Abstract
IntroductionNeuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection.MethodsA case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9).ResultsBaseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia.ConclusionHypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear.Clinical Trial Registration https://clinicaltrials.gov, identifier NCT03102801.
Highlights
Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2)
Nine type 2 diabetes (T2D) subjects were treated with ACE inhibitor (ACEi) therapy
Baseline levels of Soluble isoforms of NRP1 (sNRP1) did not differ between T2D and controls (2298 ± 385 vs 2279 ± 488 Relative Fluorescent Units (RFUs), T2D vs control, p=ns); normalization of glucose in T2D did not alter sNRP1 (2298.1 ± 80.3 vs 2279.1 ± 101.6 RFU of NRP1, T2D vs control, p=ns) (Figure 2A), and levels were unchanged in response to insulin induced normalization of glycemia (Figure 2A) and hypoglycaemia (Figure 2B)
Summary
Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection. Neuropilin-1 (NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with ACE2 [1]. NRP-1 serves as a receptor for a number of isoforms of vascular endothelial growth factor (VEGF). Soluble isoforms of NRP1 (sNRP1) exist without transmembrane or cytoplasmic domains and function as natural ligand sequesters, inhibiting the interaction of VEGF-A or other growth factors with their specific receptors and with membrane-bound NRP1 [3]. NRP1 interacts with the RAS, a risk factor for COVID-19 disease [5], contributing to protection from angiotensin II-induced hypertension [6]
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