TSH Combined with TSHR Aggravates Diabetic Peripheral Neuropathy by Promoting Oxidative Stress and Apoptosis in Schwann Cells

Abstract

Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid-stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA-induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA-induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN.

Tauroursodeoxycholic acid protects Schwann cells from high glucose–induced cytotoxicity by targeting NLRP3 to regulate cell migration and pyroptosis

“…DPN is a highly prevalent complication of T2DM and severely affects the quality of patients. 3,4,7,8 Recent stud-ies have revealed that the gut microbiota is involved in the onset of T2DM by decreasing glucose tolerance and insulin resistance. 1 Parabacteroides species have been shown to regulate glycolipid metabolic.…”

“…7 DPN may cause a high risk of sensory dysfunction, pain, and falls and reduce the quality of patients. 8 Therefore, DPN poses a significant threat to public health. The pathogenesis of DPN is complicated and related to neuronal damage, Schwann cells, and microvessels.…”

“…The pathogenesis of DPN is complicated and related to neuronal damage, Schwann cells, and microvessels. 8 Schwann cells play a critical role in supporting neuronal survival and function. 9 In diabetes, Schwann cells are damaged by hyperglycemia and the support function is disrupted, thereby causing peripheral nerve dysfunction.…”

Hypothyroidism and Diabetes-Related Dementia: Focused on Neuronal Dysfunction, Insulin Resistance, and Dyslipidemia

“…TSH level is related with diabetic peripheral neuropathy [ 118 ], and one study has shown that TSH and TSH receptor administration aggravates diabetic peripheral neuropathy by inducing apoptotic responses in Schwann cells [ 119 ].…”

Mechanism of Schwann cells in diabetic peripheral neuropathy: A review

“…The possible mechanism is that the functional TSH receptor palmitoylation expressed by SCs enhances the oxidative stress induced by high GLU/palmitate (PA) in RSC96 cells. [ 10 ]…”