Search

Background: Diabetes, which is characterized by an increase in blood glucose concentration, is accompanied by low bone turnover, increased fracture risk, and the formation of embryonic skeletal malformations. Yet, there are few studies elucidating the underlying alterations in signaling pathways leading to these osteogenic defects. We hypothesized here that bone formation deficiencies in a high glucose environment result from altered activity of beta-catenin (CTNNB1), a key contributor to osteogenic differentiation, dysregulation of which has also been implicated in the development of diabetes. Methods: To test this hypothesis, we used a previously established embryonic stem cell (ESC) model of differentiation that mimics the diabetic environment of the developing embryo. We differentiated murine ESCs within osteogenic-inducing media containing either high (diabetic) or low (physiological) levels of D-glucose and performed time course analyses to study the influence of high glucose on early and late bone cell differentiation. Results: Endpoint measures for osteogenic differentiation were reduced in a glucose-dependent manner and expression of precursor-specific markers altered at multiple time points. Furthermore, transcriptional activity of the lymphoid enhancer factor (LEF)/T cell factor (TCF) transcription factors during precursor formation stages was significantly elevated while levels of CTNNB1 complexed with Forkhead box O 3a (FOXO3a) declined. Modulation of AKT, a known upstream regulator of both LEF/TCF and FOXO3a, as well as CTNNB1 rescued some of the reductions in osteogenic output seen in the high glucose condition. Conclusions: Within our in vitro model, we found a clear involvement of LEF/TCF and FOXO3a signaling pathways in the regulation of osteogenic differentiation, which may account for the skeletal deficiencies found in newborns of diabetic mothers.

Valve disease and particularly calcific aortic valve disease (CAVD) and diabetes (DM) are progressive diseases constituting a global health burden for all aging societies (Progress in Cardiovascular Diseases. 2014;56(6):565: Circulation Research. 2021;128(9):1344). Compared to non‐diabetic individuals (The Lancet. 2008;371(9626):1800: The American Journal of Cardiology. 1983;51(3):403: Journal of the American College of Cardiology. 2017;69(12):1523), the diabetic patients have a significantly greater propensity for cardiovascular disorders and faster degeneration of implanted bioprosthetic aortic valves. Previously, using an original experimental model, the diabetic‐hyperlipemic hamsters, we have shown that the earliest alterations induced by these conditions occur at the level of the aortic valves and, with time these changes lead to calcifications and CAVD. However, there are no pharmacological treatments available to reverse or retard the progression of aortic valve disease in diabetes, despite the significant advances in the field. Therefore, it is critical to uncover the mechanisms of valve disease progression, find biomarkers for diagnosis and new targets for therapies. This review aims at presenting an update on the basic research in CAVD in the context of diabetes. We provide an insight into the accumulated data including our results on diabetes‐induced progressive cell and molecular alterations in the aortic valve, new potential biomarkers to assess the evolution and therapy of the disease, advancement in targeted nanotherapies, tissue engineering and the potential use of circulating endothelial progenitor cells in CAVD.

Cognitive dysfunction is one of the complications of diabetes. Unfortunately, there is no effective methods to block its progression currently. One of the pathophysiological mechanisms is synaptic protein damage and neuronal signal disruption because of glucose metabolism disorder. Dystroglycan protein, located in the post‐synaptic membrane of neurons, links the intracellular cytoskeleton with extracellular matrix. Abnormal expression of dystroglycan protein affects neuronal biological functions and leads to cognitive impairment. However, there are no relevant studies to observe the changes of β‐dystroglycan protein in diabetes rat brain and in primary neurons under high glucose exposure. Our data demonstrated the alterations of cognitive abilities in the diabetic rats; β‐dystroglycan protein degradation occurred in hippocampal and cortical tissues in diabetic rat brain. We further explored the mechanisms underlying of this phenomenon. When neurons are exposed to high glucose environment in long‐term period, microRNA‐132 (miR‐132) would be down‐regulated in neurons. Matrix Metalloproteinases‐9 (MMP‐9) mRNA, as a target of miR‐132, could be up‐regulated; higher expression and overlay activity of MMP‐9 protein could increase β‐DG protein degradation. In this way, β‐DG degradation may affect structure and functions among the synapses, which related to cognition decline. It may provide some theoretical basis for elucidating the molecular mechanism of diabetes‐induced cognitive dysfunction.

