Search

Gremlin-1 is part of the TGF-β superfamily and is a BMP antagonist that blocks BMP signalling to precisely control BMP gradients. Gremlin-1 is primarily involved in organogenesis and limb patterning however, has recently been described as being involved in fibrotic diseases. Initially described as a key factor involved in diabetic kidney fibrosis due to being induced by high glucose, it has now been described as being associated with lung, liver, eye, and skin fibrosis. This suggests that it is a key conserved molecule mediating fibrotic events irrespective of organ. It appears that Gremlin-1 may have effects mediated by BMP-dependent and independent pathways. The aim of this review is to evaluate the role of Gremlin-1 in fibrosis, its mechanisms and if this can be targeted therapeutically in fibrotic diseases, which currently have very limited treatment options and are highly prevalent.

Yuan Chen,1,* Yiheng Chen,2,* Chonghui Tang,3 Qian Zhao,1 Tailin Xu,1 Qi Kang,1 Bin Jiang,2 Li Zhang4 1Department of Endocrinology, The First People’s Hospital of Zunyi, Zunyi, Guizhou, 563000, People’s Republic of China; 2Department of Hand and Plastic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 3Department of Neurosurgery, Affiliated Cixi Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 315300, People’s Republic of China; 4Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li ZhangDepartment of Neurosurgery, China-Japan Friendship Hospital, No. 2 Yinghua East Road, District of Chaoyang, Beijing, 100029, People’s Republic of ChinaEmail ftzy73129@sina.comAim: Endothelial dysfunction is a key pathological basis for diabetes mellitus complications, including diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. This study aimed to reveal the functional role of ribosomal protein S4 Y-linked 1 (RPS4Y1) in endothelial dysfunction.Methods: Human umbilical vein endothelial cells (HUVECs) were subjected to high glucose. The expression of RPS4Y1 in cells was overexpressed or silenced by plasmid or siRNA transfection. MTT assay, flow cytometry, JC-1 probe, scratch test, tube formation, and ELISA were conducted to assess the effects of RPS4Y1 on cell. Western blot was performed to assay the downstream signaling of RPS4Y1. The inhibitors of p38, ERK, and Jnk were used to treat cells to validate the involvement of them in RPS4Y1-mediated endothelial dysfunction.Results: RPS4Y1 was upregulated in HUVECs in response to high glucose in both dose- and time-dependent manners. Overexpression of RPS4Y1 induced viability loss, apoptosis, and inflammation, but inhibited cell migration and tube formation. Silence of RPS4Y1 impacted these aspects in a contrary trend. The phosphorylation of p38 rather than ERK and Jnk was activated by RPS4Y1. In addition, the dysfunction of HUVECs mediated by RPS4Y1 was attenuated by SB203580 (a specific inhibitor of p38 signaling).Conclusion: The highly expressed RPS4Y1 in endothelial cells may contribute to high glucose-induced dysfunction through regulating p38 MAPK signaling. RPS4Y1 might be a potential therapeutic target for treating diabetes mellitus complications.Keywords: RPS4Y1, HUVEC, diabetes mellitus, high glucose, p38 MAPK signaling

Objective Low-magnitude high-frequency vibration (LMHFV) has been reported to be capable of promoting osteoblast proliferation and differentiation. Reduced osteoblast activity and impaired bone formation were related to diabetic bone loss. We investigated the potential protective effects of LMHFV on high-glucose (HG)-induced osteoblasts in this study. In addition, the assessment of LMHFV treatment for bone loss attributed to diabetes was also performed in vivo. Method MC3T3-E1 cells induced by HG only or treated with LMHFV were treated in vitro. The experiments performed in this study included the detection of cell proliferation, migration and differentiation, as well as protein expression. Diabetic bone loss induced by streptozotocin (STZ) in rats was established. Combined with bone morphometric, microstructure, biomechanical properties and matrix composition tests, the potential of LMHFV in treating diabetes bone loss was explored. Results After the application of LMHFV, the inhibiting effects of HG on the proliferation, migration and differentiation of osteoblasts were alleviated. The GSK3β/β-catenin pathway was involved in the protective effect of LMHFV. Impaired microstructure and biomechanical properties attributed to diabetes were ameliorated by LMHFV treatment. The improvement of femur biomechanical properties might be associated with the alteration of the matrix composition by the LMHFV. Conclusion LMHFV exhibited a protective effect on osteoblasts against HG by regulating the proliferation, migration and differentiation of osteoblasts. The function of promoting bone formation and reinforcing bone strength made it possible for LMHFV to alleviate diabetic bone loss.

Different infections have been presenting danger to mankind every once in a while and in 2019 a serious respiratory illness (COVID-19) reported in Wuhan, Hubei province of China, became a threat to general wellbeing not only in China but all the nations throughout the world. COVID-19 disease which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found to be associated with a wide range of opportunistic fungal and bacterial infections. Candidial and aspergillus infections leading to mucormycosis and orbital compartment syndrome have been reported to be the main co-infections in COVID-19 patients, which must be recognized and treated promptly to avoid any morbidity and mortality. Low oxygen environment, acidic medium, high glucose, decreased phagocytic activity and increased ferritin levels in addition to prolonged hospitalization with or without mechanical ventilators are considered as the main risk factors. Thus, the main aim of the article is to briefly survey and discuss about the types, causes, methods to prevent and treatment modalities of main co-morbidity of COVID 19 i.e. mucormycosis.

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.

Qingmei Xu,1 Xin Tan,1 Wei Xian,1 Jiayi Geng,2 Haoyu Li,3 Bi Tang,1,4 Heng Zhang,1 Hongju Wang,1,4 Qin Gao,5 Pinfang Kang1,4 1Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of China; 2Department of Preventive Medicine, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China; 3Clinic Medical College of AnHui Medical University, Hefei, Anhui, 230000, People’s Republic of China; 4Cardiovascular Disease Research Center of Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 5Department of Physiology, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of ChinaCorrespondence: Pinfang KangDepartment of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People’s Republic of ChinaTel +86 552-3086107Email kangpinfang.1016@163.comBackground: Diabetic cardiomyopathy (DCM) is strongly linked to microvascular disease, renin-angiotensin system (RAS) activation, cardiac inflammation and cell apoptosis. Irbesartan is an angiotensin II (Ang II) receptor antagonist in RAS system, which inhibited the conversion of Ang I into Ang II, while the specific mechanism is still obscure.Objective: This study aims to investigate the expressions necroptosis RIP1-RIP3-MLKL pathway in myocardium of diabetic rats, and the protective action of irbesartan on myocardial damage.Materials and Methods: In our study, 30 Sprague–Dawley rats were divided into 5 groups: CON4W, high glucose and high caloric (HC4W), diabetes mellitus 4 weeks (DM4W group), diabetes mellitus 8 weeks (DM8W group), and irbesartan diabetes 8 weeks (Ir DM8W group).Results: We discovered that as diabetes progresses, the rats gradually lost weight, the HW/BW ratio were increased gradually, and the cardiac function became worse accompanied with the aggravation of inflammatory injury. Meanwhile, the myocardial fibers and cells were disordered, and the expression of positive substances, RIP1 and RIP3 increased significantly. The mRNA and protein levels of myocardial RIP1, RIP3 and MLKL were all increased with the progression of DM. After the intervention of irbesartan in diabetic rats, the cardiac function was improved, whereas inflammatory injury and HW/BW ratio were decreased. Also, the myocardial fibrosis injury was attenuated, and the PAS positive substances, RIP1 and RIP3 were significantly decreased. The curative effect of irbesartan was related to decreased myocardial RIP1, RIP3 and MLKL mRNA and protein levels.Conclusion: In conclusion, irbesartan has a cardioprotective effect on the diabetic rats, and its mechanism may be connected with inhibition of RIP1-RIP3-MLKL pathway.Keywords: cardiomyocyte, high glucose, irbesartan, inflammatory, necroptosis

