Sensorimotor and pain-related alterations of the gray matter and white matter in Type 2 diabetic patients with peripheral neuropathy.

Although diabetic peripheral neuropathy (DPN) has long been considered a disease of the peripheral nervous system, recent neuroimaging studies have shown that alterations in the central nervous system may play a crucial role in its pathogenesis. Here, we used surface-based morphometry (SBM) and tract-based spatial statistics (TBSS) to investigate gray matter (GM) and white matter (WM) differences between patients with DPN (n = 67, 44 painless and 23 painful) and healthy controls (HCs; n = 88). Compared with HCs, patients with DPN exhibited GM abnormalities in the pre- and postcentral gyrus and in several deep GM nuclei (caudate, putamen, medial pallidum, thalamus, and ventral nuclear). They also exhibited altered WM tracts (corticospinal tract, spinothalamic tract, and thalamocortical projecting fibers). These findings suggest impaired motor and somatosensory pathways in DPN. Further, patients with DPN (particularly painful DPN) exhibited morphological differences in the cingulate, insula, prefrontal cortex, and thalamus, as well as impaired WM integrity in periaqueductal WM and internal and external capsules. This suggests pain-perception/modulation pathways are altered in painful DPN. Intermodal correlation analyses found that the morphological indices of the brain regions identified by the SBM analysis were significantly correlated with the fractional anisotropy of brain regions identified by the TBSS analysis, suggesting that the GM and WM alterations were tightly coupled. Overall, our study showed sensorimotor and pain-related GM and WM alterations in patients with DPN, which might be involved in the development of DPN.

High glucose induces tau hyperphosphorylation in hippocampal neurons via inhibition of ALKBH5-mediated Dgkh m6A demethylation: a potential mechanism for diabetic cognitive dysfunction.

Tau hyperphosphorylation in hippocampal neurons has an important pathogenetic role in the development of diabetic cognitive dysfunction. N6-methyladenosine (m6A) methylation is the most common modification of eukaryotic mRNA and is involved in regulating diverse biological processes. However, the role of m6A alteration in tau hyperphosphorylation of hippocampus neurons has not been reported. We found lower ALKBH5 expression in the hippocampus of diabetic rats and in HN-h cells with high-glucose intervention, accompanied by tau hyperphosphorylation. ALKBH5 overexpression significantly reversed tau hyperphosphorylation in high-glucose-stimulated HN-h cells. Furthermore, we found and confirmed by m6A-mRNA epitope transcriptome microarray and transcriptome RNA sequencing coupled with methylated RNA immunoprecipitation that ALKBH5 regulates the m6A modification of Dgkh mRNA. High glucose inhibited the demethylation modification of Dgkh by ALKBH5, resulting in decreases in Dgkh mRNA and protein levels. Overexpression of Dgkh reversed tau hyperphosphorylation in HN-h cells after high-glucose stimulation. Overexpression of Dgkh by adenovirus suspension injection into the bilateral hippocampus of diabetic rats significantly ameliorated tau hyperphosphorylation and diabetic cognitive dysfunction. In addition, ALKBH5 targeted Dgkh to activate PKC-α, leading to tau hyperphosphorylation under high-glucose conditions. The results of this study reveal that high glucose suppresses the demethylation modification of Dgkh by ALKBH5, which downregulates Dgkh and leads to tau hyperphosphorylation through activation of PKC-α in hippocampal neurons. These findings may indicate a new mechanism and a novel therapeutic target for diabetic cognitive dysfunction.

Favorable Genotypes of Type III Interferon Confer Risk of Dyslipidemia in the Population With Obesity.

Background: Studies have indicated that the chronic state of inflammation caused by obesity leads to dyslipidemia. However, how the polymorphisms involved in these inflammatory pathways affect the lipid metabolism in people with obesity is poorly understood. We investigated the associations of inflammation-related gene polymorphisms with dyslipidemia in individuals with obesity living in China. Methods: This case-control study in a population with obesity involved 194 individuals with dyslipidemia and 103 individuals without dyslipidemia. Anthropometric indices of obesity, fasting plasma glucose, blood pressure, blood lipids, and C-reactive protein were evaluated. The genes we tested were IL6 (interleukin 6), IL6R (interleukin 6 receptor), FOXP3 (forkhead box P3), TLR2 (toll-like receptor 2), TLR4 (toll-like receptor 4), IFNL3 (interferon lambda 3, formerly known as IL28B), and IFNL4 (interferon lambda 4, formerly known as IL29). Polymorphisms were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: There were significant differences in the allelic and genotype frequencies of IFNL3 (IL28B) rs12971396, rs8099917, rs11882871, rs12979860, rs4803217 between non-dyslipidemia and dyslipidemia groups in people with obesity. These single nucleotide polymorphisms (SNPs) of IFNL3 were highly linked (D' and r > 0.90), so the result of one SNP could represent the result of other SNPs. For IFNL3 rs12971396, people with the homozygous genotype (the major group) carried a higher risk of dyslipidemia than people with the heterozygous genotype (P < 0.001, OR = 4.46, 95%CI, 1.95-10.22). Conclusions: The favorable genotypes of type III interferon, which have a beneficial role in anti-virus function, were associated with dyslipidemia in a Chinese population with obesity. Type III interferon could have a pathologic role and confer risk of dyslipidemia in people with obesity and chronic inflammation.