Aim To investigate the glucose profile of women with and without gestational diabetes mellitus (GDM) by simultaneously analyzing several factors of continuous glucose monitoring (CGM) data. Methods CGM was conducted for 2 weeks in the second trimester of pregnant women whose random blood glucose level was ≥100 mg/dl. A 75-g oral glucose tolerance test was performed around day 7, and the index of hyperglycemia, relative hypoglycemia, and indices of glucose variability were extracted from CGM data. Unsupervised hierarchical clustering was performed to categorize glucose profiles of the participants. Results CGM data were obtained from 29 women. Glucose profiles were categorized into three clusters: low glucose levels with less glucose variability group (L group, n = 7); moderate glucose levels with moderate-to-high glucose variability group (M group, n = 18); and high glucose levels with high glucose variability group (H group, n = 4). The waveforms of the glucose profiles were very different among the three groups. Women with GDM tended to be more frequent in the H group than in the M and L groups (75.0%, 16.7%, and 14.3%, respectively; p = 0.053). Maternal age was significantly higher and the proportion of multiparous women was significantly larger in the H group compared to L group (p = 0.002 and 0.015, respectively). Conclusions A comprehensive analysis of CGM data could help us extract a subgroup of women with characteristics of GDM.

In CTLs: High glucose-culture enhances thapsigargin-induced SOCE but decreases target recognition-induced Ca2+ influx. High glucose-culture regulates expression of ORAIs and STIMs without affecting glucose uptake. More high glucose-cultured CTLs are prone to necrosis after execution of killing.

Cardiomyocyte dysfunction is attributed to excess oxidative damage, but the molecular pathways involved in this process have not been completely elucidated. Evidence indicates that isosteviol sodium (STVNa) has cardioprotective effects. We therefore aimed to identify the effect of STVNa on cardiomyocytes, as well as the potential mechanisms involved in this process. We established two myocardial hypertrophy models by treating H9c2 cells with high glucose (HG) and isoprenaline (ISO). Our results showed that STVNa reduced H9c2 mitochondrial damage by attenuating oxidative damage and altering the morphology of mitochondria. The results also indicated that STVNa had a positive effect on HG‐ and ISO‐induced damages via mitochondrial biogenesis. The protective effects of STVNa on cardiomyocytes were associated with the regulation of the SIRT1/PGC‐1α signalling pathway. Importantly, the effects of STVNa involved different methods of regulation in the two models, which was confirmed by experiments using an inhibitor and activator of SIRT1. Together, the results provide the basis for using STVNa as a therapy for the prevention of cardiomyocyte dysfunctions.

Pathogenesis and treatment for diabetic neuropathy are still complex. A deficit of neurotrophic factors affecting Schwann cells is a very important cause of diabetic neuropathy. Neuritin is a newly discovered potential neurotrophic factor. In this study, we explored the effect of exogenous neuritin on survivability and functions of diabetic Schwann cells of rats with experimental diabetic neuropathy. Diabetic neuropathy was induced in rats. 12‐week diabetic rats contrasted with non‐diabetic normal rats had decreased levels of serum neuritin and slowed nerve conduction velocities (NCVs). Schwann cells isolated from these diabetic rats and cultured in high glucose showed reduced cell neuritin mRNA and protein and supernatant neuritin protein, increased apoptosis rates, increased caspase‐3 activities and progressively reduced viability. In contrast, exogenous neuritin treatment reduced apoptosis and improved viability, with elevated Bcl‐2 levels (not Bax) and decreased caspase‐3 activities. Co‐cultured with diabetic Schwann cells pre‐treated with exogenous neuritin in high glucose media, and diabetic DRG neurons showed lessened decreased neurite outgrowth and supernatant NGF concentration occurring in co‐culture of diabetic cells. Exogenous neuritin treatment ameliorated survivability and functions of diabetic Schwann cells of rats with diabetic neuropathy. Our study may provide a new mechanism and potential treatment for diabetic neuropathy.

