Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome

Abstract

Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20–250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8–30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance.

Exenatide prevents statin-related LDL receptor increase and improves insulin secretion in pancreatic beta cells (1.1E7) in a protein kinase A-dependent manner

“…Increased LDL cholesterol uptake, which is responsible for lipid lowering effects, takes place predominantly in the liver (Hafner et al, 2011). However, increased cholesterol uptake was also observed in other organs and tissues (Sarsenbayeva et al, 2021). In this scenario, it was connected with abnormal organ function, leading to insulin resistance.…”

Statins and risk of type 2 diabetes: mechanism and clinical implications

“…Our metabolomics study showed that genetic inhibition of HMG-CoA reductase was negatively correlated with sphingomyelins and phosphatidylcholines, which increase insulin resistance (15). Sarsenbayeva et al (84) investigated the association of genetic or pharmacological HMG-CoA reductase inhibition in adipose tissue and concluded that high concentrations of simvastatin decreased adipocyte glucose uptake. They also found a positive association of HMGCR with the insulin signalling pathway, suggesting that reduced activity of HMGCR may contribute to insulin resistance.…”

“…Sarsenbayeva et al. ( 84 ) investigated the association of genetic or pharmacological HMG-CoA reductase inhibition in adipose tissue and concluded that high concentrations of simvastatin decreased adipocyte glucose uptake. They also found a positive association of HMGCR with the insulin signalling pathway, suggesting that reduced activity of HMGCR may contribute to insulin resistance.…”

Autophagy: A Silent Protagonist in Kidney Transplantation

“…118 In the presence of macrophages, glucocorticoids may exert profibrotic effects and adipose tissue fibrosis. 119 It is possible to speculate that autophagy may be involved in this process because autophagy receptors regulate the macrophage functions. 120 Conversely, autophagy inhibition may prevent glucocorticoid-induced obesity.…”