The possible correlation between serum GRB2 levels and carotid atherosclerosis in patients with type 2 diabetes mellitus

Abstract

Background and purposeGrowth factor receptor-bound protein 2(GRB2), a bridging protein. An animal study showed that downregulation of GRB2 inhibited the activation of PI3K/AKT/NF-kB pathway which improved lipid accumulation and inflammatory infiltration in rats with atherosclerosis (AS), resulting in an anti-AS effect. This was the first study to investigate blood GRB2 levels in type 2 diabetes mellitus(T2DM) patients with carotid atherosclerosis (CAS), exploring its relationship with various metabolic indicators, and further, examining whether GRB2 has an AS effect in patients with T2DM.MethodsA total of 203 participants were recruited in the study, including 69 T2DM patients without CAS (T2DM group), 67 T2DM patients with CAS (CAS group), and 67 in the age-sex-matched healthy subjects (Control group). Serum GRB2 levels were measured using enzyme-linked immunosorbent assay (ELISA) in 203 subjects who had received carotid ultrasonography. In addition, cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), glycosylated hemoglobin (HBA1c), fasting insulin (FINS), hypersensitive C-reactive protein (Hs-CRP), and Interleukin 6 (IL-6) were also tested. The correlation between serum GRB2 levels and other indexes was analyzed. Finally, we analyzed the risk factors affecting carotid intima-media thickness (CIMT) in T2DM patients.ResultsSerum GRB2 levels were increased in the T2DM group than in the control group, and further elevated in the CAS group (median 3.05 vs 4.40 vs 7.09 ng/ml, P<0.001). Spearman correlation analysis showed that GRB2 concentrations were negatively correlated with HDL-C, and positively associated with duration of diabetes, waist-to-hip ratio (WHR), TC, HBA1c, FPG, FINS, homeostasis model assessment-insulin resistance index (HOMA-IR), Hs-CRP, IL-6 and CIMT (P<0.01). Furthermore, serum GRB2 levels (P<0.001) remained independently related to CIMT after adjusting for the age, sex, duration of diabetes, and Body Mass Index (BMI) variables. Stepwise multiple linear regression analysis showed that IL-6, HDL-C, HBA1c, and CIMT are independent correlation factors of serum GRB2 (P<0.01). Univariate logistic regression suggested that disease duration, WHR, systolic blood pressure (SBP), TG, HDL-C, HBA1c, FPG, HOMA-IR, IL-6, Hs-CRP, and GRB2 independently associated with T2DM is combined with CAS(P<0.05). And multivariate logistic regression analysis showed that duration of diabetes, IL-6, and serum GRB2 levels were independent risk factors for T2DM combined with CAS (P<0.05), and serum GRB2 levels were a highly sensitive indicator of early AS (OR=1.405, 95% CI: 1.192-1.658 P<0.001). Moreover, the ROC curve AUC area of serum GRB2 expression levels was 0.80 (95%CI: 0.7291-0.8613, P < 0.001), with a sensitivity of 83.58% and specificity of 70.59%. The risk of CAS was substantially higher in patients with T2DM whose serum GRB2 concentration was >4.59 ng/ml.ConclusionsSerum GRB2 concentrations were significantly increased in T2DM combined with CAS, and serum GRB2 levels were linearly correlated with CIMT, suggesting that GRB2 may be involved in the occurrence and development of T2DM with CAS, which can be used as a predictor of whether T2DM is combined with CAS.

Phytochemicals from Piper betle (L.) as Putative Modulators of a Novel Network-Derived Drug Target for Coronary Artery Disease: An In Silico Study

“…Proctor et al (2007) demonstrated the necessity of GRB2 for atherosclerotic lesion formation through oxidized LDL uptake by macrophages in a mice model [31]. Similarly, Dong et al (2022) found increased serum GRB2 concentrations in individuals with both T2DM and carotid atherosclerosis (CAS) [32]. Also, they observed a linear correlation between the serum GRB2 level and carotid intima-media thickness, indicating the potential involvement of GRB2 in the development of T2DM with CAS [32].…”

“…Similarly, Dong et al (2022) found increased serum GRB2 concentrations in individuals with both T2DM and carotid atherosclerosis (CAS) [32]. Also, they observed a linear correlation between the serum GRB2 level and carotid intima-media thickness, indicating the potential involvement of GRB2 in the development of T2DM with CAS [32]. Additionally, Wang et al (2021) established the link between cardiorenal syndrome type 3 (CRS-3) and elevated IL-6/GRB2, which plays an important role in cardiac dysfunction by suppressing the Akt/mTOR signaling pathway and inducing impairment in cardiomyocyte mitochondrial bioenergetics [33].…”

“…From the downloaded GRB2 (PDB ID: 1GRI) protein, two distinct structures (1: dimeric (Chain A and B) and 2: monomeric (Chain B)) were constructed for further analysis. Both the structures (dimeric and monomeric) were prepared, and the missing residues (28)(29)(30)(31)(32)(33), hydrogen atoms, and side chains were added using the Protein Preparation Wizard of Maestro (Schrödinger Release 2018-2, Schrödinger, LLC, New York, NY, USA, 2018). The PROPKA tool (Schrödinger Release 2018-2, Schrödinger, LLC, New York, NY, USA, 2018), as implemented in Maestro, was employed to generate an accurate ionization state under pH 7.4 conditions, and finally, the prepared structures were energy-minimized using the OPLS_2005 force field.…”

Meta-analysis of risk factors for carotid plaque formation in type 2 diabetes mellitus

“…Foreign language retrieval was conducted in Pubmed using Diabetes/T2DM, Extremities,Lower Extremities and RiskFactors as search terms.With the subject words "Type 2 diabetes mellitus, carotid plaque formation AND risk factors" as the main search terms, the combination of subject words AND free words was adopted, and finally "(type 2 diabetes ORT2DM) AND (related factors OR risk factors ISSN 2618-1584 Vol. 5…”

“…The 32 literatures included were case-control studies, published between 2003 and 2023, with a total of 5710 cases in the case group and 5405 cases in the control group. (Table 1) Dong Xia [5] 2021 Hebei Case control 105 50 (6) 7 2…”