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 × 1,000 vs. 23.8 ± 6.2, P < 0.01), and this was accompanied by an increase in cell surface LDLR (5.2 ± 3.0 mean fluorescence intensity × 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 significant independent determinants of IDOL expression. IDOL knockdown human monocyte-derived macrophages produced higher concentrations of interleukin 1 beta, interleukin 6, and TNFα than control macrophages upon stimulation with lipopolysaccharide (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.

Effect of type 2 diabetes on A disintegrin and metalloprotease 10.

BACKGROUND: As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), can be influenced by type 2 diabetes. METHODS: A total of 1091 individuals with type 2 diabetes and 358 age-matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX-1 (sLOX-1) released by cleavage of LOX-1 by ADAM were measured by enzyme-linked immunosorbent assay kits (ELISA). RESULTS: Serum ADAM10 was increased in subjects with diabetes compared with control (40.5 ng/mL [22.3-65.7] vs 10.3 ng/mL [7.0-17.9], respectively; P < .01); the highest levels were seen in insulin-treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX-1. Subjects with diabetes had higher serum sLOX-1 than the control (110 pg/mL [89-153] vs 104 pg/mL [85-138], respectively; P < .01), and there was a significant correlation between serum ADAM10 and sLOX-1 (r = 0.26, P < .01). CONCLUSIONS: Serum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker.

Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia.

The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL expression and influence LDLR protein abundance. IDOL expression in monocytes and serum IDOL level was determined in statin-treated familial hypercholesterolemia (FH) patients and compared with control subjects. Serum IDOL level was also evaluated in a group of untreated FH patients before and after the initiation of statin. The mechanism underlying the inhibitory effect of statin on IDOL expression was investigated in vitro. In statin-treated FH patients, serum IDOL level and its expression in monocytes was reduced compared with control (P < 0.05). In contrast, untreated FH patients had higher serum levels of IDOL and proprotein convertase subtilisin/kexintype 9 (PCSK9) than control (P < 0.05), and serum IDOL level decreased after statin therapy (P < 0.05) whereas an increase was observed in PCSK9 level (P < 0.01). In vitro, atorvastatin significantly decreased IDOL abundance in a dose-dependent manner in cultured macrophages and hepatocytes with a concomitant increase in LDLR expression. The transcription of IDOL was restored by adding either an LXR agonist T0901317 or oxysterol 22(R)-hydroxycholesterol, indicating that statin inhibited IDOL expression by reducing LXR activation. The LXR-IDOL-LDLR axis can be modulated by statins in vitro and in vivo. Statins inhibit IDOL expression by reducing LXR activation and upregulate LDLR, and statins exert the opposite effect on IDOL and PCSK9.

Comparison of Serum Ketone Levels and Cardiometabolic Efficacy of Dapagliflozin versus Sitagliptin among Insulin-Treated Chinese Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Insulin-treated patients with long duration of type 2 diabetes mellitus (T2DM) are at increased risk of ketoacidosis related to sodium-glucose co-transporter 2 inhibitor (SGLT2i). The extent of circulating ketone elevation in these patients remains unknown. We conducted this study to compare the serum ketone response between dapagliflozin, an SGLT2i, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, among insulin-treated T2DM patients. METHODS: This was a randomized, open-label, active comparator-controlled study involving 60 insulin-treated T2DM patients. Participants were randomized 1:1 for 24-week of dapagliflozin 10 mg daily or sitagliptin 100 mg daily. Serum ß-hydroxybutyrate (BHB) levels were measured at baseline, 12 and 24 weeks after intervention. Comprehensive cardiometabolic assessments were performed with measurements of high-density lipoprotein cholesterol (HDL-C) cholesterol efflux capacity (CEC), vibration-controlled transient elastography and echocardiography. RESULTS: Among these 60 insulin-treated participants (mean age 58.8 years, diabetes duration 18.2 years, glycosylated hemoglobin 8.87%), as compared with sitagliptin, serum BHB levels increased significantly after 24 weeks of dapagliflozin (P=0.045), with a median of 27% increase from baseline. Change in serum BHB levels correlated significantly with change in free fatty acid levels. Despite similar glucose lowering, dapagliflozin led to significant improvements in body weight (P=0.006), waist circumference (P=0.028), HDL-C (P=0.041), CEC (P=0.045), controlled attenuation parameter (P=0.007), and liver stiffness (P=0.022). Average E/e', an echocardiographic index of left ventricular diastolic dysfunction, was also significantly lower at 24 weeks in participants treated with dapagliflozin (P=0.037). CONCLUSION: Among insulin-treated T2DM patients with long diabetes duration, compared to sitagliptin, dapagliflozin modestly increased ketone levels and was associated with cardiometabolic benefits.