Changed cerebral function and morphology serve as neuroimaging evidence for subclinical type 2 diabetic polyneuropathy.

Introduction: Central and peripheral nervous systems are all involved in type 2 diabetic polyneuropathy mechanisms, but such subclinical changes and associations remain unknown. This study aims to explore subclinical changes of the central and peripheral and unveil their association. Methods: A total of 55 type-2 diabetes patients consisting of symptomatic (n = 23), subclinical (n = 12), and no polyneuropathy (n = 20) were enrolled in this study. Cerebral morphology, function, peripheral electrophysiology, and clinical information were collected and assessed using ANOVA and post-hoc analysis. Gaussian random field correction was used for multiple comparison corrections. Pearson/Spearman correlation analysis was used to evaluate the association of the cerebral with the peripheral. Results: When comparing the subclinical group with no polyneuropathy groups, no statistical differences were shown in peripheral evaluations except amplitudes of tibial nerves. At the same time, functional connectivity from the orbitofrontal to bilateral postcentral and middle temporal cortex increased significantly. Gray matter volume of orbitofrontal and its functional connectivity show a transient elevation in the subclinical group compared with the symptomatic group. Besides, gray matter volume in the orbitofrontal cortex negatively correlated with the Neuropathy Symptom Score (r = -0.5871, p < 0.001), Neuropathy Disability Score (r = -0.3682, p = 0.009), and Douleur Neuropathique en 4 questions (r = -0.4403, p = 0.003), and also found correlated positively with bilateral peroneal amplitude (r > 0.4, p < 0.05) and conduction velocities of the right sensory sural nerve(r = 0.3181, p = 0.03). Similarly, functional connectivity from the orbitofrontal to the postcentral cortex was positively associated with cold detection threshold (r = 0.3842, p = 0.03) and negatively associated with Neuropathy Symptom Score (r = -0.3460, p = 0.01). Discussion: Function and morphology of brain changes in subclinical type 2 diabetic polyneuropathy might serve as an earlier biomarker. Novel insights from subclinical stage to investigate the mechanism of type 2 diabetic polyneuropathy are warranted.

Associations of TCF7L2 rs11196218 (A/G) and GLP-1R rs761386 (C/T) Gene Polymorphisms with Obesity in Chinese Population.

INTRODUCTION: This study aimed to investigate the genetic polymorphism associations with obesity of the transcription factor 7-like 2 (TCF7L2) gene rs11196218 (A/G) and glucagon-like peptide 1 receptor (GLP1-R) gene rs761386 (C/T) in the Chinese population. PATIENTS AND METHODS: This was a case-control pilot study involving 60 patients with obesity and 69 non-obesity Chinese adults, and the two groups were sex and age matched. Anthropometric indices of obesity, fasting blood glucose, blood pressure, and blood lipids were assessed. Both polymorphisms were genotyped using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). RESULTS: There were significant differences in the allelic frequencies of the TCF7L2 rs11196218 and GLP1-R rs761386 between obesity and non-obesity groups (P = 0.003, OR = 2.32, 95% CI [1.31~4.09]; P = 0.034, OR = 1.94, 95% CI [1.05~3.60], respectively). In allele model, the genotypic frequencies of TCF7L2 rs11196218 and GLP1-R rs761386 also differed between obesity and non-obesity groups (P = 0.014 and 0.033, respectively). In dominant model, the TCF7L2 rs11196218 A-carrier (AA/AG) had a higher risk of obesity than GG genotype (P = 0.014, OR = 2.54, 95% CI [1.21~5.35]). Comparison of clinical and biochemical parameters between genotypes showed no significant difference. CONCLUSION: These findings suggest that the rs11196218 (A/G) polymorphism of the TCF7L2 gene and the rs761386 (C/T) polymorphism of the GLP1-R gene were associated with obesity in the Chinese population.

Aberrant Brain Network Integration and Segregation in Diabetic Peripheral Neuropathy Revealed by Structural Connectomics.

Diabetic peripheral neuropathy (DPN) is one of the most common forms of peripheral neuropathy, and its incidence has been increasing. Mounting evidence has shown that patients with DPN have been associated with widespread alterations in the structure, function and connectivity of the brain, suggesting possible alterations in large-scale brain networks. Using structural covariance networks as well as advanced graph-theory-based computational approaches, we investigated the topological abnormalities of large-scale brain networks for a relatively large sample of patients with DPN (N = 67) compared to matched healthy controls (HCs; N = 88). Compared with HCs, the structural covariance networks of patients with DPN showed an increased characteristic path length, clustering coefficient, sigma, transitivity, and modularity, suggestive of inefficient global integration and increased local segregation. These findings may improve our understanding of the pathophysiological mechanisms underlying alterations in the central nervous system of patients with DPN from the perspective of large-scale structural brain networks.

