Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies

This study evaluated the role for 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, in nitrosative stress in peripheral nervous system and peripheral prediabetic and diabetic neuropathies. The experiments were performed in C57Bl6/J mice made diabetic with streptozotocin or fed high-fat diet, and human Schwann cells cultured in 5.5 mM or 30 mM glucose. 12/15-lipoxygenase overexpression and activation were present in sciatic nerve and spinal cord of diabetic and high fat diet-fed mice, as well as in human Schwann cells cultured in high concentrations of D-, but not L-glucose. 12/15-lipoxygenase inhibition with cinnamyl-3,4-dihydroxy-α-cyanocinnamate (8 mgkg(-1)d(-1) s.c., for 4 weeks after 12 weeks without treatment) alleviated accumulation of nitrated proteins in sciatic nerve and spinal cord, and large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss. 12/15-lipoxygenase gene deficiency alleviated nitrosative stress and nerve conduction deficit, but not small sensory fiber neuropathy, in high-fat diet fed mice. In conclusion, 12/15-lipoxygenase is implicated in nitrosative stress and peripheral neuropathy in mouse models of Type 1 and early Type 2 diabetes. Its presence in human Schwann cells and upregulation by high glucose suggest a potential involvement in human disease

Obstructive sleep apnea and diabetic neuropathy

Rationale: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. Objectives: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. Methods: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. Measurements and Main Results: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0–93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44–5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. Conclusions: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes

Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Nav1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Nav1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Nav1.8 knockout (Scn10−/−) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy