Omega-3-Fatty Acids Hold Therapeutic Potential for the Prevention and Treatment of Diabetic Neuropathy

Diabetic neuropathy is a debilitating complication of diabetes, affecting over 50% of diabetic patients. Overweight humans display manifestations of diabetic neuropathy before developing overt diabetes and mice fed a high fat diet exhibit signs of neuropathy including mechanical hindpaw hypersensitivity and neuronal inflammation, suggesting fat diet-induced inflammation may play a role in the development of neuropathy. Omega-3 (n-3) fatty acids have anti-inflammatory properties and may hold therapeutic potential as a preventative treatment for prediabetic and diabetic patients at risk for neuropathy. PURPOSE: Investigate the impact of diet composition on signs of neuropathy. We hypothesized that a diet rich in n-3 fatty acids would attenuate hindpaw hypersensitivity during prolonged feeding of a high fat diet. METHODS: C57BL/6 mice were randomized into four diet groups (n = 12/group) for 32 weeks: 10% low fat-fish oil (LFFO), 41% high fat-fish oil (HFFO), 10% low fat-lard (LFL), or 41% high fat-lard (HFL). Neuropathy was characterized at baseline and every other week thereafter using the von Frey behavioral test for hindpaw mechanical sensitivity. A glucose tolerance test was performed at end study, and total area under the curve (AUC) was calculated using the trapezoidal method. RESULTS: At end study, body weight was greater in HFL compared to all other groups. Body weight was also greater in HFFO compared to LFFO. Fasting glucose and glucose AUC were higher in HFL compared to LFFO and HFFO. Following the same pattern as body weight, fasting glucose was higher in HFFO compared to LFFO. Although percent paw withdrawal was greater in HFL compared to HFFO and LFFO, there were no significant differences for LF vs. HF for fish oil or lard. CONCLUSION: A HFL diet induced signs of neuropathy including hindpaw hypersensitivity, whereas a fish oil diet was protective against hindpaw hypersensitivity. Moreover, omega-3-fatty acids may hold therapeutic potential for neuropathy prevention in nondiabetic and diabetic patients

Omega-3-Fatty Acids Hold Therapeutic Potential for the Prevention of "Metabolic" Neuropathy

Diabetic neuropathy is one of the most common complications of diabetes, affecting most diabetic patients. Overweight humans display manifestations of diabetic neuropathy before developing overt diabetes. Mice fed a high fat diet exhibit signs of neuropathy including mechanical hindpaw hypersensitivity and neuronal inflammation, suggesting fat diet-induced inflammation may play a role in the development of neuropathy. Omega-3 (n-3) fatty acids have anti-inflammatory properties and may hold therapeutic potential as a preventative treatment for prediabetic and diabetic patients at risk for neuropathy. PURPOSE: We investigated the impact of diet composition on signs of neuropathy. We hypothesized that a diet rich in n-3 fatty acids would attenuate hindpaw hypersensitivity during prolonged feeding of a high fat diet. METHODS: C57BL/6 mice were randomized into four diet groups (n = 12/group) for 32 weeks: 10% low fat-fish oil (10%FO), 41% high fat-fish oil (41%FO), 10% low fat-lard (10%L), or 41% high fat-lard (41%L). Neuropathy was characterized at baseline and every other week thereafter using the von Frey behavioral test for hindpaw mechanical sensitivity. A glucose tolerance test was performed at end study, and total area under the curve (AUC) was calculated using the trapezoidal method. Upon sacrifice hindpaw footpads were dissected and immunohistochemistry was performed to quantify intraepidermal nerve fiber density (IENFD) and tyrosine kinase-A (TrkA) specific nerve fibers. RESULTS: At the end of the study, body weight was greater in 41%L compared to all other groups. Body weight was a higher in 41%L compared to 10%FO and 41%FO. Although percent paw withdrawal was greater in 41%L compared to 41%FO and 10%FO, there were no significant differences for 10% vs. 41% for fish oil or lard. Fasting glucose and glucose AUC were significantly greater in 41%L compared to 10%FO. Additionally, glucose AUC was greater in 41%FO compared to 10%FO. There were no significant differences in IENF or TrkA nerve fiber density. CONCLUSION: A 41%L diet induced signs of neuropathy including hindpaw hypersensitivity, whereas a fish oil diet was protective against hindpaw hypersensitivity. Moreover, n-3 acids may hold therapeutic potential for neuropathy prevention in nondiabetic and diabetic patients

Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value

Abstract Mutations in the TET2 gene are frequent in myeloid disease, although their biologic and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using “next-generation” sequencing for TET2 aberrations, 91 of whom were also subjected to single-nucleotide polymorphism 6.0 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) ≥ 10%, were identified in 39 of 320 (12%) myelodysplastic syndrome and 16 of 35 (46%) chroni myelomonocytic leukemia patients (P &lt; .001). Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. “Deeper” sequencing of 96 patient samples identified 4 additional mutations (RMA, 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells, in addition to CD34+ and total bone marrow cells (23.5%, 38.5%, and 43% RMA, respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia. On multivariate analysis, age (&gt; 50 years) was associated with a higher incidence of TET2 mutation (P = .02).</jats:p