Symmetric dimethylarginine (SDMA) serum levels in rheumatoid arthritis: correlations with insulin resistance and disease activity scores

Abstract

Vascular abnormalities predisposing to atherosclerosis are present in patients with rheumatoid arthritis (RA) and associate with excess cardiovascular risk. Symmetric dimethylarginine (SDMA), an endogenous inhibitor of nitric oxide (NO) synthase activity, has been recognised as novel risk factor for endothelial dysfunction and cardiovascular disease. We aimed to compare SDMA levels in RA patients and controls and to investigate whether they are influenced by demographic, inflammatory or metabolic factors. Serum SDMA levels were measured in 197 RA individuals [median age: 67 years (quartiles: 59-3), 153 (78 %) females] and 82 controls [median age: 44 years [quartiles: 33-55, 50 (61 %) females]. Routine biochemistry tests, lipid profile, glycemic profile [glucose, insulin, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI)], as well as inflammatory markers were measured in all patients. Paired analysis was employed for the comparison of SDMA in two groups and multivariable regression models were performed to identify predictors of SDMA in the RA cohort. SDMA was significantly lower in RA than control patients in both unpaired and paired analyses (P < 0.001 and P = 0.005, respectively), with the magnitude of the difference being similar in both models. QUICKI (P = 0.005) and disease activity score-28 (P = 0.007) were positively related to SDMA in the RA cohort, whilst a negative correlation with renal function (eGFR) was detected (P = 0.005). The molecular explanation of lower serum SDMA is unclear, but the established relationships with indices of disease activity and insulin resistance, may underline the pathogenetic role of the L-arginine/NO pathway dysregulation in the development of atherosclerosis in RA. The biological and clinical importance of SDMA in RA remains to be evaluated in clinical and experimental studies.

Symmetric Dimethylarginine in Cats with Hypertrophic Cardiomyopathy and Diabetes Mellitus

“…One study found SDMA to be a reliable marker of GFR in children with type 1 DM, whereas another study found lower serum SDMA concentrations in people with poorly controlled type 2 DM than in healthy controls. In accordance with the latter study, it has been shown that humans with evidence of insulin resistance have lower serum SDMA concentrations . Possible mechanisms include increased cellular uptake or enhanced elimination in response to hyperfiltration .…”

“…In accordance with the latter study, it has been shown that humans with evidence of insulin resistance have lower serum SDMA concentrations. 13,33 Possible mechanisms include increased cellular uptake or enhanced elimination in response to hyperfiltration. 33 Additionally, it has been suggested that hepatic metabolism of SDMA could be upregulated in patients with insulin resistance.…”

“…The cause has not been determined with certainty, but the effect may be endothelial dysfunction of which SDMA is believed to be a mediator . The vascular endothelium releases vasoactive substances such as nitric oxide (NO) which help maintain vascular integrity and regulate its homeostasis . Nitric oxide influences vascular tone, blood pressure, and regional blood flow while also having anti‐inflammatory, antithrombotic, and antiatherosclerotic effects .…”

“…6 The vascular endothelium releases vasoactive substances such as nitric oxide (NO) which help maintain vascular integrity and regulate its homeostasis. 12,13 Nitric oxide influences vascular tone, blood pressure, and regional blood flow while also having anti-inflammatory, antithrombotic, and antiatherosclerotic effects. 6 SDMA is believed to decrease NO synthesis by competing with its substrate, arginine, for cellular uptake.…”

Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation

“…The inverse correlation between SDMA and microvascular function demonstrated in our study may look at first glance fundamentally counterintuitive. However, SDMA levels are lower in RA subjects compared to controls [ 16 ] similarly to what occurs in diabetes mellitus and insulin-resistant patients [ 35 , 36 ]. It appears that common mechanisms affecting intracellular migration of endogenous dimethylarginines in RA and insulin resistance are associated with atherosclerosis in both conditions [ 1 ].…”