Abstract
Background and Purpose: Patients with type 2 diabetes (T2D) have increased risk of cardiovascular disease (CVD), encompassing myocardial infarction, stroke, and peripheral vascular disease. We hypothesized that those biomarkers indicative of acute ischemic stroke (AIS) seen in large vessel occlusion (LVO) may also be elevated in T2D and further enhanced by stress conditions; therefore, these proteins represent potentially predictive biomarkers for those T2D patients at high risk of AIS. Methods: We performed an exploratory proteomic analysis in control subjects (n = 23) versus those with type 2 diabetes (T2D) (n = 23) who underwent a hyperinsulinemic clamp study to transient severe hypoglycemia [blood glucose <2.0 mmol/L (36 mg/dl)] in a prospective case-control study. We compared these proteins described as diagnostic and prognostic biomarkers for AIS due to LVO: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE1), thrombospondin-1 (THBS1), pro-platelet basic protein (PPBP), and cadherin 1 (CDH1). Results: At baseline (BL), PPBP (p < 0.05), THBS1 (p < 0.05), and CDH1 (p < 0.01) were elevated in T2D; LYVE1 was not different between controls and T2D subjects at BL or at subsequent timepoints. PPBP and THBS1 tended to increase at hypoglycemia in both cohorts, though reached significance only in controls (p < 0.05), returning to BL levels post-hypoglycemia. CDH1 levels were higher in T2D at BL, at hypoglycemia and up to 2-h posthypoglycemia, thereafter reverting to BL levels. Conclusion: Elevated levels of PPBP, THBS1, and CDH1, circulatory proteins suggested as biomarkers of AIS due to LVO, may, in T2D patients, be prognostically indicative of a cohort of T2D patients at increased risk of ischaemic stroke. Prospective studies are needed to determine if this reflects future clinical risk.Clinical trial reg. no: NCT03102801.
Highlights
Patients with type 2 diabetes (T2D) have a well-documented 2-3fold increased risk for cardiovascular disease (CVD), encompassing myocardial infarction, stroke, and peripheral vascular disease (Einarson et al, 2018), with ∼80% of mortality in T2D due to underlying CVD (Morrish et al, 2001)
Elevated levels of pro-platelet basic protein (PPBP), THBS1, and cadherin 1 (CDH1), circulatory proteins suggested as biomarkers of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), may, in T2D patients, be prognostically indicative of a cohort of T2D patients at increased risk of ischaemic stroke
Seven differentially expressed proteins were identified: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE1), thrombospondin-1 (THBS1), pro-platelet basic protein (PPBP), secreted phosphoprotein-2 (SPP2), insulin-like growth factor-2 (IGF2), cadherin 1 (CDH1), and apolipoprotein C 4-2 (APOC4-APOC2), four of which were elevated (LYVE1, THBS1, PPBP, and IGF2) and subsequently validated by Western blot analysis in patients with AIS caused by LVO versus healthy control subjects
Summary
Patients with type 2 diabetes (T2D) have a well-documented 2-3fold increased risk for cardiovascular disease (CVD), encompassing myocardial infarction, stroke, and peripheral vascular disease (Einarson et al, 2018), with ∼80% of mortality in T2D due to underlying CVD (Morrish et al, 2001). Patients with type 2 diabetes (T2D) have increased risk of cardiovascular disease (CVD), encompassing myocardial infarction, stroke, and peripheral vascular disease. We hypothesized that those biomarkers indicative of acute ischemic stroke (AIS) seen in large vessel occlusion (LVO) may be elevated in T2D and further enhanced by stress conditions; these proteins represent potentially predictive biomarkers for those T2D patients at high risk of AIS
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