Abstract
Cholesterol 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.
Highlights
Like extreme plunges in plasma membrane cholesterol negatively impacting insulin action, Tsuchiya et al found that cholesterol composition of insulin secretory granule (SG) membrane is crucial for glucose-stimulated insulin secretion (GSIS) and SG formation.[13]
We have found that AMPK stimulation improves glucose transporter type 4 (GLUT4)-mediated glucose transport and ABCA1/ apolipoprotein A1 (ApoA1)-mediated cholesterol efflux from insulin-resistant 3T3-L1 adipocytes via lowering membrane cholesterol levels.[2,29,94]
Research summarized in this review suggests that caloric excess modifies nutrient sensing pathways to favor cellular cholesterol accumulation
Summary
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. 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. Disclosure: Brian A Grice and Jeffrey S Elmendorf have nothing to declare in relation to this article
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