BACKGROUND: Type 2 diabetes (T2DM) is a metabolic disease that arises from insulin resistance and facilitates progression to cardiovascular consequences including myocardial infarction, coronary artery disease, and stroke. A contributor to the cardiovascular complications seen in T2DM is endothelial dysfunction. From a molecular standpoint, studies have shown that the pathophysiology of T2DM involves an altered metabolic milieu and increased oxidative stress, which both arise from insulin resistance, and lead to endothelial dysfunction. There is still much to discover on the pathways that are altered in this disease.
Proteomics is a rapidly improving technique that can elucidate the differences in serum biomarkers, and their relationship to vascular endothelial health to further understand the pathophysiology of T2DM.
OBJECTIVE: To evaluate the proteomic background and the implicated pathways in T2DM, and to understand how these biomarkers are associated with endothelial cell phenotype and systemic vascular function.
METHODS: Age and sex similar individuals with T2DM and control individuals without T2DM between the ages of 30 and 80 were enrolled in this study. Blood was obtained for blood glucose and insulin levels and two proteomics panels assessing 192 serum biomarkers. Baseline vascular measures were obtained including blood pressure, heart rate, and flow-mediated dilation. Endothelial cells collected from participants were stimulated with insulin ex vivo and stained with phosphorylated endothelial nitric oxide synthase (p-eNOS) to measure changes in the insulin-mediated eNOS pathway. Associations between biomarker levels and insulin-stimulated p-eNOS levels were evaluated.
RESULTS: The present study includes 69 subjects including 37 subjects with T2DM (age 57±8 years, 41% female) and 32 control subjects (age 53±9 years, 38% female). Measures of vascular health showed evidence of impairment in patients with T2DM including higher pulse pressure (56±12 mmHg versus 48±11 mmHg, p=0.02) and lower flow-mediated dilation (6.04±3.41% versus 9.1±4.4%, p=0.01).
The proteomic panels revealed 24 serum biomarkers that were significantly upregulated and 2 that were significantly downregulated (adjusted p<0.05) in patients with T2DM compared to nondiabetic controls. These biomarkers are mainly involved in metabolism, vascular and fluid homeostasis, immune response, and apoptosis.
Endothelial cell phenotype was abnormal in patients with T2DM compared to controls: mean fold change in insulin-stimulated p-eNOS was 0.34±0.07 for nondiabetic controls and -0.14±0.03 (p=0.01) for patients with T2DM.
Renin and Adrenomedullin were significantly associated with lower insulin stimulated p-eNOS activation (r=-0.38, r=-0.27, and p=0.004, p=0.049 respectively). Whereas Chymotrypsin C (r=0.37, p=0.006), Paraoxonase 3 (r=0.35, p=0.009), Lipoprotein Lipase (r=0.34, p=0.01), and Superoxide Dismutase 2 (r=0.31, p=0.02) were significantly associated with higher insulin stimulated p-eNOS activation.
CONCLUSIONS: We found associations between serum biomarker levels and insulin-stimulated p-eNOS levels which showed that there is a relationship between altered biomarkers and endothelial cell phenotype.
Patients with T2DM had worse vascular endothelial health as shown by measures of endothelial dysfunction and arterial stiffness. Endothelial cell insulin resistance was present in patients with T2DM. In the same group, serum biomarkers showed elevated adiposity, inflammation and oxidative stress, and upregulation of the renin-angiotensin-aldosterone system.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48343 |
| Date | 05 March 2024 |
| Creators | Minetti, Erika Teresa |
| Contributors | Hamburg, Naomi, Han, Jingyan |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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