Endoplasmic reticulum (ER) stress plays a critical role in the development of diabetic nephropathy (DN). We previously demonstrated that pyruvate (Pyr)‐enriched oral rehydration solution improved glucometabolic disorders and ameliorated DN outcome in db/db mice. Here, we investigated the effects of Pyr on high glucose‐induced ER stress and apoptosis in HK‐2 cells. Our results suggest that high glucose can induce reactive oxygen species production, apoptosis and ER stress in HK‐2 cells, and that Pyr treatment can ameliorate these effects and restore the expression of key proteins involved in ER stress. Thus, Pyr may have potential for the development of novel strategies for the prevention and treatment of clinical DN., Pyruvate is a scavenger of reactive oxygen species in the presence of oxygen and during hyperglycemia, and it protects against tissue injuries of various insults. Here, we investigated the effects of pyruvate on the HK‐2 cell line under high glucose and concluded that pyruvate ameliorated endoplasmic reticulum stress and inhibited apoptosis under high glucose. Pyruvate may have potential for using in novel strategies for clinical intervention of diabetic nephropathy.

Aim The aim of the present study was to characterize the role of Smad3 signalling on high glucose‐induced podocyte injury. Methods Synchronized conditionally immortalized mouse podocyte cell line (MPC5) cells were treated with either D‐glucose alone or D‐glucose plus the Smad3 inhibitor SIS3. The distribution of F‐actin and transgelin in a high glucose‐induced model of podocyte injury were examined by immunofluorescence. Levels of transgelin and Smad3 signalling proteins in MPC5 cells were determined by Western blot. Results A disordered distribution of F‐actin, as well as co‐localization of F‐actin and transgelin, was observed in podocytes exposed to high glucose. Increased levels of transgelin were first observed 10 minutes after treatment with glucose, suggesting that this protein is sensitive to hyperglycaemic injury. Levels of phosphorylated Smad3 and cleaved caspase 3 increased significantly with glucose stimulation. Moreover, expression of the downstream protein c‐Myc, but not JAK1/STAT3, was induced in conditions of high glucose. The Smad3‐specific inhibitor SIS3 prevented the effects of high glucose on Smad3 phosphorylation, expression of transgelin and c‐Myc, caspase 3 cleavage and cytoskeletal organization. Expression of the tumour suppressor protein p15INK4B increased after podocyte injury but was unaffected by Smad3 inhibition, suggesting that Smad3 regulation of high glucose‐induced podocyte injury occurs through a p15INK4B‐independent mechanism. Conclusion Smad3 signalling plays a critical role in the modulation of hyperglycaemic injury. Targeted inhibition of the Smad3 pathway may offer a novel route for treatment of podocyte damage, especially in cases of diabetic nephropathy., SUMMARY AT A GLANCE Podocyte damage is characteristic of diabetic kidney disease. This study showed that inhibition of Smad‐3 signalling using the specific inhibitor SIS3 in vitro, could alleviate podocyte abnormalities induced by high glucose including actin cytoskeletal rearrangement and actviation of cell death pathways.

Diabetic wounds are a common complication of diabetes and therefore a pressing issue for clinicians. High-glucose (HG)-induced fibroblast senescence is mainly responsible for delayed wound healing. Calcium silicate (CS), a kind of bioceramic, is thought to have regenerative properties. The aim of this study was to determine the regenerative and protective effects of CS on senescent fibroblasts induced by HG. Fibroblasts were passaged five times and treated with HG and CS. Compared with the normal glucose (NG) group, the proliferation, migration, and differentiation capacity of HG-induced fibroblasts significantly decreased (P < .05). After treatment with CS, the functions of HG-induced senescent fibroblasts were partly restored (P < .05). The mechanism of the regenerative and protective effects of CS may be related to the decreased reactive oxygen species generation, improved senescent state (SA-β-gal expression decreased), up-regulated expression of Smad2 and phosphorylated Smad2, and down-regulated expression of p16, p21, and p53. An in vivo experiment also demonstrated that CS had a therapeutic effect on diabetic wounds via differentiation of fibroblasts into myofibroblasts and enhanced collagen deposition. These results indicate that CS may be a promising candidate for diabetic wound therapy.

