A sensitivity indicator screening and intelligent classification method for the diagnosis of T2D-CHD.

Background: The prevalence of Type 2 Diabetes Mellitus (T2D) and its significant role in increasing Coronary Heart Disease (CHD) risk highlights the urgent need for effective CHD screening within this population. Despite current advancements in T2D management, the complexity of cardiovascular complications persists. Our study aims to develop a comprehensive CHD screening model for T2D patients, employing multimodal data to improve early detection and management, addressing a critical gap in clinical practice. Methods: We analyzed data from 699 patients, including 471 with CHD (221 of these also had T2D) and a control group of 228 without CHD. Employing strict diagnostic criteria, we conducted significance testing and multivariate analysis to identify key indicators for T2D-CHD diagnosis. This led to the creation of a neural network model using 21 indicators and a logistic regression model based on an 8-indicator subset. External validation was performed with an independent dataset from an additional 212 patients to confirm the models' generalizability. Results: The neural network model achieved an accuracy of 90.7%, recall of 90.78%, precision of 90.83%, and an F-1 score of 0.908. The logistic regression model demonstrated an accuracy of 90.13%, recall of 90.1%, precision of 90.22%, and an F-1 score of 0.9016. External validation reinforced the models' reliability and effectiveness in broader clinical settings. Conclusion: Our AI-driven diagnostic models significantly enhance early CHD detection and management in T2D patients, offering a novel, efficient approach to addressing the complex interplay between these conditions. By leveraging advanced analytics and comprehensive patient data, we present a scalable solution for improving clinical outcomes in this high-risk population, potentially setting a new standard in personalized care and preventative medicine.

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation.

The receptor for advanced glycation end products (RAGE) contributes to diabetes-associated cognitive dysfunction (DACD) through the interaction of its C-terminal AAs 2-5 with mitogen-activated protein kinase kinase 3 (MKK3). However, the associated MKK3 binding site is unknown. Here, db/db mice were used as a model for type 2 diabetes. GST pull-down assays and AutoDock Vina simulations were conducted to identify the key RAGE binding site in MKK3. This binding site was mutated to investigate its effects on DACD and to elucidate the underlying mechanisms. The interaction of MKK3 and RAGE, the levels of inflammatory factors, and the activation of microglia and astrocytes were tested. Synaptic morphology and plasticity in hippocampal neurons were assessed via electrophysiological recordings and Golgi staining. Behavioral tests were used to assess cognitive function. In this study, MKK3 bound directly to RAGE via its lysine 329 (K329), leading to the activation of the nuclear factor-κB (NF-κB) signaling pathway, which in turn triggered neuroinflammation and synaptic dysfunction, and ultimately contributed to DACD. MKK3 mutation at K329 reversed synaptic dysfunction and cognitive deficits by downregulating the NF-κB signaling pathway and inhibiting neuroinflammation. These results confirm that neuroinflammation and synaptic dysfunction in the hippocampus rely on the direct binding of MKK3 and RAGE. We conclude that MKK3 K329 binding to C-terminal RAGE (ct-RAGE) is a key mechanism by which neuroinflammation and synaptic dysfunction are induced in the hippocampus. This study presents a novel mechanism for DACD and proposes a novel therapeutic avenue for neuroprotection in DACD.

Binding of RAGE and RIPK1 induces cognitive deficits in chronic hyperglycemia-derived neuroinflammation.