The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes.

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

High glucose up-regulates Semaphorin 3A expression via the mTOR signaling pathway in keratinocytes: A potential mechanism and therapeutic target for diabetic small fiber neuropathy.

Small fiber neuropathy (SFN) is a common complication in diabetes, and is characterized by decreased intraepidermal nerve fiber density (IENFD). Semaphorin 3A (Sema3A), which is produced by keratinocytes, has a chemorepulsive effect on intraepidermal nerve fibers. mTOR signaling can mediate local protein synthesis that is critical for growth of axons and dendrites. Therefore, this study aimed to investigate whether Sema3A is up-regulated in diabetic keratinocytes via the mTOR-mediated p70 S6K and 4E-BP1 signaling pathways, and furthermore whether it is involved in the pathogenesis of diabetic SFN. IENFD, expression of Sema3A, and mTOR signaling, were evaluated in the skin of diabetic patients with SFN as well as control subjects. Sema3A and mTOR signaling were also assessed in HaCaT cells which had been treated with high glucose (HG) or recombinant Sema3A (rSema3A) in the presence or absence of rapamycin. Small fiber dysfunction was evaluated by examining IENFD and using behavioral tests in control and streptozotocin-induced diabetic rats treated with or without rapamycin. We found that higher Sema3A expression and over-activation of mTOR signaling, was accompanied by reduced IENFD in the skin of diabetic patients compared with control subjects. The expression of Sema3A, and mTOR signaling were up-regulated in HaCaT cells incubated with HG or rSema3A, and this could be attenuated by rapamycin. Hyperalgesia, reduced IENFD, and up-regulated Sema3A and mTOR signaling were also detected in diabetic rats. These effects were ameliorated by rapamycin treatment. Our data indicate that HG up-regulates Sema3A expression by activating mTOR signaling in diabetic keratinocytes. This pathway may therefore play a critical role in diabetic SFN.

Waist-to-hip ratio is the most relevant obesity index at each phase of insulin secretion among obese patients.

We aimed to explore the relationship between different obesity indices and insulin secretion at each phase among obese subjects and to find out the most relevant obesity index. Height, weight, waist circumstance, and hip circumstance were obtained among 419 obese subjects to calculate body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio, body adiposity index (BAI), conicity index, abdominal volume index and a body shape index (ABSI). Fasting plasma glucose and fasting insulin were detected to calculate HOMA-ß. Early and late insulin secretion indices: ΔI30/ΔG30 and DI60-120 were calculated according to the result of a 75-g oral glucose tolerance test among the 235 subjects not meeting the standard of diabetes. Pearson correlation analysis and multiple linear regression analysis were used. BMI (ß = 0.022, p = 0.000) and WHR (ß = -1.557, p = 0.000) were independent correlation factors with HOMA-ß. In 235 OGTT subjects, WHR was independently and negatively associated with ΔI30/ΔG30 and DI60-120 (ß = -1.187, p = 0.026; ß = -1.241, p = 0.001, respectively). ABSI was independently and negatively associated with ΔI30/ΔG30 (ß = -17.249, p = 0.012). WHR was the best and consistently correlated factor with insulin secretion at each phase among obese subjects from Hunan Province in China.

High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction.

The abnormally hyperphosphorylated tau is thought to be implicated in diabetes-associated cognitive deficits. The role of mammalian target of rapamycin (mTOR) / S6 kinase (S6K) signalling in the formation of tau hyperphosphorylation has been previously studied. Caveolin-1 (Cav-1), the essential structure protein of caveolae, promotes neuronal survival and growth, and inhibits glucose metabolism. In this study, we aimed to investigate the role of Cav-1 in the formation of tau hyperphosphorylation under chronic hyperglycemic condition (HGC). Diabetic rats were induced by streptozotocin (STZ). Primary hippocampal neurons with or without molecular intervention such as the transient over-expression or knock-down were subjected to HGC. The obtained experimental samples were analyzed by real time quantitative RT-PCR, Western blot, immunofluorescence or immunohistochemisty. We found: 1) that a chronic HGC directly decreases Cav-1 expression, increases tau phosphorylation and activates mTOR/S6K signalling in the brain neurons of diabetic rats, 2) that overexpression of Cav-1 attenuates tau hyperphosphorylation induced by chronic HGC in primary hippocampal neurons, whereas down-regulation of Cav-1 using Cav-1 siRNA dramatically worsens tau hyperphosphorylation via mTOR/S6K signalling pathway, and 3) that the down-regulation of Cav-1 induced by HGC is independent of mTOR signalling. Our results suggest that tau hyperphosphorylation and the sustained over-activated mTOR signalling under hyperglycemia may be due to the suppression of Cav-1. Therefore, Cav-1 is a potential therapeutic target for diabetes-induced cognitive dysfunction.