The current therapeutic strategy for hyperglycemia is reasonable diet and appropriate exercise with drugs, whose outcome is unsatisfied. Therefore, we aimed to explore the new candidate drug 7-Ethoxyrosmanol (7ERM) on hyperglycemia-induced endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) were treated with different doses of 7ERM in the presence of 33 mM high glucose to measure cell injury, inflammation, and reactive oxygen species (ROS) production. Then F-box/LRR-repeat protein 7 (FBXL7) knockdown by siRNA or overexpressed by plasmid in HUVECs was assessed its effect in the protective role on hyperglycemia-induced endothelial dysfunction. 7ERM time-dependently increased high glucose-induced cell injury, the secretions of pro-inflammatory cytokines and ROS production in HUVECs. Moreover, high glucose time-dependently increased the FBXL7 expressions, which could be gradually inhibited by 7ERM. FBXL7 knockdown ameliorated high glucose-induced cell injury. On the contrary, FBXL7 over-expression inhibited the protective effect of 7ERM on cell injury. In conclusion, 7ERM effectively attenuates high glucose-induced endothelial dysfunction in HUVECs by regulating FBXL7 expression, indicating its potential as a therapeutic drug to treat hyperglycemia.

Diabetes mellitus, a very common and multifaceted metabolic disorder is considered as one of the fastest growing public health problems in the world. It is characterized by hyperglycemia, a condition with high glucose level in the blood plasma resulting from defects in insulin secretion or its action and in some cases both the impairment in secretion and also action of insulin coexist. Historically, animal models have played a critical role in exploring and describing malady pathophysiology and recognizable proof of targets and surveying new remedial specialists and in vivo medicines. In the present study, we reviewed the experimental models employed for diabetes and for its related complications. This paper reviews briefly the broad chemical induction of alloxan and streptozotocin and its mechanisms associated with type 1 and type 2 diabetes. Also we highlighted the different models in other species and other animals.

Background Diabetic nephropathy (DN) is a common complication of diabetes. Long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is reported to exert a protective role in DN by a previous study. The working mechanism underlying the protective role of CASC2 in DN progression was further explored in this study. Methods The expression of CASC2 and microRNA-135a-5p (miR-135a-5p) was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation ability was assessed by Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-29-deoxyuridine (EDU) assay. Enzyme-linked immunosorbent assay (ELISA) was conducted to analyze the production of inflammatory cytokines in the supernatant. Western blot assay was performed to analyze protein expression. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the target relationship between miR-135a-5p and CASC2 or tissue inhibitors of metalloproteinase 3 (TIMP3). Results High glucose (HG) treatment reduced the expression of CASC2 in human glomerular mesangial cells (HMCs) in a time-dependent manner. CASC2 overexpression suppressed HG-induced proliferation, inflammation and fibrosis in HMCs. miR-135a-5p was validated as a target of CASC2, and CASC2 restrained HG-induced influences in HMCs partly by down-regulating miR-135a-5p. miR-135a-5p bound to the 3ʹ untranslated region (3ʹUTR) of TIMP3, and CASC2 positively regulated TIMP3 expression by sponging miR-135a-5p in HMCs. miR-135a-5p silencing inhibited HG-induced effects in HMCs partly by up-regulating its target TIMP3. CASC2 overexpression suppressed HG-induced activation of Jun N-terminal Kinase (JNK) signaling partly through mediating miR-135a-5p/TIMP3 signaling. Conclusions In conclusion, CASC2 alleviated proliferation, inflammation and fibrosis in DN cell model by sponging miR-135a-5p to induce TIMP3 expression.

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. In vitro assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.

Objective This study examined cardiovascular disease risk factors by BMI category in firefighters, the association of BMI and age with risk factor prevalence, and the prevalence of risk factors by BMI category within age groups. Methods Cardiovascular measures from the medical evaluations of 4,453 firefighters, performed between 2015 and 2018 at four occupational health clinics in the United States (South-West Cohort, Mid-Atlantic Cohort, South-East Cohort, and Mid-West Cohort), were analyzed cross-sectionally by BMI and age categories. Results Among female firefighters with normal weight, 25% had high blood pressure, 8% had low high-density lipoprotein cholesterol, and 0% had high glucose, whereas the prevalence in female firefighters with obesity was 57%, 45%, and 11%, respectively. Among male firefighters, there were independent and significant associations of BMI and age for the prevalence of high blood pressure, high cholesterol, high triglycerides, and high glucose. Higher BMI category was associated with a higher prevalence of high blood pressure, high triglycerides, and low high-density lipoprotein cholesterol within all age groups and with a higher prevalence of high glucose and high cholesterol within ages 40 to 49 and 50 to 59 years. Conclusions An increasing prevalence of risk factors with older age and higher BMI suggests that preventive strategies should be initiated in younger firefighters and aggressively promoted or mandated throughout firefighters' careers.

Introduction: Extreme natural and climatic conditions of the Arctic have led to development of a special type of glucose metabolism and its regulating links, although the evidence on age-related changes in these mechanisms among Arctic residents is still scarce. Aim: To study age-related changes in blood concentrations of glucose, proinsulin and insulin in residents of Russian circumpolar territories. Methods: In total 1 058 healthy individuals of both genders aged 16-74 years took part in a multicenter cross-sectional study. Of them, 629 permanently lived in the Arctic region while 429 were residents of the Subarctic areas. By age the participants were classified as 16-21, 22-35, 36-45, 46-60 and 61-74 years old. Concentrations of proinsulin and insulin were determined by the enzyme immunoassay methods while glucose level was assessed by spectrophotometric analysis. Between group differences in numeric characteristics were analyzed using Mann-Whitney tests with Bonferroni correction. Associations between variables were studied by non-parametric correlation analysis. Results. Blood glucose concentration increased with age. Among the 16-21-year-olds, higher concentrations of glucose was observed among Subarctic residents. Regional differences reduced in parallel with age. In the Arctic region, an increase in blood glucose in comparison with the youngest group began from 22-35 years while in the Subarctic region. The proportion of people with high glucose levels in age-groups 46-60 and 61-74 years was greater among the Arctic residents compared with their Subarctic counterparts (22.5% and 33.3 % vs. 14.7% and 27.9 %). This was combined with greater proportions of people in the AR with increased proinsulin levels (37.5% and 33.3 % vs. 24.7% and 28.8%) and decreased levels of insulin (57.5% and 53.8 % vs. 74.0 and 36.8 %). Conclusion: A gradual decrease in glucose utilization with age seems to be associated with a decrease in the intensity of proinsulin processing into insulin suggesting early depletion of the functional and receptor activity of pancreatic p-cells. The changes were more pronounced among the residents of the Arctic areas compared to their Subarctic counterparts.