AIMS: Chronic hyperglycemia-induced inflammation of the hippocampus is an important cause of cognitive deficits in diabetic patients. The receptor for advanced glycation end products (RAGE), which is widely expressed in the hippocampus, is a crucial factor in this inflammation and the associated cognitive deficits. We aimed to reveal the underlying mechanism by which RAGE regulates neuroinflammation in the pathogenesis of diabetes-induced cognitive impairment. METHODS: We used db/db mice as a model for type 2 diabetes to investigate whether receptor-interacting serine/threonine protein kinase 1 (RIPK1), which is expressed in microglia in the hippocampal region, is a key protein partner for RAGE. GST pull-down assays and AutoDock Vina simulations were performed to identify the key structural domain in RAGE that binds to RIPK1. Western blotting, co-immunoprecipitation (Co-IP), and immunofluorescence (IF) were used to detect the levels of key proteins or interaction between RAGE and RIPK1. Cognitive deficits in the mice were assessed with the Morris water maze (MWM) and new object recognition (NOR) and fear-conditioning tests. RESULTS: RAGE binds directly to RIPK1 via the amino acid sequence (AAs) 362-367, thereby upregulating phosphorylation of RIPK1, which results in activation of the NLRP3 inflammasome in microglia and ultimately leads to cognitive impairments in db/db mice. We mutated RAGE AAs 362-367 to reverse neuroinflammation in the hippocampus and improve cognitive function, suggesting that RAGE AAs 362-367 is a key structural domain that binds directly to RIPK1. These results also indicate that hyperglycemia-induced inflammation in the hippocampus is dependent on direct binding of RAGE and RIPK1. CONCLUSION: Direct interaction of RAGE and RIPK1 via AAs 362-367 is an important mechanism for enhanced neuroinflammation in the hyperglycemic environment and is a key node in the development of cognitive deficits in diabetes.

Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE2 synthase but can metabolize PGH2 to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPGES-2 in AKI remain unclear. To examine the role of mPGES-2, both global and tubule-specific mPGES-2-deficient mice were treated with cisplatin to induce AKI. mPGES-2 knockdown or overexpressing HK-2 cells were exposed to cisplatin to cause acute renal tubular cell injury. The mPGES-2 inhibitor SZ0232 was used to test the translational potential of targeting mPGES-2 in treating AKI. Additionally, mice were subjected to unilateral renal ischemia/reperfusion to further validate the effect of mPGES-2 on AKI. Interestingly, both genetic and pharmacological blockage of mPGES-2 led to decreased renal dysfunction and morphological damage induced by cisplatin and unilateral renal ischemia/reperfusion. Mechanistic exploration indicated that mPGES-2 deficiency inhibited ferroptosis via the heme-dependent regulation of the p53/SLC7A11/GPX4 axis. The present study indicates that mPGES-2 blockage may be a promising therapeutic strategy for AKI.

Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.

AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.

Exploring the molecular targets for Type 2 diabetes-induced Alzheimer's disease through bioinformatics analysis.

Aim: The purpose of this study was to elucidate the potential mechanisms of Alzheimer's disease (AD) induced by Type 2 diabetes mellitus (T2DM) through bioinformatics analysis, to provide new treatment targets for this disease. Methods: We used weighted gene coexpression network analysis and differentially expressed genes analysis to identify significantly differentially expressed genes shared by T2DM and AD. Molecular docking was used to predict possible protein targets for T2DM-induced AD. Results: The direct interaction of CD44 and STAT3 may play a significant role in the development of T2DM-induced AD. Conclusion: A new approach to treating T2DM-associated AD may be provided by these hub genes and their predicted molecular targets.

Targeting mTOR/YY1 signaling pathway by quercetin through CYP7A1-mediated cholesterol-to-bile acids conversion alleviated type 2 diabetes mellitus induced hepatic lipid accumulation.

