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Peripheral neuropathy (PN) is a prevalent and debilitating complication of obesity, prediabetes, and type 2 diabetes, which remains poorly understood and lacks disease-modifying therapies. Fortunately, diet and/or exercise have emerged as effective treatment strategies for PN. Here, we examined the impact of caloric restriction (CR) and high-intensity interval training (HIIT) interventions, alone or combined (HIIT-CR), on metabolic and PN outcomes in high-fat diet (HFD) mice. HFD feeding alone resulted in obesity, impaired glucose tolerance, and PN. Peripheral nerves isolated from these mice also developed insulin resistance (IR). CR and HIIT-CR, but not HIIT alone, improved HFD-induced metabolic dysfunction. However, all interventions improved PN to similar extents. When examining the underlying neuroprotective mechanisms in whole nerves, we found that CR and HIIT-CR activate the fuel-sensing enzyme AMPK. We then performed complimentary in vitro work in Schwann cells, the glia of peripheral nerves. Treating primary Schwann cells with the saturated fatty acid palmitate to mimic prediabetic conditions caused IR, which was reversed by the AMPK activator, AICAR. Together, these results enhance our understanding of PN pathogenesis, the differential mechanisms by which diet and exercise may improve PN, and Schwann cell-specific contributions to nerve insulin signaling and PN progression. Article Highlights: Diet and exercise are recommended for treating peripheral neuropathy in prediabetes. To identify the optimal regimen and the underlying neuroprotective mechanisms, we compared the effects of caloric restriction (CR), high-intensity interval training (HIIT), and their combination (HIIT-CR), on metabolic and neuropathy outcomes following high-fat diet feeding. While all interventions improved neuropathy, CR and HIIT-CR, but not HIIT alone, improved metabolic profiles and promoted insulin sensitivity in peripheral nerves of high-fat diet–fed mice. In vitro, palmitate-treated Schwann cells developed insulin resistance, which was reversed by AMPK activation. CR, alone or combined with HIIT, ameliorates neuropathy by restoring nerve insulin sensitivity. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is one of the most common complications of diabetes mellitus (DM). Based on our previous results we identified HbA1c as the sole significantly associated clinical factor with myelinated fiber density change(%delta-MFD). Here, we performed a RNA-Seq profiling on 78 sural nerves from DN patients with type 2 diabetes (T2DM). We performed unbiased clustering analyses on the RNA-Seq gene expression data and identified three distinctive groups of samples. Multifactorial logistic regression analyses on the clinical data of these groups identified that these groups were significantly different in terms of baseline HbAlc level and O'Brien neuropathy score. 997 differentially expressed genes were identified between Group1 and Group2, respectively with the highest and lowest average HbA1c levels. Functional enrichment analysis in terms of Gene Ontology terms and KEGG pathways reveals that these DEGs were highly enriched with genes related to extracellular matrix organization, phagosome, antigen processing and presentation pathway as well as adaptive immune system. In conclusion, a deep-sequencing analysis of the peripheral nerves affected by T2DM revealed that the global gene expression patterns in these samples did not correlate with %delta-MFD. However, they were significantly associated with the baseline HbA1c and O'Brien neuropathy score, suggesting their critical roles in driving gene expression changes in peripheral nerves in T2DM., Kai Guo * (P1), Guillermo de Anda-Jauregui (1), Brett A McGregor (1), Carey Backus (2), Crystal Pacut (2), Eva L Feldman (2), and Junguk Hur (1) (1) Department of Biomedical [...]

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes, and dyslipidemia, and insulin resistance (IR) is the central feature of MetS. Recent studies suggest that MetS is a risk factor for Alzheimer disease (AD). AMP-activated kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme and a key player in regulating energy metabolism. In this report, we examined the role of IR on the regulation of AMPK phosphorylation and AMPK-mediated Tau phosphorylation. We found that AMPKSer-485, but not AMPKThr-172, phosphorylation is increased in the cortex of db/db and high fat diet-fed obese mice, two mouse models of IR. In vitro, treatment of human cortical stem cell line (HK-5320) and primary mouse embryonic cortical neurons with the AMPK activator, 5-aminoimidazole-4-carboxamide l-β-D-ribofuranoside (AICAR), induced AMPK phosphorylation at both Thr-172 and Ser-485. AMPK activation also triggered Tau dephosphorylation. When IR was mimicked in vitro by chronically treating the cells with insulin, AICAR specifically induced AMPKSer-485, but not AMPKThr-172, hyperphosphorylation whereas AICAR-induced Tau dephosphorylation was inhibited. IR also resulted in the overactivation of Akt by AICAR treatment; however, preventing Akt overactivation during IR prevented AMPKSer-485 hyperphosphorylation and restored AMPK-mediated Tau dephosphorylation. Transfection of AMPKS485A mutant caused similar results. Therefore, our results suggest the following mechanism for the adverse effect of IR on AD pathology: IR → chronic overactivation of Akt → AMPK Ser-485 hyperphosphorylation → inhibition of AMPK-mediated Tau dephosphorylation. Together, our results show for the first time a possible contribution of IR-induced AMPK Ser-485 phosphorylation to the increased risk of AD in obesity and diabetes. [ABSTRACT FROM AUTHOR]