Summary Aim Linoleic acid (LA) is an essential fatty acid involved in the biosynthesis of arachidonic acid and prostaglandins. LA is known to induce obesity and insulin resistance. In this study, two concentrations of LA with or without added glucose (G) were fed to mice to investigate their effects on endocannabinoid (EC) biology. Materials and Methods Four groups of C57BL/6 mice were provided with diets containing 1% or 8% LA with or without added G (LAG) for 8 weeks. Body weights, food intake, circulating glucose and insulin levels were measured throughout the study. Following euthanasia, plasma, bowel and hepatic ECs, monoacylglycerol lipase and fatty acid amide hydroxylase protein levels (enzymes responsible for EC degradation) and transcriptional activity of PPARα in liver were quantified. Liver was probed for evidence of insulin receptor activity perturbation. Results Increasing dietary LA from 1% to 8% significantly increased circulating, small bowel and hepatic ECs. 1%LAG fed mice had lowest feed efficiency, and only liver levels of both ECs were reduced by addition of G. Addition of G to 1% LA diets resulted in elevated monoacylglycerol lipase and fatty acid amide hydroxylase protein levels (p

Aims/Introduction Diabetes is an important risk factor for atherosclerotic disease. The initiating factor of atherosclerosis is local endothelial cell injury. The arachidonic acid metabolite, 12(S)‐hydroxyeicosatetraenoic acid (12[S]‐HETE), might be involved in this process. In recent years, some studies have discussed the effect of 12(S)‐HETE on vascular endothelial cell function. In the present study, we investigated the effect of 12(S)‐HETE on vascular endothelial cell function in high‐glucose conditions and the mechanisms involved. Materials and Methods Human umbilical vein endothelial cells were cultured in conventional M199 medium and high‐glucose M199 medium. Human umbilical vein endothelial cells were stimulated with 12(S)‐HETE and cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate (a 12/15‐lipoxygenases inhibitor). A type 1 diabetes mellitus model was established in C57BL/6 or 12/15‐lipoxygenases knockout mice with streptozotocin. Aortic tissue was harvested for subsequent testing. The transmembrane transport of dextran and human acute monocytic leukaemia cell line (THP‐1) cells was measured. The adherens junction protein, IkBα, nuclear factor kappa Bp65 (P65), intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression and phosphorylation, and the binding/dissociation of endothelial cell components were observed. Results Transendothelial migration of dextran and THP‐1 cells was significantly increased by stimulation of human umbilical vein endothelial cell monolayers with high glucose and 12(S)‐HETE (P

Background Diabetes mellitus (DM) is linked to an increased risk of lung cancer; however, the exact molecular basis is unclear. Methods We used a microarray method and found a group of microRNAs differently expressed in lung cancer cells at high or low glucose treatment. Results Among these, miR-194 changed significantly, which indicated further analysis. miR-194 was significantly downregulated in non-small cell lung cancer (NSCLC) cells cultured in high glucose (HG) medium and clinical NSCLC tissues with DM. The introduction of miR-194 significantly suppressed the proliferation, migration, and invasion of lung cancer cells induced by HG, suggesting that miR-194 may be a suppressor during HG-induced NSCLC progression. Further analysis indicated that NFAT5 was a direct target gene of miR-194, evidenced by the direct binding of miR-194 with the 3'untranslated region of NFAT5. MiR-194 could decrease the expression of NFAT5 at both messenger RNA and protein levels, while overexpression of NFAT5 reversed the decreased proliferation, migration, and invasion ability mediated by miR-194 in lung cancer cells. Conclusion Our findings provide new insight into the mechanism of NSCLC progression. Therapeutically, miR-194 may serve as a potential target for the treatment of lung cancer patients with DM.

Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)‐treated endothelial cells (ECs) were subjected to pifithrin‐α (PFT‐α)—a specific inhibitor of P53, or P53‐small interfering RNA (siRNA), both of which attenuated the HG‐induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT‐α or P53‐siRNA prohibited P53 acetylation, decreased microRNA‐34a (miR‐34a) level, leading to a dramatic increase in sirtuin 1 (SIRT1) protein level. Interestingly, the miR‐34a inhibitor (miR‐34a‐I) and PFT‐α increased SIRT1 protein level and alleviated the HG‐induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT‐α were completely abrogated by the miR‐34a mimic. In addition, SIRT1 inhibition by EX‐527 or Sirt1‐siRNA completely abolished miR‐34a‐I's protection against HG‐induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin‐induced diabetic mice, both PFT‐α and miR‐34a‐I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR‐34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR‐34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.

Both diabetes and breast cancer are common diseases worldwide, and diabetes is also linked to higher rates of breast cancer. Epidemiological data also indicate that diabetes may be one of the risk factors for breast cancer. However, the effect of diabetes on breast cancer progression in vivo is rarely reported. We established an ideal animal model of breast cancer using transgenic MMTV-PyMT mice, which spontaneously developed breast cancer. In this model, the animals copresented with diabetes mellitus, which allowed us to study the effect of high glucose on breast cancer. Compared with MMTV-PyMT mice without diabetes, MMTV-PyMT mice with diabetes developed heavier tumors and exhibited greater tumor volumes. Furthermore, high glucose promoted the invasiveness and metastasis of breast cancer in MMTV-PyMT mice. This breast cancer model in which mice copresented with diabetes provides a useful tool to study the effect of diabetes on breast cancer. Anat Rec, 302:269-277, 2019. © 2018 Wiley Periodicals, Inc.

Near infrared spectroscopy (NIR) is a promising technique for continuous blood glucose monitoring for diabetic patients. Four interferents, at physiological concentrations, were introduced to study how the glucose predictions varied with a standard multivariate calibration model. Lactate and ethanol were found to interfere strongly with the glucose predictions unless theywere included in the calibration models. Lactate was mistaken for glucose and gave erroneously high glucose predictions, with a dose response of 0.46 mM/mM. The presence of ethanol resulted in too low glucose predictions, with a dose response of -0.43 mM/mM. Acetaminophen (APAP), a known interferent in the glucose monitoring devices used for diabetes management today, was not found to be an interferent in NIR spectroscopy, nor was caffeine. Thus, interferents that may appear in high concentrations, such as ethanol and lactate, must be included in the calibration or model building of future NIR-based glucose measurement devices for diabetes monitoring. © 2021 The Authors. Journal of Biophotonics published by Wiley‐VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Objectives The present study clarified the role and signalling pathway of Ski in regulating proliferation and apoptosis in fibroblasts under high‐glucose (HG) conditions. Materials and Methods The proliferation and apoptosis of rat primary fibroblasts were assessed using EdU incorporation and TUNEL assays. The protein and phosphorylation levels of the corresponding factors were measured using immunofluorescence staining and Western blotting. Immunoprecipitation was used to determine the interactions between Ski and FoxO1 or Ski and HDAC1. The Ski protein was overexpressed via recombinant adenovirus transfection, and FoxO1 and HDAC1 were knocked down using targeted small‐interfering RNA. Results The present study found that HG inhibited fibroblast proliferation, increased apoptosis and reduced Ski levels in rat primary fibroblasts. Conversely, increasing Ski protein levels alleviated HG‐induced proliferation inhibition and apoptosis promotion. Increasing Ski protein levels also increased Ski binding to FoxO1 to decrease FoxO1 acetylation, and interfering with FoxO1 caused loss of the regulatory effect of Ski in fibroblasts under HG. Increasing Ski protein levels decreased FoxO1 acetylation via HDAC1‐mediated deacetylation. Conclusions Therefore, these findings confirmed for the first time that Ski regulated fibroblast proliferation and apoptosis under HG conditions via the FoxO1 pathway., Under HG conditions, FoxO1 acetylation level was increased. As a transcription factor, FoxO1 involved in the induction of a special subset of genes that regulate cellular proliferation or apoptosis, etc Increased Ski protein increased the binding of Ski to FoxO1, which mediated deacetylation through Ski binding with HDAC1 and resulted in a reduction in FoxO1 acetylation level. Therefore, the role of FoxO1 transcription factor was inhibited.