Valeria De Nigris,1 Francesco Prattichizzo,2 Hiroaki Iijima,3 Antonio Ceriello2 1Institut d’Investigación Biomédiques August Pi i Sunyer, Barcelona, Spain; 2IRCCS MultiMedica, Milan, Italy; 3Medical Affairs Department, Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, JapanCorrespondence: Valeria De NigrisInsititut d’Investigacions Biomèdiques August Pi i Sunyer, C/Rosselló, 149-153, Barcelona, 08036, SpainTel +34932275400 Ext. 4562Fax +34932279240Email valeriadenigris@yahoo.itPurpose: We explored the anti-inflammatory role of the DPP-4 inhibitor teneligliptin, using sitagliptin as comparator, in different in vitro models of low-grade inflammation (LGI), evaluating the hyperglycemia-induced endothelial inflammation, the macrophage polarization, and the endothelium–macrophage interaction.Methods: The effects of DPP-4 and its inhibitors on macrophage polarization were evaluated in THP-1 cells by measuring mRNA expression of M1-M2 markers. HUVEC cells were used to analyze the effects of DPP-4 inhibitors on endothelial inflammation under normal and high glucose conditions. To evaluate the link between eNO and M1-M2 polarization, HUVECs were transfected with eNOS siRNA and co-cultured with THP-1 cells. The effects of DPP-4 inhibitors on macrophage polarization and eNO content were evaluated in a co-culture model of differentiated THP-1 cells + HUVECs under normal glucose (NG), high glucose (HG) and high metabolic memory (HM) conditions.Results: DPP-4 regulated M1/M2 macrophage polarization. Teneligliptin reduced M1 and enhanced M2 macrophage phenotype under DPP-4 stimulation, and attenuated hyperglycemia-induced endothelial inflammation. In THP-1 cells co-cultured with eNOS depleted HUVECs, M1 markers were enhanced, while M2 reduced, indicating an important role of eNO in polarization to M2 phenotype. In the co-culture model with HUVECs exposed to HG and HM, teneligliptin reduced M1 and enhanced M2 population, by increasing eNO levels. The anti-inflammatory effects of sitagliptin were not observed in these LGI models.Conclusion: Teneligliptin, but not sitagliptin, has anti-inflammatory effects in the various LGI models, by promoting a switch from M1 toward M2 phenotype and by decreasing hyperglycaemia-induced endothelial inflammation, suggesting that effects for LGI are different among DPP-4 inhibitors.Keywords: DPP-4 inhibitors, low-grade inflammation, teneligliptin, macrophage polarization, endothelial inflammation, endothelial NO, high glucose, antioxidant defense

Hyperglycemia exacerbates edema formation and worsens neurological outcome in ischemic stroke. Edema formation in the early hours of stroke involves transport of ions and water across an intact blood-brain barrier (BBB), and swelling of astrocytes. We showed previously that high glucose (HG) exposures of 24 hours to 7 days increase abundance and activity of BBB Na+-K+-2Cl− cotransport (NKCC) and Na+/H+ exchange 1 (NHE1). Further, bumetanide and HOE-642 inhibition of these transporters significantly reduces edema and infarct following middle cerebral artery occlusion in hyperglycemic rats, suggesting that NKCC and NHE1 are effective therapeutic targets for reducing edema in hyperglycemic stroke. The mechanisms underlying hyperglycemia effects on BBB NKCC and NHE1 are not known. In the present study we investigated whether serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCβII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCβII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCβII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCβII abundance or phosphorylation (activity) after 24 or 48 h HG exposures. Further, we found that HG-induced increases in NKCC and NHE1 abundance were abolished by inhibition of SGK1 but not PKCβII, whereas the increases in NKCC and NHE activity were abolished by inhibition of either kinase. Finally, we found evidence that STE20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 (SPAK/OSR1) participate in the HG-induced effects on BBB NKCC.

Background: This in vitro study was designed to reveal the role of miR-29a in high glucose-induced cellular injury through the modulation of IL-6/STAT3 in diabetic cataracts. Methods: The expressio...

Purpose Several roles are attributed to the myometrium including sperm and embryo transport, menstrual discharge, control of uterine blood flow, and labor. Although being a target of diabetes complications, the influence of high glucose on this compartment has been poorly investigated. Both miRNAs and IGF1R are associated with diabetic complications in different tissues. Herein, we examined the effects of high glucose on the expression of miRNAs and IGF1R signaling pathway in the human myometrium. Methods Human myometrial explants were cultivated for 48 h under either high or low glucose conditions. Thereafter, the conditioned medium was collected for biochemical analyses and the myometrial samples were processed for histological examination as well as miRNA and mRNA expression profiling by qPCR. Results Myometrial structure and morphology were well preserved after 48 h of cultivation in both high and low glucose conditions. Levels of lactate, creatinine, LDH and estrogen in the supernatant were similar between groups. An explorative screening by qPCR arrays revealed that 6 out of 754 investigated miRNAs were differentially expressed in the high glucose group. Data validation by single qPCR assays confirmed diminished expression of miR-215-5p and miR-296-5p, and also revealed reduced miR-497-3p levels. Accordingly, mRNA levels of IGF1R and its downstream mediators FOXO3 and PDCD4, which are potentially targeted by miR-497-3p, were elevated under high glucose conditions. In contrast, mRNA expression of IGF1, PTEN, and GLUT1 was unchanged. Conclusions The human myometrium responds to short-term exposure (48 h) to high glucose concentrations by regulating the expression of miRNAs, IGF1R and its downstream targets.

Aim To evaluate the long-term clinical effect of continuous subcutaneous insulin infusion (CSII) in adult type 1 diabetes mellitus (T1DM) patients in a regional public healthcare system real-world scenario. Methods All adult T1DM patients on CSII for ≥10 years subjected to follow-up in the regional Castilla-La Mancha Public Health Service were included. The primary efficacy outcome was the variation in HbA1c during follow-up. Direct patient data were compiled through the web-based Spanish national registry on CSII therapy. Results A total of 69 T1DM adult patients were treated with insulin pumps for ≥10 years in our region. The mean age was 45.0 ± 10.5 years, with a T1DM duration of 13.9 ± 8.5 years. The mean duration of CSII therapy was 11.4 ± 2.1 years. The main indications for treatment were high glucose variability (39%), problematic hypoglycemia (26%), and HbA1c > 53 mmol/mol (7%) on multiple daily injections (20%). Sensor-augmented pump therapy was used by 31% of the patients. Glycosylated hemoglobin did not change during follow-up (58 ± 11 mmol/mol vs. 58 ± 11 mmol/mol; 7.5 ± 1.0 vs. 7.5 ± 1.0; p = 0.66). However, the percentage of patients with at least one episode of severe hypoglycemia during the last year and unnoticed hypoglycemia decreased from 36% to 7% (p = 0.006) and from 38% to 32% (p Conclusions The reduction of severe hypoglycemia without deterioration of glycemic control can be sustained over long-term CSII therapy.

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.

Purpose: To investigate F2 and miR-451a levels in gestational diabetes mellitus (GDM) patients, evaluate the potential role of miR-451a in GDM, and to explore its possible downstream targets. Methods: Thromboelastography (TEG) analysis was conducted to analyze coagulation differences between the GDM and control groups. Quantitative polymerase chain reaction (qPCR) and immunoblot were performed to analyze miR-451a and F2 levels after exposure to high glucose and miR-451a mimics or an miR-451a inhibitor. Luciferase assay was used to explore the potential regulatory mechanism. Results: Enhancement of the patients' blood coagulation ability and down-regulated miR-451a expression levels occurred in the plasma of GDM patients. The data further show that hepatocytes exposed to high glucose reduced miR-451a levels and enhanced F2 expression. The overexpression of miR-451a inhibited the expression of F2. Conclusion: MiR-451a may serve as a promising marker for hypercoagulable state GDM patients Keywords: Gestational diabetes mellitus (GDM), MiR-451a, F2, Hypercoagulable state, Prothrombin, Thromboelastography (TEG)

In recent years there is a positive trend in the development of preventive medicine, in particular, primary prevention of diseases. However, in most cases, patients seek help from a doctor after the manifestation of the disease, and therefore, early identification of risk factors (RF) remains relevant. Conduction of a large number of studies that are aimed at studying modifiable RF associated with the development of cardiovascular diseases (CVD), allowed the experts of the American Heart Association to develop recommendations “Life's Simple 7”, which makes it possible to structure methods of primary prevention of CVD and minimize the risk of their development. In 2019, experts from the American College of Cardiology presented a simplified version of these recommendations, to improve approaches to primary prevention and their effectiveness not only for doctors but also for patients. Thus, by involving the patient in the decision-making process about follow-up treatment, doctors can achieve a high level of compliance, which is essential for improving the prognosis. The “ABCDE” recommendations, in name of which are reflected the first letters of the leading CVD RF, include such paragraphs as RF assessment, the use of antiaggregating therapy, correction of blood pressure, cholesterol levels, smoking elimination, correction of high glucose levels and diabetes treatment, weight loss, assessment of social and economic factors affecting the morbidity in a particular patient. Despite the undoubted benefit of the “ABCDE” recommendations, some problems of primary prevention currently cannot be solved: the inability to accurately assess social and economic RF; the imperfection of the used CVD risk scales. The updated version of the recommendations allows not only to assess the existing RF of the patient, but also to effectively correct them. In addition, the patient himself can read the recommendations, which improves understanding of the primary prevention importance.

