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

Mita, Tomoya; Watada, Hirotaka; Nakayama, Shiho; Abe, Michiko; Ogihara, Takeshi; Shimizu, Tomoaki; Uchino, Hiroshi; Hirose, Takahisa; Kawamori, Ryuzo

doi:10.1507/endocrj.k06-198

Cited by 42 publications

(28 citation statements)

References 36 publications

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“…However, the effect of statins on insulin secretion has been controversial. [43][44][45] A previous study shows that pravastatin does not affect insulin secretion in a pancreatic b-cell line, 45 which is consistent with our result. In contrast, atorvastatin and simvastatin are reported to inhibit glucose-dependent insulin secretion by blocking calcium signaling in b-cells, 43,45 which differs from our result with atorvastatin.…”

Section: Discussionsupporting

confidence: 92%

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

et al. 2015

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(2015) Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction, Autophagy, 11:11, 2089-2101, DOI: 10.1080/15548627.2015 Keywords: autophagy, diabetes, gluconeogenesis, HMG-CoA reductase inhibitor, statin Abbreviations: ACTB, actin beta; AKT1, v-akt murine thymoma viral oncogene homolog 1; ATG7, autophagy-related 7; Baf A1, bafilomycin A 1 ; BECN1, Beclin 1 autophagy related; CQ, chloroquine; FOXO1, forkhead box O1; G6PC, glucose-6-phosphatase catalytic subunit; GCK, glucokinase (hexokinase 4); GFP, green fluorescent protein; HMGCR/HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA reductase; MAP1LC3A/LC3A, microtubule-associated protein 1 light chain 3 alpha; MTOR, mechanistic target of rapamycin (serine/threonine kinase); O-GluNAc, O-linked b-N-acetyl glucosamine; PCK1, phosphoenolpyruvate carboxykinase 1 (soluble); PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PKLR, pyruvate kinase liver and RBC; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; RFP, red fluorescent protein; RPS6KB1, ribosomal protein S6 kinase; 70kDa, polypeptide 1; shRNA, short hairpin RNA; T2DM, type 2 diabetes mellitus; XBP1, X-box binding protein 1.Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.

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Section: Discussionsupporting

confidence: 92%

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

et al. 2015

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“…4 Pravastatin (PRA), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin), also prevents new onset of DM 5 and improves glucose tolerance in patients. [6][7][8] We and others have shown that PRA upregulates adiponectin messenger RNA expression in adipose tissue 8 and in cultured adipocytes, 9 and prevents the development of DM in animal models. [9][10][11] Clinical studies have also shown that PRA treatment increases plasma adiponectin in patients with hypercholesterolemia and is associated with improved glucose metabolism.…”

Section: Introductionmentioning

confidence: 96%

“…12,13 However, the effect of the combined therapy on glucose intolerance, which often coexists with other risks and worsens prognosis by increasing cardiovascular oxidative stress, remains to be investigated. 5,6,7,, an essential cofactor for endothelial nitric oxide synthetase (eNOS), tends to be oxidized to 7,8-dihydrobiopterin (BH2) in DM. 14 Decreased BH4 limits eNOS dimerization, resulting in decreased nitric oxide (NO) synthesis and increased superoxide production, so-called eNOS uncoupling, and is a major mechanism of endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model

et al. 2009

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Hypertension and dyslipidemia frequently coexist in patients with progressive insulin resistance and thus constitute metabolic syndrome. We sought to determine the merits of combining an angiotensin II receptor blocker and a 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor in treating this pathological condition. Five-week-old Otsuka Long-Evans Tokushima Fatty rats, a model of metabolic syndrome, were untreated or treated with olmesartan 3 mg kg À1 per day, pravastatin 30 mg kg À1 per day or their combination for 25 weeks. Long-Evans Tokushima Otsuka rats served as normal controls. The antihypertensive effect of olmesartan and the lipid-lowering properties of pravastatin were both augmented by the combination. The oral glucose tolerance test revealed that only the combined treatment significantly reduced the area under the time-glucose curve, which was accompanied by augmented adiponectin messenger RNA expression in epididymal adipose tissue. Although the total cardiac endothelial nitric oxide synthetase (eNOS) content did not significantly differ among the groups, the combined treatment significantly increased the content of dihydrofolate reductase, a key eNOS coupler. Dihydroethidium staining of the aorta showed that the combination most significantly attenuated superoxide production. Moreover, Azan-Mallory staining revealed that the combination most significantly limited the perivascular fibrosis and wall thickening of intramyocardial coronary arteries. In conclusion, the combination of olmesartan and pravastatin augmented adiponectin expression in white adipose tissue and improved glucose tolerance in a rat model of metabolic syndrome, which was associated with more significant ameliorations of cardiovascular redox state and remodeling than those by treatments with either agent alone.

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“…Rather, atorvastatin has been reported to worsen glycemic control in a few case reports and some clinical trials in Japan. In recent studies that compared pravastatin with atorvastatin directly, the former acted favorably on glycemic control among diabetic 6,7) and non-diabetic patients 8) . These results indicate that the beneficial effect of pravastatin on glucose metabolism is unique among the currently used statins.…”

Section: Introductionmentioning

confidence: 99%

Pravastatin Potentiates Increases in Serum Adiponectin Concentration in Dyslipidemic Patients Receiving Thiazolidinedione: the DOLPHIN Study

Nezu

Tsunoda

Yoshimura

et al. 2010

JAT

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Aim: A reduced risk of type 2 diabetes has been reported following treatment with pravastatin. Adiponectin is an adipocyte-derived protein that has an antidiabetic property. The objective of this study was to evaluate the effect of pravastatin on serum adiponectin concentration and other influencing factors. Methods: This study was a multicenter observational study: Dyslipidemia Open-labeled observational study by Lipid-lowering therapy with Pravastatin of the effect on High-molecular weight adiponectin in Nippon Yokohama (DOLPHIN). The protocol was registered in the UMIN Clinical Trial Registry as UMIN000000791. All patients received pravastatin 10 mg/day for 6 months and the change in concentration of total and high molecular weight adiponectin was assessed before and after follow-up. The difference in the change in total adiponectin concentration by patient characteristics was analyzed by an unpaired t-test. Influences of continuous variable factors on the change in total adiponectin concentration were estimated by simple linear regression analyses. Finally, in order to estimate the influences of factors that potentially affect the change in total adiponectin concentration induced by pravastatin, multiple linear regression analysis was conducted. Results: After 6 months, total adiponectin concentration was increased significantly by 23.2% from 11.7 6.4 to 13.7 8.6 g/mL (p 0.002). The use of thiazolidinedione as a concomitant medication was the only significant influencing factor ( 0.580, p 0.001). Conclusion: Pravastatin increased the serum adiponectin concentration in Japanese dyslipidemic patients without previous coronary artery disease. Interestingly, this effect was seen synergistically in combination with thiazolidinedione.

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

Cited by 42 publications

References 36 publications

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model

Pravastatin Potentiates Increases in Serum Adiponectin Concentration in Dyslipidemic Patients Receiving Thiazolidinedione: the DOLPHIN Study

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