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Uric acid in the balance — neuropathy

Neil Baker OBE
Welcome to another Diabetes Digest commentary on a recent paper, as well as several short abstracts of other papers that you may find interesting or useful to your clinical or research practice.

The paper I have chosen to focus upon is from a group in Quanzhou, China, led by Zhuang et al. This group looked at Serum uric acid (SUA) levels in relation to diabetic peripheral neuropathy (DPN). As we all know, the aetiological jigsaw puzzle for peripheral neuropathy pathogenesis is incomplete, with many factors identified and accepted. One of these, although having limited recent data, is the effect of hyperuricaemia and DPN. This study by Zhang et al hypothesised that perhaps low serum uric acid may also play a similar role. The rationale for this hypothesis was that a high SUA may cause vascular smooth muscle cells migration and inhibit endothelial cell release of nitric oxide; whereby resulting in vascular dysfunction and irreversible damage and thus tissue ischaemia and impaired peripheral nerve function. 

Therefore, due to the important antioxidant effect of SUA, maintaining a too-low SUA level over the long-term may conversely expose people with diabetes to increased oxidative stress and, thus, nerve pathologies. This was a prospective observational study that enrolled 525 type 2 diabetes mellitus (T2DM) subjects without hyperuricemia, into those with symptomatic neuropathy (SDPN; n=150), asymptomatic neuropathy (ASDPN; n=125) and no neuropathy (NDPN; n=250). 

Exclusion criteria were extensive, including <20 or >75 years old, hyperuricemia, gout, medication influencing SUA, malnutrition, severe liver or kidney damage, acute infection, alcohol abuse, non-diabetic neuropathies, etc. Neuropathy was determined by deficits in 10 g monofilament, vibration, temperature pain sensations and neurogenic symptoms. Additionally, bilateral motor and sensory nerve conduction studies were performed at the median nerve, ulnar nerve, tibial nerve and common peroneal nerves. Retinol examinations included retinal photographs, optical coherence tomography and fluorescein angiography.

Venous blood samples were obtained for SUA, fasting plasma glucose, HbA1c, creatinine, lipids, liver and renal function, and these were recorded.

There were no significant differences between the groups for: age, sex ratio, BMI, blood pressure, blood lipids, liver and kidney function, vitamin B12 and PLT. The incidence of diabetic retinopathy was found to be higher in those with diabetes with symptomatic neuropathy.

In all three groups, SUA was less than 420 (313.7±73.1) umol/L. It was more reduced in ASDPN compared with NDPN (P< 0.001) but even further decreased in SDPN group (P<0.001). Nerve conduction in SDPN showed the greatest impairment. In a multivariate model controlling for other covariables and after adjustment, the low SUA was independently associated with diabetic neuropathy (odds ratio 0.985 [0.981 ~ 0.988], P<0.001). Similarly, low SUA level was positively correlated with the mean of values in all nerve conduction parameters: Motor and sensory action potentials and conduction velocities (r=0.470, P<0.001; r = 0.396, P<0.001, respectively). The SUA level was shown to distinguish between patients with and without diabetic neuropathy. 

The study has shown that low SUA appears to have detrimental adverse effects on nerve function and may equally contribute to the pathogenesis of DP regarding uric acid and nerve damage. It appears it is a balance — not too high and not too low.

REFERENCES:

Zhuang Y, Huang H, Hu X et al (2022) Serum uric acid and diabetic peripheral neuropathy: a double-edged sword. Acta Neurol Belg doi: 10.1007/s13760-022-01978-1. [Online ahead of print]

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