Context Simvastatin is the first line therapeutic drug for coronary heart disease and atherosclerosis. The protective effect mechanism of simvastatin on cardiomyocytes is unclear. Objective This study explores the effect of simvastatin on high glucose induced cardiomyocyte injury and the role of autophagy during the process. Materials and methods H9c2 cells were incubated with different doses of glucose (0, 50, 100, 200 mM) for 24 h to verify the glucose induced injury. The H9c2 cells were pre-treated with simvastatin at different dosages (0, 0.1, 0.5, 1 μM) for 30 min to rescue the injury followed by the autophagy evaluation. 3-MA was used as an autophagy inhibitor to confirm the role of autophagy in simvastatin treated process. CCK-8 assay, FACS assay, confocal microscopy, western blotting and immunofluorescence analysis were conducted to evaluate the high glucose induced injury or protective effects of simvastatin in H9c2 cell line. Results High glucose dramatically decreased H9c2 cell viability (0 mM, 0.58 ± 0.09%; vs. 50 mM, 8.67 ± 0.43%; 100 mM, 16.1 ± 3.56%; 200 mM, 32.9 ± 2.63%), induced significant cell apoptosis (0 mM, 0.96 ± 0.16%, vs. 50 mM, 7.00 ± 0.63%; 100 mM, 12.9 ± 0.78%; 200 mM, 21.8 ± 1.17%) and suppressed cell autophagy. Simvastatin decreased apoptosis and attenuate injury by decreasing cell apoptosis ratio, elevating Bcl-2 expression while decreasing Bax and caspase-3 protein expressions. Meanwhile, simvastatin restored the autophagy depicted by western blotting with increased ATG-5, Beclin1 and LC3II/LC3I protein expression and decreased p62 expression, as well as immunofluorescence with elevated LC3 fluorescence density. Discussion and conclusions The myocardial protective effect mediated by autophagy activated by simvastatin to some extent elucidated the mechanism of the protective effect of simvastatin on H9c2 cell injury, which provided a certain theoretical basis for the clinical application of simvastatin in the treatment of cardiovascular diseases. In addition, we speculate that simvastatin may be used for diabetes associated cardiovascular diseases.

Diabetic cardiomyopathy (DCM) is a major diabetes-related microvascular disease. LncRNA MALAT1 is widely expressed in cardiomyocytes responding to hypoxia and high levels of glucose (high glucose). In this study, cardiac fibroblasts (CFs) were transfected with si-MALAT1 and exposed to high glucose. CFs in the high glucose groups were treated with 30 mmol/L glucose, and the control CFs were treated with 5.5 mmol/L glucose. The expression of MALAT1 in the nucleus and cytoplasm of CFs was detected. The biological behavior of CFs, as well as collagen production, activity of the Hippo–YAP pathway, and nuclear localization of YAP were measured. Mouse models of DCM were established to observe the pathological changes to myocardium and determine the levels of collagen I, Bax, and Bcl-2. The interaction between MALAT1 and YAP was analyzed, and CREB expression in the high-glucose treated CFs was detected. MALAT1 was upregulated in high-glucose CFs and located in the nucleus. High-glucose increased collagen production, inflammation, cell proliferation, cell invasiveness, and phosphorylation of MST1 and LATS1, and also promoted nuclear translocation of YAP. These trends in high-glucose treated CFs and the DCM mice were reversed by transfection with si-MALAT1. MALAT1 positively regulated the nuclear translocation of YAP by binding to CREB. CREB levels were increased in the high-glucose CFs, but decreased after silencing MALAT1. These results indicate that si-MALAT1 reduces inflammation and collagen accumulation in high-glucose CFs and DCM mice via the Hippo–YAP pathway and CREB.

Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes mellitus, and glomerular sclerosis and renal tubular interstitial fibrosis are the main pathological features. Current evidence indicates that the Notch pathway can mediate the impairment of renal tubular function and induce angiogenesis and renal interstitial fibrosis. This study was conducted to explore the potential signaling pathway through which Notch regulates oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose. mRNA and protein expression levels were assessed using real-time PCR and Western blot, respectively. The protein expression levels of Jaggedl, Notchl, pro-caspase-3, Drpl, and PGC-1α were increased by high glucose, but N-[N-(3,5-difluorohenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT; an inhibitor of the Notch signaling pathway) reversed these effects. Furthermore, DAPT reduced the mRNA expression of Jaggedl, Notchl, MnSOD2, Drpl, and PGC-1α in renal tubular epithelial cells induced by high glucose. In conclusion, the Notch signaling pathway may regulate oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose by regulating mitochondrial dynein and biogenesis genes, which can accelerate renal interstitial fibrosis in DN. The Notch signaling pathway might be a potential therapeutic target for DN, and DAPT might become a potential drug for the treatment of DN.

Diabetic retinopathy (DR) is a primary complication of diabetes mellitus. DR can cause severe vision loss for patients. miR-122 is elevated in DR patients, while its role in DR is unclear. Hence, the purpose of this study was to analyze the effect of miR-122 on the function of high glucose-induced REC cells and the underlying molecular mechanisms. In this study, our results revealed that miR-122 was up-regulated in high glucose-induced human retinal pigment epithelial cells (ARPE-19). High glucose decreased the cell viability of ARPE-19 cells, which was then restored by miR-122 knockdown. In addition, miR-122 knockdown suppressed apoptosis of high glucose-induced ARPE-19 cells. High glucose also inhibited B-cell lymphoma-2 (Bcl-2) level and increased cleaved caspase-3 level in ARPE-19 cells, which were reversed by miR-122 knockdown. Tissue inhibitor of metalloproteinases-3 (TIMP3) was a direct target of miR-122. TIMP3 was decreased in high glucose-induced ARPE-19 cells, and the decrease was abrogated by miR-122 knockdown. In addition, the effects of miR-122 overexpression in cell viability and apoptosis of high glucose-induced ARPE-19 were abolished by overexpression of TIMP3. In conclusion, the effect and mechanism of miR-122 on high glucose-induced ARPE-19 cells were demonstrated for the first time. miR-122 promoted diabetic retinopathy through targeting TIMP3, making miR-122 a promising target for diabetic retinopathy therapy.

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.

