Abstract
Peripheral diabetic neuropathy (DPN) is a complication observed in up to half of all patients with type 2 diabetes. DPN has also been shown to be associated with obesity. High-fat diet (HFD) affects glucose metabolism, and the impaired glucose tolerance can lead to type 2 diabetes. There is evidence to suggest a role of adenosine 2A receptors (A2ARs) and semaphorin 3A (Sema3a) signaling in DPN. The link between the expression of Sema3a and A2AR in DPN was hypothesized, but the underlying mechanisms remain poorly understood. In this study, we investigated the regulation of Sema3a by A2AR in the spinal cord and the functional implications thereof in DPN. We examined the expression of A2ARs and Sema3a, as well as Neuropilin 1 and Plexin A, the coreceptors of Sema3a, in the dorsal horn of the lumbar spinal cord of an animal model with HFD-induced diabetes. Our results demonstrate that HFD dysregulates the A2AR-mediated Sema3a expression, with functional implications for the type 2 diabetes-induced peripheral neuropathy. These observations could stimulate clinical studies to improve our understanding on the subject.
Highlights
Peripheral diabetic neuropathy (DPN) is a common diabetes complication that affects approximately 50% of type 2 diabetes patients and brings an enormous strain on both patients and society [1]
We looked at the role of A2A receptor stimulation and semaphorin 3A (Sema3a) levels in the spinal cord in peripheral neuropathy using an animal model with high-fat diet (HFD)-induced diabetes
Based on the results presented here, it is reasonable to assume that exposure to HFD can cause adenosine 2A receptors (A2ARs)-regulated decrease in the spinal cord’s Sema3a expression
Summary
Peripheral diabetic neuropathy (DPN) is a common diabetes complication that affects approximately 50% of type 2 diabetes patients and brings an enormous strain on both patients and society [1]. While research showed that hyperglycemia plays a key role in DPN by causing systemic and neuronal oxidative stress [2,3,4], clinical trials have shown that obese patients may show symptoms of peripheral neuropathy even if they have normal blood sugar level [5,6,7]. Studies in animal models of obesity have reported peripheral neuropathy in obese animals [8, 9]. HFD may cause large myelinated nerve and small sensory nerve fiber damage, leading to peripheral neuropathy [8, 9, 11]. The study of HFDfed C57BL/6 mice showed deficits in motor and sensory nerve conduction velocity (NCV), thermal hyperalgesia, and reduced mean dendrite length [11]
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