From cholesterol to glucose: uncovering how statins induce β-cell dysfunction to promote type 2 diabetes

Abstract

Statins are the most commonly used cholesterol-lowering medications, with proven efficacy in reducing cardiovascular disease in humans; however, statins are associated with a higher risk of new-onset type 2 diabetes (T2D). Mechanisms contributing to statin-induced diabetes are not well understood and may include effects on body composition, tissue insulin sensitivity, and/or pancreatic β-cell function. Given the essential role of the β-cell in maintaining normoglycemia, this review focuses on how statins may lead to the demise of the β-cell. We revisit what is known about the impact of statins on inhibition of the mevalonate pathway, including blockade of the synthesis of cholesterol and non-cholesterol products. We discuss aberrant expression of key β-cell genes and proteins, as well as dysregulation of β-cell components that facilitate normal insulin secretion, e.g., mitochondria and calcium channels. Importantly, we highlight areas that are understudied, including how statins alter cholesterol transport and metabolism in the β-cell, and the role of sex/gender in statin-induced β-cell dysfunction. As the number of statin users increases, there is an urgent need to address these gaps in our knowledge in order to shed light on strategies that limit statin-induced T2D.

Keywords: cholesterol; diabetes; islets; mevalonate; statins.

Figure 1:

Simplified schematic of the mevalonate pathway. This multistep pathway leads to downstream products in cholesterol- and non-cholesterol synthesis pathways. Besides cholesterol itself, other products include CoQ10, dolichols, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are required for many cellular functions and in post-translational modifications of signaling proteins. Statins inhibit the rate limiting enzyme of the mevalonate pathway, HMG-CoA reductase, which limits generation of downstream products in both cholesterol- and non-cholesterol synthesis pathways.

Figure 2:

Potential downstream effects of mevalonate pathway inhibition by statins in the β-cell. Statins disrupt the pathway and lead to decreases in cholesterol and isoprenoid (FPP and GGPP) production. (A) Decreases in cholesterol alter plasma membrane composition, which can interfere with lipid rafts and affect Ca²⁺ channel function and insulin granule exocytosis. (B) Reductions in protein prenylation can alter protein interactions and signaling, and directly or indirectly alter expression of many genes. (C) Reductions in CoQ10 can lead to accumulation of ROS, decreased ATP production and mitochondrial dysfunction. (D) Reduced dolichol generation can limit N-glycosylation events, thus altering post-transcriptional modifications of proteins. These changes can all lead to dysfunctional insulin secretion from β-cells.

Figure 3:

Potential routes for cholesterol transport and metabolism in the β-cell. Low-density lipoprotein (LDL) particles undergo receptor-mediated endocytosis primarily by the LDL receptor. After dissociation from receptor proteins in the early endosome, and endosome-lysosome fusion, lysosomal digestion of LDL yields free cholesterol. Cholesterol can be transported from late endosomes by Stard3 to the mitochondria, or by NPC intracellular cholesterol transporter 1 (NPC1) to the endoplasmic reticulum (ER). The ER is also capable of de novo cholesterol synthesis via the mevalonate pathway. Cholesterol in the ER can be converted to cholesteryl esters (CE) by acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) for storage in lipid droplets. It may also be metabolized by CYP46A1 to generate 24S-hydroxycholesterol. Transport of sterols from the ER to other organelles can also be facilitated by oxysterol-binding proteins (OSBP)/OSBP-related proteins (OSP) or Stard1. Stard1 is localized to the mitochondria-associated ER membrane (MAM), as well as the outer mitochondrial membrane where it transports cholesterol to the inner mitochondrial membrane. Mitochondrial cholesterol can be metabolized by CYP27A1 to generate 27-hydroxycholesterol. Both 24S-hydroxycholesterol and 27-hydroxycholesterol are potent ligands of liver X receptors (LXR), which activate transcription of genes that regulate cholesterol homeostasis, including the transporters ABCA1 and ABCG1. Oxysterols can also be effluxed out of the cell. Other sterol transfer proteins, like Stard4 and Stard5, may also transport cholesterol to various organelles; however, little is known about their potential role in the β-cell.