BACKGROUND: Hepatic lipid accumulation was a major promoter for the further development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2DM). mTOR/YY1 signaling pathway regulated many metabolic processes in different organs, and played an important role in hepatic lipid metabolism. Thus, targeting mTOR/YY1 signaling pathway might be a novel therapeutic strategy of T2DM-associated NALFD. PURPOSE: To investigate the effects and the mechanism of quercetin against T2DM-associated NAFLD. STUDY DESIGN AND METHODS: The combine abilities of 24 flavonoid compounds with mTOR were detected by computer virtual screening (VS) and molecular modeling. mTOR/YY1 signaling pathway was examined in the liver of db/db mice, and high glucose (HG) and free fatty acid (FFA) co-cultured HepG2 cells. YY1 overexpression lentivirus vector and mTOR specific inhibitor rapamycin were used to further identify the indispensable role of mTOR/YY1 signaling pathway in quercetin's amelioration effect of hepatic lipid accumulation in vitro. Clinical studies, luciferase assay and chromatin immunoprecipitation (ChIP) assay were all carried out to investigate the potential mechanisms by which quercetin exerted its amelioration effect of hepatic lipid accumulation. RESULTS: Quercetin had the strongest ability to combine with mTOR and could competitively occupy its binding pocked. Along with the alleviated hepatic injury by quercetin, mTOR/YY1 signaling pathway was down-regulated in vivo and in vitro. However, the alleviation effect of quercetin against hepatic lipid accumulation was inhibited by YY1 overexpression in vitro. Mechanistically, the down-regulated nuclear YY1 induced by quercetin directly bound to CYP7A1 promoter and activated its transcription, resulting in the restoration of cholesterol homeostasis via the conversion of cholesterol-to-bile acids (BAs). CONCLUSION: The hepatoprotective effect of quercetin on T2DM-associated NAFLD was linked to the restoration of cholesterol homeostasis by the conversion of cholesterol-to-BAs via down-regulating mTOR/YY1 signaling pathway, leading to the increased CYP7A1 activity.

Diagnosis, treatment and genetic analysis of a case with fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a rare type of diabetes mellitus with both impaired endocrine and exocrine functions of the pancreas. In this report, we presented a case with FCPD, who had recurrent abdominal pain since early childhood and was diagnosed with diabetes mellitus at the age of 25, with pancreatic calcification on abdominal computed tomography (CT) scan. Genetic testing revealed two homozygous mutations in the SPINK1 gene (c.194+2T>C and -191-24G>A). Both the homozygous variants were shared by his unaffected sibling, and the heterozygous variants had been verified on their unaffected parents. Based on this case and 90 other reported cases in China, we retrospectively analyzed the clinical characteristics of FCPD. It is recommended that unclassified diabetic patients with a lean body type, no ketosis tendency but poor islet function should be considered for the possibility of FCPD. Pancreatic imaging and genetic testing may be beneficial for the differential diagnosis. This study improves our understanding and management of FCPD, and also enriches clinical evidence for subsequent research on pathogenic mechanisms and drug target screening.

Treadmill exercise training alleviates diabetes-induced depressive-like behavior and cognitive impairment by improving hippocampal CA1 neurons injury in db/db mice.

Patients with diabetes mellitus (DM) have an increased risk of diabetic encephalopathy symptoms such as depressive-like behaviour and cognitive impairment. Exercise is an effective strategy for preventing and treating DM and diabetic complications. The aim of this study is to investigate the effects and potential mechanisms of treadmill exercise training on diabetes-induced depressive-like behavior and cognitive impairment in db/db mice. In this study, the mice were divided into three groups (n = 10 per group) as follows: healthy-sedentary (db/m), diabetes-sedentary (db/db), and diabetes-treadmill exercise training (db/db-TET). The db/db-TET mice were performed five days per week at a speed of 8 m/min for 60 min/day for 8 weeks, following which body weight, fasting blood glucose, insulin resistance, behavioral, synaptic ultrastructure, oxidative stress, apoptotic signaling, and inflammatory responses were evaluated. As a result, treadmill exercise training significantly decreased body weight and fasting blood glucose levels, increased insulin sensitivity, protected synaptic ultrastructure, reduced depression-like behavior, and improved learning and memory deficits in db/db mice. In addition, treadmill exercise training significantly suppressed NOX2-mediated oxidative stress, resulting in a decrease in NOX2-dependent ROS generation in the db/db mouse hippocampus CA1 region. Reduced ROS generation prevented the apoptotic signaling pathway and NLRP3 inflammasome activation, thereby ameliorating hippocampus neuronal damage. In summary, the results indicated that treadmill exercise training significantly ameliorates hippocampus injury by suppressing oxidative stress-induced apoptosis and NLRP3 inflammasome activation, consequently ameliorating diabetes-induced depressive-like behavior and cognitive impairment in db/db mice.