Type 2 Diabetes (T2D) has become a serious concern as it contributes to 90% of the total diabetic population. The high glucose levels in diabetic patients result in damage to eyes, kidneys and nerves collectively known as microvascular complications. The paper presents a critical review of existing statistical and machine learning models with respect to such complications namely retinopathy, neuropathy and nephropathy. The statistical tests like chi-square, odds ratio, t-test, ANOVA enables inferential and descriptive analysis. On the other side, machine learning models like support vector machines, k-nearest neighbour, deep neural network, naive bayes also assures predictive analytics. It is worth mentioning that both analytics can reverse impaired glucose regulation early in its course resulting in the prevention of long-term complications associated with T2D. Despite variation in both analytic techniques, their integration in medical health practices can assist patients to effectively adapt a healthy lifestyle and reduce significant healthcare overheads for an individual's family as well as society.

The purpose of this study was to explore the functional implication of microRNA-218 (miR-218) in diabetic nephropathy (DN) through high-glucose-stimulated renal proximal tubule impairment. Biological function experiments showed that miR-218 and inflammatory factors TNF-α and IL-1β were highly expressed in renal proximal tubule under high-glucose conditions. Inhibiting miR-218 alleviated renal tubular cell injury, which was represented by miR-218 inhibitor facilitating renal tubular cell vitality whilst reducing its apoptosis and levels of inflammation factors. In addition, we confirmed that miR-218 directly targeted GPRC5A and negatively regulated its expression. Co-transfection assay showed that overexpression of GPRC5A accentuated the mitigated action of miR-218 inhibitor on renal proximal tubule cell injury induced by high-glucose. Accordingly, these data indicated that downregulation of miR-218 can assuage high-glucose-resulted renal tubular cell damage, and its ameliorative effect was achieved by negative regulation of GPRC5A, which provides a novel direction for unearthing the pathogenesis and even further biological treatment of DN.

Objectives: To investigate the effect of androgens and estrogens on surtuin 1 (SIRT1) expression in human aortic endothelial cells (HAECs). Methods: Real-time polymerase chain reaction analysis of SIRT-1 expression over 48 hours (h) was performed in HAECs treated with various concentrations of dehydroepiandrostendione (DHEA), androstenedione and testosterone (androgens), estrone (E1), estradiol (E2), and estriol (E3) (estrogens) to investigate the dose-dependency of time courses. The influence of high glucose on SIRT1 expression induced by the androgens and estrogens was also examined. Results: Dehydroepiandrostendione, androstenedione, and testosterone remarkably produced a dose-dependent increase in SIRT1 expression in the range of 10 to 20 μg/ml. High glucose (40mM) medium had significantly inhibitory effects on 10 μg/ml DHEA-induced SIRT1 expression (p=0.024). Estrone and E2, but not E3, caused a marked dose-dependent increase in SIRT1 expression from 10 to 20 μg/ml. Treatment with 20 mM or 40 mM glucose medium did not significantly inhibit E1- and E3-induced SIRT1 expression in control medium; however, both high glucose mediums significantly emphasized E2-induced SIRT1 expression in control medium (p=0.007, p=0.005). Conclusion: These results suggest that DHEA, androstenedione, testosterone, E1, and E2 definitely activate SIRT1 expression in HAECs. A high glucose medium is potent to inhibit the basal gene expression; however, it could not reduce powerful androgen- and estrogen-induced SIRT1 expression in HAECs.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM), which results in vision loss. This study explored the role of miR-126 in high-glucose-induced human retinal endothelial cells (HRECs) and its underlying molecular mechanisms. The results showed that the expression levels of miR-126 and interleukin-17A (IL-17A) in high-glucose-induced HRECs were downregulated and upregulated, respectively. Functionally, overexpression of miR-126 promoted proliferation and suppressed apoptosis in high-glucose-induced HRECs, while IL-17A reversed the effects induced by miR-126. However, overexpression of IL-17A inhibited the proliferation and induced apoptosis, while knockdown of IL-17A accelerated the proliferation and repressed apoptosis. In addition, miR-126 repressed the expression of IL-17A, Bax, and caspase-3, while promoting the expression of survivin and phosphorylation of PI3K and AKT; restoration of IL-17A rescued these effects. Furthermore, IL-17A was identified as a target of miR-126. This indicates that miR-126 enhances proliferation and inhibits apoptosis in high-glucose-induced HRECs by activating the PI3K–AKT pathway, increasing survivin levels, and decreasing Bax and caspase-3 expression by targeting IL-17A, suggesting that miR-126 could be a novel target for preventing DR.

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.

Objective: Insulin resistance (IR) is the major cause in Type 2 diabetes mellitus (T2DM). Expression of some miRNAs can be changed in response to a drug treatment for IR, and used as the biomarker in IR. This study set out to determine the effect of cinnamon extract (cinnamaldehyde) on some miRNAs expression in IR adipocytes. Materials and Methods: In this In-vitro study the 3T3L1 cells were expanded in Dulbecco’s modified Eagle’s medium (DMEM), differentiated into adipocytes phenotype and insulin resistant with high glucose medium, then the cells were treated with cinnamaldehyde. To determine of the miRNAs profiling in 3T3L1 adipocytes, insulin-resistant adipocytes and treated insulin-resistant adipocytes quantitative real-time PCR method was performed. Results: IR adipocytes exhibited a significantly increase in miRs 29a, 223 and 320 expression, and decrease in miR26-b expression in compare to the normal adipocytes (P-value

Background: Inflammatory response plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Drugs that carry anti-inflammatory effects have the potential to treat diabeti...

Lei Yang,1 Guangping Zhou,2 Mingyang Li,1 Yan Li,1 Liqing Yang,1 Qin Fu,1 Ye Tian1 1Orthopedics Department, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 2Orthopedics Department, Shenyang Orthopedics Hospital, Shenyang, Liaoning Province, People’s Republic of ChinaCorrespondence: Qin Fu Tel +86-18940251086Email fuqsj_hospital@126.comPurpose: Osteocyte network structure correlates with bone material quality. This network is profoundly altered in diabetic mice; however, the underlying mechanisms are unknown. The gap junction protein connexin 43 (Cx43) is necessary for normal osteocyte function and osteocyte network formation. Here, we evaluated Cx43 expression in patients with diabetes, the effect of high glucose on Cx43 expression, and the function of Cx43 gap junctions and hemichannels in osteocyte-like MLO-Y4 (MLO-Y4) cells.Patients and Methods: Human cortical bone samples were obtained from patients with or without type II diabetes mellitus (T2DM) who underwent arthroplasty surgery to treat osteoporosis-induced femoral neck fracture.Cx43 expression was quantified in human cortical bone samples from both groups of patients and MLO-Y4 cells. The functions of Cx43 gap junctions and hemichannels in MLO-Y4 cells were evaluated using dye transfer and dye uptake assays, respectively. Furthermore, we evaluated levels of membrane Cx43 (mCx43), the functional form, and p38MAPK/ERK1/2 signaling, which is involved in mCx43 internalization, to characterize the mechanism of decreased Cx43 expression and gap junctions and hemichannels function.Results: Osteocyte Cx43 expression was decreased in femoral neck cortical bone samples of patients with T2DM patients compared with the non-diabetic control group. In addition, Cx43 expression was decreased in MLO-Y4 cells treated with high glucose. The functions of Cx43 gap junctions and hemichannels were inhibited in MLO-Y4 cells treated with high glucose. mCx43 expression was decreased in response to activation of p38-MAPK/ERK signaling. Inhibition of the p38-MAPK/ERK pathway partially reversed the decreases in Cx43 hemichannels and gap-junctions function.Conclusion: High glucose dampened Cx43 gap junction and hemichannel function in MLO-Y4 cells by activating the p38MAPK/ERK pathway leading to subsequent mCx43 internalization.Keywords: high glucose, osteocyte, connexin 43, gap junction, hemichannel

