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.

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.

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 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.

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.