Aerobic exercise training alleviates renal injury in db/db mice through inhibiting Nox4-mediated NLRP3 inflammasome activation.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, with few therapeutic options available to slow its progression. Aerobic exercise training is an effective strategy for diabetes mellitus and its complications' prevention and treatment. The purpose of this study was to determine the effects of aerobic exercise training on diabetic kidney injury in db/db mice and to characterize the mechanism underlying the renal protective effects. The db/db mice were exercised 5 days a week for 60 min each day for 8 weeks at a speed of 5.6 m/min, after which renal function, morphology, oxidative stress, inflammation, fibrosis, and the expression of the Nox4/ROS/NF-κB/NLRP3 signaling pathway-related protein were assessed. Our results showed that aerobic exercise training significantly reduced body weight and microalbuminuria, improved renal function, and attenuated renal pathological changes in db/db mice independent of hyperglycemic state. Aerobic exercise training was also found to significantly improve oxidative stress and inflammation in the kidneys of db/db mice by decreasing the activity of complex I, the levels of MDA, 8-OHdG, Nox4, ROS, TNF-α, MCP-1, IL-6, and IL-18, increasing the activities of SOD and GSH-Px, the expression of klotho and NPHS2, and decreasing the phosphorylation of NF-κB p65 and IκBα, as well as the expression of NLRP3, ASC, caspase-1 p20, and IL-1ß. Additionally, aerobic exercise training decreased TGF-ß, collagen I, collagen IV, and α-SMA expression, thereby slowing the progression of kidney fibrosis in db/db mice. In conclusion, aerobic exercise training effectively reduces oxidative stress, inflammation, and renal fibrosis by modulating the Nox4/ROS/NF-κB/NLRP3 signaling pathway, implying that aerobic exercise training has significant potential to protect diabetic kidney injury and should be given more emphasis in DKD treatment.

Preoperative platelet distribution width-to-platelet ratio combined with serum thyroglobulin may be objective and popularizable indicators in predicting papillary thyroid carcinoma.

OBJECTIVES: The incidence of papillary thyroid carcinoma (PTC) has increased more rapidly than that of any other cancer type in China. Early indicators with high sensitivity and specificity during diagnosis are required. To date, there has been a paucity of studies investigating the relationship between preoperative platelet distribution width-to-platelet count ratio (PPR) and PTC. This study thus aimed to assess the diagnostic value of PPR combined with serum thyroglobulin (Tg) in patients with PTC. METHODS: A total of 1001 participants were included in our study. 876 patients who underwent surgery for nodular goiter were divided into the PTC group or benign thyroid nodule (BTN) group according to pathology reports, and 125 healthy controls (HCs) were included. Preoperative hemogram parameters and serum Tg levels were compared among three groups. Receiver operating characteristic (ROC) curve was used to evaluate the value of PPR combined with serum Tg for diagnosing PTC. RESULTS: Platelet distribution width (PDW) and PPR levels were higher in the PTC group than in the BTN and HC groups (both p < 0.05) but did not significantly differ between the BTN and HC groups. PDW and PPR levels significantly differed in the presence/absence of lymph node metastasis, the presence/absence of capsule invasion (p = 0.005), and TNM stages (p < 0.001). Multivariable analyses indicated that high serum Tg levels [adjusted odds ratio (OR), 1.007; 95% confidence interval (CI), 1.004-1.009; p < 0.001], high neutrophil-to-lymphocyte ratio (NLR,adjusted OR, 1.928; 95% CI, 1.619-2.295; p < 0.001), and high PPR (adjusted OR, 1.378; 95% CI, 1.268-1.497; p < 0.001) were independent risk factors for PTC. In ROC analysis, the areas under the curves (AUCs) of serum Tg, PDW, PPR, and NLR for predicting PTC were 0.603, 0.610, 0.706, and 0.685, respectively. PPR combined with serum Tg (PPR + Tg) had a higher diagnostic value (AUC, 0.738; sensitivity, 60%; specificity, 74.7%) compared with PDW + Tg (AUC, 0.656; sensitivity, 64.4%; specificity, 59.9%) and NLR + Tg (AUC, 0.714; sensitivity, 61.6%; specificity, 71.1%). CONCLUSIONS: Preoperative PPR combined with serum Tg may be objective and popularizable indicators for effective predicting PTC.

