title: Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction.
abstract: 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.
authors.affiliation: a Division of Endocrinology and Metabolism ; Department of Internal Medicine ; Yonsei University College of Medicine ; Seoul , Korea.|b Institute of Endocrine Research; Yonsei University College of Medicine ; Seoul , Korea.|c Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: d Department of Clinical Nursing Science ; Yonsei University College of Nursing ; Seoul , Korea.|e Nursing Policy and Research Institute; Biobehavioral Research Center; Yonsei University ; Seoul , Korea.
authors.forename: Jae Yeo
authors.initials: JY
authors.lastname: Park
authors.affiliation: c Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine ; Seoul , Korea.|f Department of Pharmacology ; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Obin
authors.initials: O
authors.lastname: Kwon
authors.affiliation: a Division of Endocrinology and Metabolism ; Department of Internal Medicine ; Yonsei University College of Medicine ; Seoul , Korea.|b Institute of Endocrine Research; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Eun Yeong
authors.initials: EY
authors.lastname: Choe
authors.affiliation: c Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine ; Seoul , Korea.|f Department of Pharmacology ; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: g Department of Medicine ; Samsung Medical Center; Sungkyunkwan University School of Medicine ; Seoul , Korea.
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.affiliation: g Department of Medicine ; Samsung Medical Center; Sungkyunkwan University School of Medicine ; Seoul , Korea.|h Samsung Advanced Institute for Health Sciences and Technology; Sungkyunkwan University School of Medicine ; Seoul , Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: i Department of Nuclear Medicine ; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Mijin
authors.initials: M
authors.lastname: Yun
authors.affiliation: a Division of Endocrinology and Metabolism ; Department of Internal Medicine ; Yonsei University College of Medicine ; Seoul , Korea.|b Institute of Endocrine Research; Yonsei University College of Medicine ; Seoul , Korea.|c Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Cha
authors.affiliation: j Division of Endocrinology , Diabetes, and Metabolism ; Department of Medicine ; Beth Israel Deaconess Medical Center and Harvard Medical School ; Boston , MA USA.
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.affiliation: d Department of Clinical Nursing Science ; Yonsei University College of Nursing ; Seoul , Korea.|e Nursing Policy and Research Institute; Biobehavioral Research Center; Yonsei University ; Seoul , Korea.
authors.forename: Hyangkyu
authors.initials: H
authors.lastname: Lee
authors.affiliation: a Division of Endocrinology and Metabolism ; Department of Internal Medicine ; Yonsei University College of Medicine ; Seoul , Korea.|b Institute of Endocrine Research; Yonsei University College of Medicine ; Seoul , Korea.|c Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Kang
keywords: HMG-CoA reductase inhibitor; autophagy; diabetes; gluconeogenesis; statin