The inhibition of high glucose on the proliferation and differentiation of osteoblast in alveolar bone are well documented. However, a comprehensive study focused on the molecular mechanisms is still unknown. Recent studies have revealed that caspase-1 participates in the pathological processes of hepatic injury, cancers and diabetes related complications. However, the relationship between pyroptosis and proliferation and differentiation of osteoblasts has not been investigated. This study aimed to explore the possible pyroptosis participating in the inhibition of high glucose on the proliferation and differentiation of osteoblast in alveolar bone. The diabetes model was constructed both in vitro and in vivo to detect the expression of pyroptosis related factors. These results show that high glucose inhibits proliferation and differentiation of osteoblast in alveolar bone through pyroptosis pathway. Furthermore, caspase-1 inhibitor was co-administered with high glucose in ME3T3-E1 cells, which shows that caspase-1 inhibitor could repress effect of high glucose on the proliferation and differentiation of osteoblast. In conclusion, High glucose could activate the pyroptosis through the caspase-1/GSDMD/IL-1β pathway to inhibit the proliferation and differentiation of osteoblast in alveolar bone, which provides a theoretical basis for clinical treatment of alveolar bone disease in diabetic patients.

espanolIntroduccion El trastorno depresivo mayor (TDM) es una enfermedad prevalente a nivel mundial, que afecta mas a mujeres que a hombres. En la genesis de la depresion se consideran diversos factores, entre ellos algunas hormonas como la testosterona y ciertos factores metabolicos Objetivo Evaluar los niveles de hormonas y variables metabolicas en mujeres con depresion mayor y controles sanas. Metodo Se realizo un estudio transversal, comparativo y analitico en 40 participantes, 23 pacientes con diagnostico de TDM y 17 controles, todas ellas mujeres de 18 a 45 anos en periodo reproductivo. Se evaluaron variables sociodemograficas, perfil hormonal y variables metabolicas, y se aplico la Escala de Depresion de Hamilton de 17 reactivos para evaluar los sintomas depresivos. Resultados No se observaron diferencias estadisticamente significativas entre los grupos en las variables hormonales y metabolicas exploradas. Sin embargo, se observo que, cuanto menores eran los niveles de testosterona y mayores los de glucosa serica, los sintomas depresivos eran de mayor intensidad. Discusion y conclusion La testosterona se asocia con un menor puntaje de sintomas depresivos en la Escala Hamilton, lo que sugiriere un potencial efecto antidepresivo, mientras que los niveles altos de glucosa se asocian con un mayor puntaje en dicha escala. Consideramos que la medicion de variables hormonales y metabolicas en la mujer puede contribuir a mejorar el conocimiento de la fisiopatologia de la depresion. EnglishIntroduction: major depressive disorder (MDD) is a prevalent disease affecting women more than men worldwide. Various factors are involved in the genesis of depression, including hormones such as testosterone and certain metabolic factors Objective: to evaluate hormone levels and metabolic variables in women with major depression and healthy controls. Method: a cross-sectional, comparative analytical study was conducted in 40 participants, 23 patients with an MDD diagnosis and 17 controls, all of women in reproductive age between the ages of 18 and 45. Sociodemographic variables, hormonal profile, and metabolic variables were assessed and the 17-item Hamilton Depression Scale was used to evaluate depressive symptoms. Results: no statistically significant differences were observed between the groups in the hormonal and metabolic variables explored. Nevertheless, it was observed that the lower the testosterone levels and the higher the serum glucose levels, the more intense depressive symptoms were. Discussion and conclusion: testosterone is associated with a lower depressive symptoms score on the Hamilton Depression scale, suggesting a potential antidepressant effect, whereas high glucose levels are associated with a higher score on this scale. We believe that the measurement of hormonal and metabolic variables in women can contribute to a better understanding of the pathophysiology of depression.

Renal proximal tubular angiotensinogen (AGT) is increased by hyperglycemia (HG) in diabetes mellitus, which augments intrarenal angiotensin II formation, contributing to the development of hypertension and kidney injury. Sodium-glucose cotransporter 2 (SGLT2) is abundantly expressed in proximal tubular cells (PTCs). The present study investigated the effects of canagliflozin (CANA), a SGLT2 inhibitor, on HG-induced AGT elevation in cultured PTCs. Mouse PTCs were treated with 5–25 mM glucose. CANA (0–10 µM) was applied 1 h before glucose treatment. Glucose (10 mM) increased AGT mRNA and protein levels at 12 h (3.06 ± 0.48-fold in protein), and 1 and 10 µM CANA as well as SGLT2 shRNA attenuated the AGT augmentation. CANA did not suppress the elevated AGT levels induced by 25 mM glucose. Increased AGT expression induced by treatment with pyruvate, a glucose metabolite that does not require SGLT2 for uptake, was not attenuated by CANA. In HG-treated PTCs, intracellular reactive oxygen species levels were elevated compared with baseline (4.24 ± 0.23-fold), and these were also inhibited by CANA. Furthermore, tempol, an antioxidant, attenuated AGT upregulation in HG-treated PTCs. HG-induced AGT upregulation was not inhibited by an angiotensin II receptor antagonist, indicating that HG stimulates AGT expression in an angiotensin II-independent manner. These results indicate that enhanced glucose entry via SGLT2 into PTCs elevates intracellular reactive oxygen species generation by stimulation of glycolysis and consequent AGT augmentation. SGLT2 blockade limits HG-induced AGT stimulation, thus reducing the development of kidney injury in diabetes mellitus.

Objective: This report was designed to assess the functional role of miR-218/dachshund family transcription factor 1 (DACH1) in diabetic kidney disease (DKD) and investigate its possible molecular mechanism. Materials and Methods: From the GEO database, we downloaded different datasets for analyzing the expression of miR-218 and DACH1 in DKD. TargetScan was adopted to predict the binding sites between miR-218 and DACH1, which was further verified by dual-luciferase reporter assays. The renal proximal tubule cells (HK-2) treated with high glucose (HG) were used as an in vitro model. QRT-PCR and western blot were used to determine the expression of DACH1 and other relative factors. Cell counting kit-8 and flow cytometer were applied to detect cell viability and apoptosis. The levels of inflammatory cytokines were determined by an ELISA assay. Results: A prominent raise of miR-218 was observed in DKD through bioinformatics analysis, which was further confirmed in the HG-induced model. DACH1 is a target of miR-218. miR-218 reduced cell viability and induced apoptosis by negatively regulating DACH1. Moreover, upregulating miR-218 in HG models increased the concentrations of pro-inflammatory cytokines TNF-α and IL-1β, reduced the level of anti-inflammatory cytokine IL-10, and promoted the epithelial-mesenchymal transition (EMT) process, which is possibly achieved by targeting DACH1. While downregulating miR-218 showed the opposite results. Conclusion: These data demonstrated that, under an in vitro HG environment, miR-218 suppressed the HK-2 cells proliferation, promoted apoptosis, caused an inflammatory response, and facilitated the EMT process largely by targeting DACH1, providing an insight into the therapeutic intervention of DKD.