Background Neural tube defects (NTDs) are severe congenital malformations. Diabetes during pregnancy is a risk factor for NTDs, but its mechanism remains elusive. Emerging evidence suggests that protein malonylation is involved in diabetes. Here, we report the correlation between histone lysine malonylation in diabetes‐induced NTDs. Methods Nano‐HPLC/MS/MS was used to screen the histone malonylation profile in human embryonic brain tissue. Then, the histone malonylation level was compared between the brains of normal control mice and mice with diabetes‐induced NTDs. Finally, the histone malonylation level was compared under high glucose exposure in an E9 neuroepithelial cell line (NE4C). Results A total of 30 histone malonylation sites were identified in human embryonic brain tissue, including 18 novel sites. Furthermore, we found an increased histone malonylation level in brain tissues from mice with diabetes‐induced NTDs. Finally, both the histone malonylation modified sites and the modified levels were proved to be increased in the NE4C treated with high glucose. Conclusion Our results present a comprehensive map of histone malonylation in the human fetal brain. Furthermore, we provide experimental evidence supporting a relationship between histone malonylation and NTDs caused by high glucose‐induced diabetes. These findings offer new insights into the pathological role of histone modifications in human NTDs., In this manuscript, we reported, for the first time, the presence of histone malonylation in human fetal brain and mouse neural stem cells. The results reveal that histone malonylation aberrant in diabetes‐induced NTDs. These results may bring a new insight in the pathological role of histone modifications in human NTDs.

Overexpression of thioredoxin-interacting protein (TXNIP) is associated with reduced insulin sensitivity and β-cell apoptosis. We have previously shown that W2476 inhibited high glucose-induced TXNIP expression at both mRNA and protein levels in INS-1E cells. In this study, we describe structural modification and optimization of W2476 leading to three more active derivatives, 8d, 8g, and 9h, capable of suppressing TXNIP expression in BG73 and INS-1E cells, increasing insulin production, and reducing high glucose-induced apoptosis in INS-1E cells.

Glucocorticoids (steroids) are widely used across many medical specialities for their anti-inflammatory and immunosuppressive properties. However, one of their major side effects is the development of hyperglycaemia. It is well recognized that high glucose levels in people with diabetes in hospital are associated with harm and increased lengths of hospital stay. The use of glucocorticoid (steroid) treatment in people with pre-existing diabetes will undoubtedly result in worsening glucose control, and this may be termed 'steroid-induced hyperglycaemia', and will warrant temporary additional, and more active, glycaemic management. A rise in glucose may occur in people without a known diagnosis of diabetes, and this may be termed 'steroid-induced diabetes'. There is a lack of evidence to guide how people with hyperglycaemia should be managed, and much of the guidance given here is a consensus based on best practice collated from around the United Kingdom. Where evidence is available, this is referenced. These guidelines on the management of people with diabetes treated with steroids has been adapted specifically for Diabetic Medicine. The full version of the guidelines can be found on line at: www.diabetes.org.uk/joint-british-diabetes-society or https://abcd.care/joint-british-diabetes-societies-jbds-inpatient-care-group.

NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti‐hyperglycaemia and anti‐inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL‐1β and IL‐18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down‐regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C‐reactive proteins (CRPs), IL‐1β and IL‐18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS‐mediated NLRP3 inflammasome activation.

