Endoplasmic reticulum stress contributes to prediabetic peripheral neuropathy

Area of Science:

• Metabolic Neuroscience
• Diabetic Neuropathy Research
• Cellular Stress Mechanisms

Background:

• Prediabetes and metabolic syndrome are linked to microvascular complications like retinopathy, nephropathy, and peripheral neuropathy.
• The exact causes of these neuropathies are unknown but may involve obesity, glucose intolerance, and oxidative stress.
• Endoplasmic reticulum stress, a cellular response to protein misfolding, is increasingly recognized as a mechanism in metabolic diseases.

Purpose of the Study:

• To investigate the role of endoplasmic reticulum stress in prediabetic neuropathy.
• To explore potential therapeutic interventions targeting endoplasmic reticulum stress in prediabetic nerve dysfunction.

Main Methods:

• Utilized two animal models: Zucker (fa/fa) rats and high-fat diet fed mice, exhibiting obesity and impaired glucose tolerance.
• Assessed endoplasmic reticulum stress markers (BiP/GRP78, GRP94) in the sciatic nerve of Zucker rats.
• Administered trimethylamine oxide (chemical chaperone) to Zucker rats and salubrinal (eIF2α dephosphorylation inhibitor) to high-fat diet mice.

Main Results:

• Endoplasmic reticulum stress was identified in the sciatic nerve of Zucker rats.
• Trimethylamine oxide treatment reduced endoplasmic reticulum stress and improved nerve dysfunction (nerve conduction velocity, hypoalgesia, allodynia) in Zucker rats.
• Salubrinal improved glucose intolerance and alleviated peripheral nerve dysfunction in high-fat diet mice.

Conclusions:

• Endoplasmic reticulum stress is implicated in the neurobiology of prediabetic peripheral neuropathy.
• Targeting endoplasmic reticulum stress pathways presents a potential therapeutic strategy for prediabetic neuropathy.