic hindlimb operation to generate a diabetic PAD model. Incidences of amputation and changes of p53/MDM2 signaling in each ischemic limb were assessed 2 weeks after the operation (at 13 weeks of age). Effects of ATR on the insulin resistance of age-matched (13-weekold) and unoperated KK/Ay mice were assessed by the glucose tolerance test, circulating adiponectin concentration, and changes in insulin signaling (IRS-1/Akt phosphorylation). Results: In intact KK/Ay, ATR treatment mitigated insulin resistance without affecting cholesterol levels. All diabetic PAD models exhibited autoamputation (100%); however, ATR treatment partially restored the limb loss (41.7%). The p53 expression level in the ischemic limb of ATR-treated KK/Ay was significantly decreased and MDM2 phosphorylation level was markedly increased in tandem with the activation of Akt. Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt/MDM2 pathway, which was restored by ATR. Conclusions: ATR was found to restore ischemic limb loss in diabetes by augmenting p53 degradation through direct activation of the Akt/MDM2 pathway in skeletal muscle.

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Section: Introductionsupporting

confidence: 62%

Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53

Morimoto

Bando

Shigeta

et al. 2011

JAT

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“…While pravastatin prevented the deterioration of glucose tolerance in OLETF rats, a recent study reported that atorvastatin impaired glucose tolerance in NSY mice [33]. On the other hand, there have been several data disputing these results [34,35]. Regarding the present study, we performed OGTT in 7 subjects just before the administration of statins.…”

Section: Discussionmentioning

confidence: 99%

Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

et al. 2007

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Abstract. While a large numbers of clinical trials using various kinds of statins has been reported, a possible preventive effect on new onset of type 2 diabetes mellitus was shown only by the subanalysis of The West of Scotland Coronary Prevention Study (WOSCOPS) using pravastatin. The aim of this study was to investigate whether pravastatin has a preferable effect on glucose tolerance among statins. An open-label prospective cross-over trial was performed to compare the effect of pravastatin (10 mg/day) or atorvastatin (10 mg/day) in Japanese early-state type 2 diabetes mellitus with hypercholesterolemia. The analyzed study subjects were treated with pravastatin (10 mg/day, n = 12) or atorvastatin (10 mg/day, n = 12) for 12 weeks. After a 4-week-washout period, the drugs were switched and treatment was continued for another 12 weeks. Oral glucose tolerance test (OGTT) was performed to evaluate several parameters including the appropriateness of beta cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter and sensitivity) at the end of each therapy. HbA 1c and 2 h-glucose levels during OGTT in the pravastatin treatment were significantly lower than atorvastatin treatment. Disposition index after pravastatin treatment was significantly higher than after atorvastatin treatment. In conclusion, our study suggests that pravastatin has a favorable effect on pancreatic beta cell function compared with atorvastatin.

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“…In a study by Satoh et al (36), glucose tolerance following an oral challenge and glucose-induced insulin secretion in adult Wistar rats was enhanced by statin treatment in excess of 6 wk. Similarly, Suzuki et al (41) used an oral 30 mg/kg dose of AT for 4 wk in KK/Ay mice, an animal model of obesity-associated type 2 diabetes with insulin resistance. After administation of a GTT, plasma glucose levels were significantly lower at 30, 60, and 120 min in the AT-treated animals.…”

Section: Discussionmentioning

confidence: 99%

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

Marchand

Arany

Hill

2010

American Journal of Physiology-Endocrinology and Metabolism

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Marchand KC, Arany EJ, Hill DJ. Effects of atorvastatin on the regeneration of pancreatic ␤-cells after streptozotocin treatment in the neonatal rodent. Am J Physiol Endocrinol Metab 299: E92-E100, 2010. First published April 13, 2010; doi:10.1152/ajpendo.00132.2010.-To investigate the role of statins in ␤-cell regeneration a model of streptozotocin (STZ)-induced ␤-cell injury was used in the neonatal rat. We hypothesized that ␤-cell growth and regeneration would increase following treatment with atorvastatin and that this would be associated with intraislet vasculogenesis. Pregnant Wistar rats were gavaged with 20 or 40 mg/kg atorvastatin for 21 days commencing on gestation day 15. Atorvastatin was detected in the circulation of the offspring. On postnatal day 4, the pups were given either a control or STZ (70 mg/kg ip) injection. ␤-Cell mass had partially recovered by postnatal day 44 following STZ treatment, and atorvastatin (20 mg/ kg) significantly increased ␤-cell mass in both STZ-treated and control animals. An increase in the numbers of small islets at postnatal day 44 was seen in STZ-treated animals following atorvastatin, suggestive of neogenesis, and glucose tolerance was improved. Treatment with atorvastatin caused an increase in the numbers of intraislet endothelial cells at postnatal day 14 and the percentage of endothelial cells undergoing DNA synthesis, suggesting that angiogenesis had preceded the increase in ␤-cell mass. The results indicate that functional ␤-cell mass was expanded with atorvastatin in both control and STZ-treated neonatal rats and suggests a novel effect of a statin in promoting islet plasticity.

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Effects of Atorvastatin on Glucose Metabolism and Insulin Resistance in KK/Ay Mice

Cited by 42 publications

References 36 publications

Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53

Atorvastatin Prevents Ischemic Limb Loss in Type 2 Diabetes: Role of p53

Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

Effects of atorvastatin on the regeneration of pancreatic β-cells after streptozotocin treatment in the neonatal rodent

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