Table 2.

Impact of Statins on Liver and Beta-Cell Function

Mechanism	Description
Liver
Activation of SREBPs	Statins inhibit HMG-CoA reductase, leading to the activation of sterol regulatory element-binding proteins (SREBPs). Activated SREBPs can induce fatty liver, obesity, ectopic lipid accumulation, and insulin resistance.
Decreased Coenzyme Q10, Heme, and Isoprenoids	Statins reduce the production of coenzyme Q10, heme, and isoprenoid intermediates (FPP, GGPP), affecting small G protein function involved in cellular processes like cytoskeletal remodeling and secretory granule transport in beta cells.
Acetyl-CoA and FFA Receptors	Increased intracellular acetyl-CoA levels from HMGCR inhibition can produce acetate, activating FFA2 and FFA3 receptors on beta cells, reducing cAMP and insulin secretion.
ER Stress and Calcium Homeostasis	Cholesterol accumulation in the endoplasmic reticulum (ER) depletes calcium stores necessary for insulin release, induces ER stress, and activates the PERK-eIF2α pathway, leading to beta-cell injury and reduced insulin production.
Beta Cells
LDL Uptake	LDLR-mediated LDL uptake into beta cells interferes with glucose-stimulated insulin secretion, potentially inhibiting insulin secretion through various pathways such as small G proteins, Ca2+ signaling, cell viability, and SNARE proteins.
Beta-Cell Dysfunction	Beta-cell-specific ablation of GGPP synthase and deletion of HMGCR lead to reduced beta-cell mass, insulin secretion, and glucose intolerance. Statins also inhibit mTOR signaling and small G protein genes, impairing beta-cell function.
Cholesterol Accumulation in Beta Cells	Overexpression of SREBP-2 in beta cells causes cholesterol accumulation, impairing insulin secretion. Excess cholesterol in beta cells disrupts granule trafficking, membrane protein distribution, and insulin granule exocytosis.
Trans-Golgi Network and Granule Trafficking	Cholesterol plays a key role in the trans-Golgi network for granule biogenesis and trafficking. Excess cholesterol disrupts granule formation and trafficking, impairing insulin release.
Lipid Rafts and SNARE Proteins	Cholesterol depletion in lipid rafts affects the spatial organization of SNARE proteins and channel proteins, impairing insulin granule exocytosis. Elevated cholesterol also reduces the density of voltage-gated Ca2+ channels.
Beta-Cell Apoptosis	Cholesterol accumulation in the plasma membrane induces beta-cell apoptosis, further impairing insulin secretion and contributing to diabetes development