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Review Diabetes New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control— Review and Perspective on the Impact of Statin Medications on Metabolic Health Brian A Grice 1 and Jeffrey S Elmendorf 2 1. Department of Cellular and Integrative Physiology and Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, US; 2. Department of Cellular and Integrative Physiology, Department of Biochemistry and Molecular Biology, and Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, US C holesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic health. Keywords Cholesterol, dyslipidemia, glucose, insulin resistance, statins, type 2 diabetes Disclosure: Brian A Grice and Jeffrey S Elmendorf have nothing to declare in relation to this article. Acknowledgments: Medical writing support was provided by Ray Ashton, Touch Medical Media and funded by Kowa Pharmaceuticals America, Inc. The authors were supported in part by National Institutes of Health Grants HL117620 (to JSE), DK097512 (to JSE.), and GM077229 and DK064466 predoctoral support (to BAG), and an American Diabetes Association and Amaranth Diabetes Foundation Grant 7-14-BS-053 (to JSE). Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: June 27, 2017 Accepted: September 18, 2017 Citation: US Endocrinology, 2017;13(2):63–8 Corresponding Author: Jeffrey S Elmendorf, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Van Nuys Medical Science Building, Rm. 307, Indianapolis, IN 46202, US. E: Support: The publication of this article was supported by Kowa Pharmaceuticals America who was given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion. TOU CH MED ICA L MEDIA In a series of recent studies, insulin-stimulated glucose disposal in animal models and human subjects was found to be inversely related to plasma membrane cholesterol content. Aberrantly increased plasma membrane cholesterol is seen uniformly in insulin-resistant mice, rats, swine, and humans, and normalization restores insulin responsivity. 1–4 Mechanistic studies in clonal cells, as well as in fat and skeletal muscle tissue demonstrate that excess plasma membrane cholesterol reduces cortical filamentous actin (F-actin), which is essential for glucose transporter type 4 (GLUT4) regulation by insulin. In addition to this negative consequence of excess plasma membrane cholesterol on insulin action, Llanos et al. found the ryanodine receptor calcium signals, which are important for GLUT4 regulation, are negatively affected by increased skeletal muscle membrane cholesterol. 4 Interestingly, exercise known to ward off diabetes development has recently been shown to prevent plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in mice fed a western-style high-fat diet. 5 While F-actin and calcium signaling defects that manifest in cholesterol-laden plasma membrane seem to represent critical determinates of impaired GLUT4 regulation and glucose transport, the precise mechanisms of cellular cholesterol accumulation and insulin resistance remain elusive. In fact, Parpal et al. demonstrated that progressive cholesterol depletion of 3T3-L1 adipocytes with beta- cyclodextrin gradually destroyed plasma membrane caveolae structures and concomitantly diminished insulin-stimulated glucose transport, in effect making cells insulin-resistant. 6 The importance of this in metabolic health is that upsurges or plunges in plasma membrane cholesterol both 63