The Scope of HbA1c Variability and Risk of Vascular Complications Among Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Prospective Studies.

Glycated hemoglobin (HbA1c) variability is emerging as an indicator of long-term glycemic control, which may play a significant role during vascular complications. We conducted a systematic review and meta-analysis to assess the association between the scope of HbA1c variability and vascular complications in patients with type 2 diabetes mellitus. PubMed and Embase were searched for studies that evaluated the association of HbA1c variability with vascular complications in patients with type 2 diabetes. Two reviewers independently completed data extraction. Random-effects meta-analysis was conducted with stratification according to the type of vascular complications. Nine studies were eligible for inclusion in our systematic review and meta-analysis. Six studies evaluated the impact of the standard deviation of HbA1c (HbA1c-SD) on cardiovascular events and showed an association of HbA1c-SD with cardiovascular events (HR: 1.25, 95% CI 1.18-1.32, 5 studies). Six studies evaluated renal disease associated with HbA1c-SD and showed that HbA1c-SD was correlated with an increased risk of renal disease (HR: 1.19, 95% CI 1.13-1.24). Two studies evaluated HbA1c-SD and the risk of retinopathy and showed that no significant association was found between retinopathy and HbA1c-SD (HR 1.08, 95% CI 0.92-125). For HbA1c-SD ranging from 0.6 to 0.8%, HbA1c-SD was associated with an increased risk of cardiovascular events (HR: 1.25, 95% CI 1.15-1.35) and renal disease (HR: 1.16, 95% CI 1.11-1.22). For individuals with index HbA1c variability greater than or equal to 0.6%, HbA1c variability was significantly associated with vascular complications in patients with type 2 diabetes mellitus.

Activation of the NLRP3 inflammasome by RAC1 mediates a new mechanism in diabetic nephropathy.

OBJECTIVE: Inflammation is central to the development and progression of diabetic nephropathy (DN). Although the exact mechanisms of inflammation in the kidney have not been well elucidated, pyrin domain containing 3 (NLRP3) inflammasome activation is involved in the onset and progression of DN. Here, we investigated the underlying regulatory mechanisms of hyperglycaemia-induced NLRP3 inflammasome activation in the kidney. METHODS: HEK293T cells received high glucose, and the cell proliferation and apoptosis were detected. Biochemical indicators in db/db mice were tested by kits, and the morphological changes in the kidney were observed using staining methods and transmission electron microscopy. The interaction of Ras-related C3 botulinum toxin substrate 1 (RAC1) and NLRP3 inflammasome in cells and in mice was assessed by co-immunoprecipitation (Co-IP) and immunofluorescence. Expression of all proteins was examined by western blotting and immunohistochemistry. In additional, the directly combination of RAC1 and NLRP3 was evaluated by GST Pulldown. RESULTS: High-glucose and hyperglycaemia conditions resulted in Ras-related C3 botulinum toxin substrate 1 (RAC1) and NLRP3 inflammasome interactions in cells and in mice. Additionally, RAC1 promoted NLRP3 inflammasome activation and then induced cell damage, and morphological and functional abnormalities in the kidney. We also observed that RAC1 activates the NLRP3 inflammasome by directly binding to NLRP3. CONCLUSION: In the present study, we confirmed that RAC1 binding to NLRP3 is sufficient to activate the NLRP3 inflammasome in the kidney and accelerate DN pathological processes. These results elucidate the upstream cellular and molecular mechanisms of NLRP3 inflammasome activation and provide new therapeutic strategies for the treatment of DN.

Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C-terminal AAs 2-5 to mitogen-activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3-MKK3-p38 module assembly.

In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)-mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull-down assays to assess the interaction between RAGE and mitogen-activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3-MKK3-p38 signaling module. Mechanistically, we found that activation of p38 mitogen-activated protein kinase (MAPK)/NF-κB signaling depends on mediation of the RAGE-MKK3 interaction by C-terminal RAGE (ctRAGE) amino acids (AAs) 2-5. We found that ctRAGE R2A-K3A-R4A-Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE-MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2-5, which leads to assembly of the MEKK3-MKK3-p38 signaling module and subsequent activation of the p38MAPK/NF-κB pathway, and ultimately results in diabetic encephalopathy (DE).

Age Moderates the Impact of TRAbs on Thyroid Hormones and Hepatic Function in Patients with Graves' Disease.

Thyrotropin receptor antibodies (TRAbs) play a significant role in the course of hepatic dysfunction (HDF) in patients with Graves' disease (GD). However, few studies have considered the factors that influence the relationships among TRAbs, thyroid hormone levels, and hepatic function in subjects with newly diagnosed GD. Here we investigated the associations of TRAbs with thyroid hormones and hepatic function and assessed potential factors that can influence these associations among patients with GD. A total of 368 patients newly diagnosed with GD were collected in this cross-sectional study. Patients who had received antithyroid drugs, radioactive iodine, or surgery were excluded. Levels of TRAbs and thyroid hormones and hepatic function were recorded. Linear and binary logistic regression analysis models were applied to investigate associations among these variables after adjusting for confounding characteristics. There was a significant difference in TRAbs indices between the HDF and normal hepatic function groups (p <0.05). After adjusting for confounders, the relationship between TRAbs and thyroid hormones was nonlinear, showing a curve with an initial positive slope and a subsequent flattening (p <0.05). Higher TRAbs were associated with HDF [odds ratio (OR) 1.036, 95% confidence interval (CI) 1.018-1.053 per 1-IU/l increase]. These associations were modified by age, but not by gender, smoking status, Graves' orbitopathy, thyroid-peroxidase antibody levels, or thyroglobulin antibody levels. In younger patients, increasing TRAbs were correlated with higher thyroid hormones and HDF (OR 1.034, 95% CI 1.017-1.052) per1-IU/l increase). In older patients, TRAbs were not correlated with thyroid hormones or HDF (OR 1.024, 95% CI 0.993-1.056) per 1-IU/l increase. Age can affect the impact of TRAbs on thyroid hormone levels and hepatic function in GD. TRAb measurement can have good predictive value in younger patients.

Ras-Related C3 Botulinum Toxin Substrate 1 Combining With the Mixed Lineage Kinase 3- Mitogen-Activated Protein Kinase 7- c-Jun N-Terminal Kinase Signaling Module Accelerates Diabetic Nephropathy.

Ras-related C3 botulinum toxin substrate 1 (RAC1) activation plays a vital role in diabetic nephropathy (DN), but the exact mechanism remains unclear. In this study, we attempted to elucidate the precise mechanism of how RAC1 aggravates DN through cellular and animal experiments. In this study, DN was induced in mice by intraperitoneal injection of streptozotocin (STZ, 150mg/kg), and the RAC1 inhibitor NSC23766 was administered by tail vein injection. Biochemical indicators, cell proliferation and apoptosis, and morphological changes in the kidney were detected. The expression of phosphorylated c-Jun N-terminal kinase (p-JNK), nuclear factor-κB (NF-κB), and cleaved caspase-3 and the interaction between RAC1 and the mixed lineage kinase 3 (MLK3)-mitogen-activated protein kinase 7 (MKK7)-JNK signaling module were determined. Furthermore, the colocalization and direct co-interaction of RAC1 and MLK3 were confirmed. Our results showed that RAC1 accelerates renal damage and increases the expression of p-JNK, NF-κB, and cleaved caspase-3. However, inhibition of RAC1 ameliorated DN by downregulating p-JNK, NF-κB, and cleaved caspase-3. Also, RAC1 promoted the assembly of MLK3-MKK7-JNK, and NSC23766 blocked the interaction between RAC1 and MLK3-MKK7-JNK and inhibited the assembly of the MLK3-MKK7-JNK signaling module. Furthermore, RAC1 was combined with MLK3 directly, but the RAC1 Y40C mutant inhibited the interaction between RAC1 and MLK3. We demonstrated that RAC1 combining with MLK3 activates the MLK3-MKK7-JNK signaling module, accelerating DN occurrence and development, and RAC1 Y40 is an important site for binding of RAC1 to MLK3. This study illustrates the cellular and molecular mechanisms of how RAC1 accelerates DN and provides evidence of DN-targeted therapy.

