New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control—Review and Perspective on the Impact of Statin Medications on Metabolic Health

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.

LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes

“…Here, we link dysregulated ABCG1 / ABCA1 / MYLIP at mRNA and protein levels to cellular cholesterol accumulation in human monocytes. Taken together with preclinical findings that cellular cholesterol accumulation causes pancreatic β cell dysfunction and insulin resistance ( 1 – 5 , 25 ), our data provide what is to our knowledge the first evidence in humans supporting a role for dysregulated LAAMP and resultant cellular cholesterol accumulation in the pathogenesis of diabetes.…”

Antidiabetic and Antihyperlipidemic Effects of Methanolic Extract of Leaves of Spondias mombin in Streptozotocin-Induced Diabetic Rats

“…HMG-CoA reductase is a rate limiting enzyme that metabolise high cholesterol LDL. However, insulin deficiency caused dyslipidemia due to inhibitory action of insulin on HMG-CoA reductase ( Grice and Elmendorf, 2017 ). Diabetes-induced hyperlipidemia is responsible for excess movement of fat from adipose due to limited usage of glucose.…”

Predictive network modeling in human induced pluripotent stem cells identifies key driver genes for insulin responsiveness

“…These results suggest that the effects on proliferation and differentiation of adipocytes and SKMCs are independent of the disturbance in insulin mediated glucose uptake. In addition, SQLE inhibition exerts a comparable effect on insulin mediated glucose uptake when compared to HMGCR inhibition, which suggests that the underlying mechanisms could be mediated by the deregulation of intracellular or membrane bound cholesterol levels [ 32 , 52 ]. Other proposed mechanisms to affect insulin facilitated glucose uptake include decreased expression levels of SLC2A4 ( GLUT-4 ) and caveolin-1 [ 51 , 53 ], disturbed RHOA and RAB4 signaling lowering GLUT-4 levels in the plasma membrane [ 54 , 55 ], perturbation of the insulin signaling pathway [ 55 , 56 ] and accumulation of free fatty acids [ 49 , 57 ].…”

“…Among the remaining top KDs, HMGCR and FDPS have the highest combined DE proximity and KD dominance scores and both genes participate, together with squalene epoxidase (SQLE)another KD that appears in both AS and ApP networks (S4 Table )-in the cholesterol biosynthesis pathway. Given, i) the high DE proximity and KD dominance scores, ii) the shared metabolic pathway, iii) the widespread use of statins (HMGCR inhibitors) as therapeutic drugs to lower cholesterol levels in patients with high LDL-cholesterol, and iv) the emerging role of HMGCR in energy balance, metabolism and diabetes risk [32][33][34][35], we sought to validate our KDA, both transcriptionally and functionally, focusing on HMGCR, FDPS and SQLE.…”