Diabetic retinopathy (DR) is the leading cause of decreased vision and blindness globally. The aim of this study was to understand the role of physcion 8-O-β-glucopyranoside (PG) in high glucose (HG)-induced DR and to investigate whether lncRNA NORAD/miR-125/STAT3 signalling was the underlying mechanism involved in DR. To this end, the serum levels of NORAD, miR-125, and STAT3 were determined in patients with DR. The APRE-19 cells were subjected to HG treatment to construct the cell model of DR. HG-disposed APRE-19 cell injury was assessed by detecting cell viability, apoptosis, concentrations of pro-inflammatory cytokines including TNF-α and IL-1β, and ROS generation. Moreover, the effect of PG on HG-disposed APRE-19 cell injury was investigated. NORAD was then overexpressed to investigate the combined effects of NORAD overexpression and PG on HG-disposed APRE-19 cell injury. Furthermore, the regulatory relationship between NORAD and miR-125 as well as miR-125 and STAT3 was investigated. The expression levels of NORAD and STAT3 were significantly increased in the serum of DR patients, while the miR-125 expression was decreased. The HG treatment-induced injury to APRE-19 cells, which were alleviated by PG treatment. Moreover, PG alleviated HG-disposed injury to ARPE-19 cells by decreasing NORAD. NORAD negatively regulated miR-125 expression and the combined effects of NORAD and PG on HG-disposed ARPE-19 cell injury were reversed by miR-125 overexpression. Furthermore, STAT3 was confirmed as a target gene of miR-125. Our results show that PG exerts protective roles in HG-disposed DR

AIMS: To investigate whether single use of 4 mm needles combined with education about injection technique and lipohypertrophy affects HbA1c, hypoglycaemia and glucose variability. METHODS: Insulin-injecting people with diabetes recruited from nine Belgian diabetes centres were prospectively followed for 6 months. They were provided 4 mm pen needles and education concerning injection technique using an online platform (BD and Me™) based on the international Forum for Injection Technique & Therapy Recommendations focused on avoidance of lipohypertrophy zones and reduction of needle reuse. RESULTS: A total of 171 people with diabetes were included of which 146 completed the study. At baseline, lipohypertrophy was present in 63.0% of those who completed the study, with 51.4% injecting in zones of lipohypertrophy, 37.0% incorrectly rotating and 95.9% reusing needles. After the intervention, 7.5% still injected in a lipohypertrophy zone, 4.1% rotated incorrectly and needle reuse decreased to 21.2%. The number of participants with severe hypoglycaemias (from 15.8% to 4.1%, p < 0.001), unexplained hypoglycaemias (from 46.6% to 16.4%, p < 0.001) and high glucose variability (from 64.4% to 29.5%, p < 0.001) was significantly reduced. HbA1c and total daily insulin dose remained stable. CONCLUSION: The combination of 4 mm pen needles and online education on injection techniques significantly reduced the number of people with severe hypoglycaemic episodes, unexplained hypoglycaemia and high glucose variability but did not improve HbA1c control nor lower insulin needs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04659330.

AIM: To investigate the effect of high concentration of glucose (HCG) on double stranded RNA-activated protein kinase-like ER kinase (PERK)-eukaryotic initiation factor-2α (eIF2α)-transcription factor C/EBP homologous protein (CHOP)-cysteine aspartate specific proteinase (caspase-12) signaling pathway activation and apoptosis in rabbit corneal epithelial cells (RCECs). METHODS: RCECs were treated by different concentrations of glucose for 0-48h. The expressions of PERK, p-PERK, eIF2α, p-eIF2α, 78 kDa glucose-regulated protein 78 (GRP78), CHOP, B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-2-associated X protein (Bax) and caspase-12 were determined by Western blot. Apoptosis was detected by TUNEL assay. Meanwhile, the function of PERK-eIF2α-CHOP-caspase-12 signaling pathway activation in high glucose-induced apoptosis was evaluated using PERK inhibitor, GSK2606414. RESULTS: HCG significantly promoted the expression of p-PERK, p-eIF2α, GRP78, CHOP, Bax and cleaved caspase-12 in RCECs (P0.05). TUNEL assay showed that the apoptosis rate of RCECs in the HCG group increased significantly in contrast with that in the normal concentration of glucose or osmotic pressure control group (P0.05). Correspondingly, GSK2606414 also significantly reduced the apoptosis rate induced by high glucose (P

BackgroundAstragaloside IV (AS-IV) was reported to play a role in improving diabetic nephropathy (DN), however, the underlying mechanisms still remain unclear. The aim of the present study is to investigate whether AS-IV ameliorates DN via the regulation of endothelial nitric oxide synthase (eNOS).MethodsDN model was induced in Sprague-Dawley (SD) male rats by intraperitoneal injection of 65 mg/kg streptozotocin (STZ). Rats in the AS-IV treatment group were orally gavaged with 5 mg/kg/day or 10 mg/kg/day AS-IV for eight consecutive weeks. Body weight, blood glucose, blood urea nitrogen (BUN), Serum creatinine (Scr), proteinuria and Glycosylated hemoglobin (HbA1c) levels were measured. Hematoxylin-Eosin (HE) and Periodic Acid-Schiff (PAS) staining were used to detect the renal pathology. The apoptosis status of glomerular cells was measured by TUNEL assay. The phosphorylation and acetylation of eNOS were detected by western blot. The effects of AS-IV on high-glucose (HG)-induced apoptosis and eNOS activity were also investigated in human renal glomerular endothelial cells (HRGECs) in vitro.ResultsTreatment with AS-IV apparently reduced DN symptoms in diabetic rats, as evidenced by reduced BUN, Scr, proteinuria, HbA1c levels and expanding mesangial matrix. AS-IV treatment also promoted the synthesis of nitric oxide (NO) in serum and renal tissues and ameliorated the phosphorylation of eNOS at Ser 1177 with decreased eNOS acetylation. Moreover, HG-induced dysfunction of HRGECs including increased cell permeability and apoptosis, impaired eNOS phosphorylation at Ser 1177, and decreased NO production, were all reversed by AS-IV treatment.ConclusionsThese novel findings suggest that AS-IV ameliorates functional abnormalities of DN through inhibiting acetylation of eNOS and activating its phosphorylation at Ser 1177. AS-IV could be served as a potential therapeutic drug for DN.

Diabetes induces vascular endothelial damage and this study investigated high-glucose-induced inflammation “metabolic memory” of human retinal vascular endothelial cells (HRVECs), the effects of resveratrol on HRVECs, and the underlying signaling. HRVECs were grown under various conditions and assayed for levels of sirtuin 1 (SIRT1); acetylated nuclear factor κB (Ac-NF-κB); NOD-like receptor family, pyrin domain containing 3 (NLRP3); and other inflammatory cytokines; and cell viability. A high glucose concentration induced HRVEC inflammation metabolic memory by decreasing SIRT1 and increasing Ac-NF-κB, NLRP3, caspase 1, interleukin-1β, inducible nitric oxide synthase, and tumor necrosis factor α, whereas exposure of HRVECs to a high glucose medium for 4 days, followed by a normal glucose concentration for an additional 4 days, failed to reverse these changes. A high glucose concentration also significantly reduced HRVEC viability. In contrast, resveratrol, a selective SIRT1 activator, markedly enhanced HRVEC viability and reduced the inflammatory cytokines expressions. In addition, high glucose reduced AMP-activated protein kinase (AMPK) phosphorylation and retained during the 4 days of the reversal period of culture. The effects of resveratrol were abrogated after co-treatment with the SIRT1 inhibitor nicotinamide and the AMPK inhibitor compound C. In conclusion, resveratrol was able to reverse high-glucose-induced inflammation “metabolic memory” of HRVECs by activation of the SIRT1/AMPK/NF-κB pathway.

Background: Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function.Methods: In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and by Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. Results: CD34+ HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation and CXCR4/SDF-1α axis activity from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9-39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects. Conclusion: We provided the first evidence that CD34+ HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients.