Patients with diabetes mellitus have an increased risk of myocardial infarction and coronary artery disease‐related death, exhibiting highly vulnerable plaques. Many studies have highlighted the major role of macrophages (MAC) and smooth muscle cells (SMC) and the essential part of metalloproteases (MMPs) in atherosclerotic plaque vulnerability. We hypothesize that in diabetes, the interplay between MAC and SMC in high glucose conditions may modify the expression of MMPs involved in plaque vulnerability. The SMC‐MAC cross‐talk was achieved using trans‐well chambers, where human SMC were grown at the bottom and human MAC in the upper chamber in normal (NG) or high (HG) glucose concentration. After cross‐talk, the conditioned media and cells were isolated and investigated for the expression of MMPs, MCP‐1 and signalling molecules. We found that upon cross‐talk with MAC in HG, SMC exhibit: (i) augmented expression of MMP‐1 and MMP‐9; (ii) significant increase in the enzymatic activity of MMP‐9; (iii) higher levels of soluble MCP‐1 chemokine which is functionally active and involved in MMPs up‐regulation; (iv) activated PKCα signalling pathway which, together with NF‐kB are responsible for MMP‐1 and MMP‐9 up‐regulation, and (v) impaired function of collagen assembly. Taken together, our data indicate that MCP‐1 released by cell cross‐talk in diabetic conditions binds to CCR2 and triggers MMP‐1 and MMP‐9 over‐expression and activity, features that could explain the high vulnerability of atherosclerotic plaque found at diabetic patients.

Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a long non‐coding RNA, broadly expressed in mammalian tissues including kidney and up‐regulated in a variety of cancer cells. To date, its functions in podocytes are largely unknown. β‐catenin is a key mediator in the canonical and non‐canonical Wnt signalling pathway; its aberrant expression promotes podocyte malfunction and albuminuria, and contributes to kidney fibrosis. In this study, we found that MALAT1 levels were increased in kidney cortices from C57BL/6 mice with streptozocin (STZ)‐induced diabetic nephropathy, and dynamically regulated in cultured mouse podocytes stimulated with high glucose, which showed a trend from rise to decline. The decline of MALAT1 levels was accompanied with β‐catenin translocation to the nuclei and enhanced expression of serine/arginine splicing factor 1 (SRSF1), a MALAT1 RNA‐binding protein. Further we showed early interference with MALAT1 siRNA partially restored podocytes function and prohibited β‐catenin nuclear accumulation and SRSF1 overexpression. Intriguingly, we showed that β‐catenin was involved in MALAT1 transcription by binding to the promotor region of MALAT1; β‐catenin knock‐down also decreased MALAT1 levels, suggesting a novel feedback regulation between MALAT1 and β‐catenin. Notably, β‐catenin deletion had limited effects on SRSF1 expression, demonstrating β‐catenin might serve as a downstream signal of SRSF1. These findings provided evidence for a pivotal role of MALAT1 in diabetic nephropathy and high glucose‐induced podocyte damage.

