Effect of type 2 diabetes on the inducible degrader of LDL receptor

The inducible degrader of LDL receptor (IDOL) acts as a post-transcriptional degrader of the LDL receptor (LDLR). IDOL is functionally active in the liver and in peripheral tissues. We have evaluated IDOL expression in circulating monocytes in subjects with and without type 2 diabetes and determined whether changes in IDOL expression could affect macrophage function like cytokine production in vitro. One hundred forty individuals with type 2 diabetes and 110 healthy control subjects were recruited. Cellular expression of IDOL and LDLR in peripheral blood CD14+ monocytes was measured by flow cytometry. The expression of intracellular IDOL was lower in individuals with diabetes than control (21.3 +/- 4.6 mean fluorescence intensity x 1,000 vs. 23.8 +/- 6.2, P < 0.01), and this was accompanied by an in-crease in cell surface LDLR (5.2 +/- 3.0 mean fluores-cence intensity x 1,000 vs. 4.3 +/- 1.5, P < 0.01), LDL binding, and intracellular lipid (P < 0.01). IDOL expression correlated with HbA1c (r = -0.38, P < 0.01) and serum fibroblast growth factor-21 (FGF21) (r = -0.34, P < 0.01). Multivariable regression analysis, including age, sex, BMI, smoking, HbA1c, and log(FGF21), showed that HbA1c and FGF21 were sig-nificant independent determinants of IDOL expres-sion. IDOL knockdown human monocyte-derived macrophages produced higher concentrations of interleukin 1 beta, interleukin 6, and TNF alpha than control macrophages upon stimulation with lipo-polysaccharide (all P < 0.01). In conclusion, the expression of IDOL in CD14+ monocytes was decreased in type 2 diabetes and was associated with glycemia and serum FGF21 concentration.

Automated summary

IDOL acts as a post-transcriptional degrader of the LDL receptor. In individuals with type 2 diabetes, the expression of IDOL is decreased and associated with glycemia and serum FGF21 concentration. Downregulation of IDOL may affect cytokine production in monocyte-derived macrophages.