This study aims at evaluating the effect of high glucose intake as a component of total parenteral nutrition on birth weight (BW) regain in very low birth weight neonates. Ninety newborns with BW

Background:High glucose is critical for diabetes.But in which way it induces diabetes, and which organ trigger the formation of diabetes are not clear.The goal of this study is to see if there is a risk of acquiring diabetic symptoms following a 2 weeks short infusion of 2g/kg/day and dietary 2.5g/kg/day in SD rats on various body organs.Methods：Twelve weeks old SD rats were randomly divided into control group,high glucose infusion group(IHG,infusion 2g/kg/day) and oral high glucose group OHG,dietary 2.5g/kg/day).Fasten blood sugar,TNF-a and IL-6 were measured. Intestine and liver samples were collected for pathological examination.Feces of rats were collected for gut microbiota tests.Results：The results indicated that short time high glucose induced hyperglycemia lasted for at least 2 weeks after ceasing of high glucose.It increased serum levels of IL-6 and TNF-a obviously.It led to jejunum mucosa injury, obvious steatosis of hepatocytes, and disturbed the balance of gut microbiota.OHG led to swelling and necrosis of individual intestinal villi.IHG led to necrosis and disappearence of cells in the upper layer of intestinal mucosa.The lesion was confined to the mucosa.Conclusions:Short time high glucose induced lesion in liver and intestine,disturbed the balance of gut microbiota and consequently induced inflammation and triggered diabetes.

Objective Hyperglycemia is associated with albuminuria and renal glomerular endothelial dysfunction in patients with diabetic nephropathy. The mTOR and RhoA/ROCK signaling pathways are involved in glomerular filtration barrier (GFB) regulation, but their role in high glucose (HG)-induced GFB dysfunction in human renal glomerular endothelial cells (HRGECs) has not been investigated. This study aimed to investigate the mechanisms of HG-induced GFB dysfunction in vitro. Materials and methods HRGECs were cultured in vitro and exposed to HG. The horseradish peroxidase–albumin leakage and transendothelial electrical resistance of the endothelial monolayer were measured after HG treatment with or without rapamycin preincubation. A fluorescence probe was used to study the distribution of F-actin reorganization. The phosphorylation levels of myosin light chain (MLC) and mTOR were measured via western blotting. RhoA activity was evaluated via GTPase activation assay. The effects of blocking mTOR or the RhoA/ROCK pathway on endothelial permeability and MLC phosphorylation under HG conditions were observed. Results HG exposure induced F-actin reorganization and increased MLC phosphorylation, leading to EC barrier disruption. This effect was attenuated by treatment with rapamycin or Y-27632. Phospho-MLC (pMLC) activation in HRGECs was mediated by RhoA/ROCK signaling. mTOR and RhoA/ROCK inhibition or knockdown attenuated pMLC activation, F-actin reorganization and barrier disruption that occurred in response to HG exposure. Conclusions Our results revealed that HG stimulation upregulated RhoA expression and activity through an mTOR-dependent pathway, leading to MLC-mediated endothelial cell cytoskeleton rearrangement and glomerular endothelial barrier dysfunction.

Hyperglycemia is a condition with high glucose levels that may result in dyslipidemia. In severe cases, this alteration may lead to diabetic retinopathy. Numerous drugs have been approved by officials to treat these conditions, but usage of any synthetic drugs in the long term will result in unavoidable side effects such as kidney failure. Therefore, more emphasis is being placed on natural ingredients due to their bioavailability and absence of side effects. In regards to this claim, promising results have been witnessed in the usage of Ipomoea batatas (I. batatas) in treating the hyperglycemic and dyslipidemic condition. Thus, the aim of this paper is to conduct an overview of the reported effects of I. batatas focusing on in vitro and in vivo trials in reducing high glucose levels and regulating the dyslipidemic condition. A comprehensive literature search was performed using Scopus, Web of Science, Springer Nature, and PubMed databases to identify the potential articles on particular topics. The search query was accomplished based on the Boolean operators involving keywords such as (1) Beneficial effect OR healing OR intervention AND (2) sweet potato OR Ipomoea batatas OR traditional herb AND (3) blood glucose OR LDL OR lipid OR cholesterol OR dyslipidemia. Only articles published from 2011 onwards were selected for further analysis. This review includes the (1) method of intervention and the outcome (2) signaling mechanism involved (3) underlying mechanism of action, and the possible side effects observed based on the phytoconstiuents isolated. The comprehensive literature search retrieved a total of 2491 articles using the appropriate keywords. However, on the basis of the inclusion and exclusion criteria, only 23 articles were chosen for further review. The results from these articles indicate that I. batatas has proven to be effective in treating the hyperglycemic condition and is able to regulate dyslipidemia. Therefore, this systematic review summarizes the signaling mechanism, mechanism of action, and phytoconstituents responsible for those activities of I. batatas in treating hyperglycemic based on the in vitro and in vivo study.

Diabetes is exploding and pandemic all over the world. High glucose peaks cause vessel wall damage, especially in the microvasculature. The retina is particularly susceptible since it is the most oxygen-consuming tissue in the body. Retinal deterioration leads to blindness, and it is estimated that 4% of diabetics will go blind at some point. Microaneurysms, haemorrhages, hard and soft exudates are few biomarkers on retinal vasculature, to identify Diabetic retinopathy. The diameter or width of retinal vessels is also a key indicator of blood flow and metabolism in the retina. The goal of this research is to employ deep learning algorithms to efficiently segment, classify and assess the retinal vascular diameters of a healthy and diabetic individual and to look at how these methodologies contribute to the identification of diabetic retinopathy and may be used as a predictor of disease diagnosis. U-Net architecture for segmentation of vessels, SVM for classification of vessels as arteries and veins and VAMPIRE for the assessment of vascular diameters are proposed in this research work.

High glucose and fructose intake have been proven to display pro-inflammatory roles during the progression of inflammatory diseases. However, mannose has been shown to be a special type of hexose that has immune regulatory functions. In this review, we trace the discovery process of the regulatory functions of mannose and summarize some past and recent studies showing the therapeutic functions of mannose in inflammatory diseases. We conclude that treatment with mannose can suppress inflammation by inducing regulatory T cells, suppressing effector T cells and inflammatory macrophages, and increasing anti-inflammatory gut microbiome. By summarizing all the important findings, we highlight that mannose treatment is a safe and promising novel strategy to suppress inflammatory diseases, including autoimmune disease and allergic disease.

Background High-fat-high-fructose (HFHF) intake contributes to developing type 2 diabetes mellitus (T2DM) as a comorbid. Intermittent fasting in Islam, such as Ramadan fasting (RF), Dawood fasting (DF), and Monday-Thursday fasting (MTF), have been suggested that ameliorate glucose levels. However, there has been no research investigating the effects of DF and MTF on glucose levels. This study investigates the effect of fasting in Islam on glucose level changes in HFHF-induced rats. Methods Twenty-five 8-week-old male Wistar rats were randomly divided into five groups after acclimatisation for seven days. Group 1 was maintained as standard diet control; Group 2 was maintained as HFHF control diet; Group 3 was treated with RF, which fasted every day; Group 4 treated with DF, which on the 1st day performed fasting (no food and drink), the 2nd day is not performed fasting (free to eat and drink), and the 3rd day is performed fasting again and repeated so on; Group 5 was treated with MTF which fasted only on Mondays and Thursdays. The treatment group fasted after 14 days of HFHF induced, with a fasting duration of 14 hours (17:00 to 07:00), for 29 days. Glucose measurement is performed after HFHF induction (pre-test) and after fasting treatment (post-test). The data was analysed using paired-samples T-test. Results After fasting treatment, glucose levels decreased significantly in the Group 3 (p=0,012), Group 4 (p=0.042), and Group 5 (p=0.008) compared to pre-tests. Meanwhile, Group 1 and Group 2 did not show any significant changes in glucose levels (p>0,05) (IDDF2021-ABS-0029 Figure 1. Glucose levels). Conclusions This result suggests a new insight into fasting in Islam, RF, DF, and MTF can be an alternative in lowering high glucose levels caused by HFHF.