Aims/Introduction Angiotensin-(1–7) (Ang-[1–7]), recognized as a new bioactive peptide in the renin–angiotensin system, shows biological and pharmacological properties in diabetic cardiovascular diseases. The leptin-induced p38 mitogen-activated protein kinase (MAPK) pathway has been reported to contribute to high glucose (HG)-induced injury. In the present study, we showed the mechanism of how Ang-(1–7) can protect against HG-stimulated injuries in H9c2 cells. Materials and Methods H9c2 cells were treated with 35 mmol/L glucose (HG) for 24 h to establish a model of HG-induced damage. Apoptotic cells were observed by Hoechst 33258 staining. Cell viability was analyzed by cell counter kit-8. The expression of protein was detected by western blot. Reactive oxygen species was tested by 2′,7′-dichlorodihydrofluorescein diacetate staining. Mitochondrial membrane potential was measured by 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide staining. Results The present results showed that treating H9c2 cells with HG obviously enhanced the expressions of both the leptin and phosphorylated (p)-MAPK pathway. However, the overexpression levels of leptin and p-p38 MAPK/p-extracellular signal-regulated protein kinase 1/2 (ERK1/2), but not p-c-Jun N-terminal kinase, were significantly suppressed by treatment of the cells with Ang-(1–7). Additionally, leptin antagonist also markedly suppressed the overexpressions of p38 and ERK1/2 induced by HG, whereas leptin antagonist had no influence on the overexpression of c-Jun N-terminal kinase. More remarkable, Ang-(1–7), leptin antagonist, SB203580 or SP600125, respectively, significantly inhibited the injuries induced by HG, such as the increased cell viability, decreased apoptotic rate, reduction of ROS production and increased mitochondrial membrane potential. Furthermore, the overexpressions of p38 MAPK, ERK1/2 and leptin were suppressed by N-actyl-L-cystine. Conclusions The present findings show that Ang-(1–7) protects from HG-stimulated damage as an inhibitor of the reactive oxygen species–leptin–p38 MAPK/ERK1/2 pathways, but not the leptin–c-Jun N-terminal kinase pathway in vitro.

Introduction High blood glucose levels may be responsible for the increased risk for dementia in diabetic patients. Methods A secondary data analysis merging electronic medical records (EMRs) with data collected from the Indianapolis–Ibadan Dementia project (IIDP). Of the enrolled 4105 African Americans, 3778 were identified in the EMR. Study endpoints were dementia, mild cognitive impairment (MCI), or normal cognition. Repeated serum glucose measurements were used as the outcome variables. Results Diabetic participants who developed incident dementia had a significant decrease in serum glucose levels in the years preceding the diagnosis compared to the participants with normal cognition ( P = .0002). They also had significantly higher glucose levels up to 9 years before the dementia diagnosis ( P = .0367). Discussion High glucose levels followed by a decline occurring years before diagnosis in African American participants with diabetes may represent a powerful presymptomatic metabolic indicator of dementia.

[Graphic][1] Emma Huntley is a fourth-year veterinary student studying at the University of Surrey. She has a special interest in small animal surgery and hopes to pursue a career in veterinary cardiology. #### The dilemma An elderly client comes into the clinic with her seven-year-old diabetic terrier, Charlie. Charlie was on a stable dose of twice daily insulin which, up until recently, his owner has been able to manage. However, within the past year the client has started to develop dementia and now struggles to remember the last time she administered Charlie’s insulin. You note high glucose readings in both blood and urine samples, as well as increased levels of ketone. Your client mentions that Charlie has been urinating in the house and he seems uncharacteristically thin and lethargic. From the consultation it is clear that Charlie isn’t receiving the care he needs and his medication isn’t being administered properly – subsequently Charlie’s condition is deteriorating. You are concerned that Charlie is at serious risk of medical complications if the owner cannot manage his treatment. The owner, who lives alone, often refers to Charlie as her only companion. What do you advise? The key stakeholders in this scenario are the dog, the client and the vet. With regards to the owner’s attachment to Charlie, there have been numerous studies conducted that detail the various psychological … [1]: /embed/inline-graphic-1.gif

This review focuses on bone mechanobiology in type 1 diabetes (T1D), an area of research on diabetes-associated skeletal complications that is still in its infancy. We first provide a brief overview of the deleterious effects of diabetes on the skeleton and of the knowledge gained from studies with rodent models of T1D. Second, we discuss two specific hallmarks of T1D, low insulin and high glucose, and address the extent to which they affect skeletal health. Third, we highlight the mechanosensitive nature of bone tissue and the importance of mechanical loading for bone health. We also summarize recent advances in bone mechanobiology that implicate osteocytes as the mechanosensors and major regulatory cells in the bone. Finally, we discuss recent evidence indicating that the diabetic bone is "deaf" to mechanical loading and that osteocytes are central players in mechanisms that lead to bone loss in T1D.