Glycemic variability indices determined by self-monitoring of blood glucose are associated with ß-cell function in Chinese patients with type 2 diabetes.

INTRODUCTION: Glycemic control plays an important role in diabetes management, and self-monitoring of blood glucose (SMBG) is critical to achieving good glycemic control. However, there are few studies about the relationship between SMBG-estimated glycemic indices and ß-cell function. Here we investigated the association between glucose variation indices estimated by SMBG and ß-cell function among Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: In this cross­sectional study, 397 patients with T2DM were recruited from February 2015 to October 2016. ß-cell function was monitored using the Homeostasis Model Assessment 2 (HOMA2)-%ß index. The parameters evaluated by SMBG were the mean blood glucose (MBG), standard deviation of MBG (SDBG), largest amplitude of glycemic excursions (LAGE), and postprandial glucose excursion (PPGE). RESULTS: HOMA2-%ß was negatively correlated with SDBG, LAGE, PPGE, and MBG (r = -0.350, -0.346, -0.178, and -0.631, respectively; all p < 0.01). After adjusting for confounding characteristics (diabetic duration, triglyceride, total cholesterol, fasting C-peptide, HOMA2-insulin resistance index, hypoglycemia, and diabetic treatments) and glycated hemoglobin A1c on a continuous scale, odds ratios of SDBG, LAGE, PPGE, and MBG between the patients in the lowest and highest HOMA2-%ß quartiles were 2.02 (1.14-3.57), 1.24 (1.04-1.49), 1.13 (0.86-1.51), and 2.26 (1.70-3.00). HOMA2-%ß was independently associated with SDBG, LAGE, and MBG. CONCLUSIONS: Increased SDBG and LAGE assessed by SMBG are associated with ß-cell dysfunction in Chinese patients with T2DM.

Glucose fluctuation increased mesangial cell apoptosis related to AKT signal pathway.

INTRODUCTION: Blood glucose fluctuation is an important factor for the development of diabetic complications. Glucose fluctuation aggravated the renal injury in diabetic nephropathy. In the present study, our aim was to investigate the effects of blood glucose fluctuation on the glomerular mesangal cells and its related mechanism. MATERIAL AND METHODS: Mesangial cells were divided into four groups: the normal glucose group (NG) cells were incubated in normal glucose conditions (5.6 mmol/l); the high glucose group (HG) cells were treated with 25 mmol/l; the glucose fluctuation (FG) group received 5.6 mmol/l and 25 mmol/l glucose repeated 3 times; the mannitol group (MG) received 5.6 mmol/l glucose plus 24.4 mmol/l mannitol as a control. Cell viability and apoptosis were detected, reactive oxygen species (ROS) level, superoxide dismutase (SOD) activity and malonaldehyde (MDA) levels were measured. Phosphorylated ser/thr protein kinase (P-AKT, phosphor-Ser473), phosphorylated glycogen synthase kinase-3ß (P-GSK-3ß, phosphor-Ser9) and cleaved cysteinyl aspartate-specific proteinase-3 (cleaved caspase-3) levels were assessed using western blot. RESULTS: Data suggested that mesangial cells in the FG group show higher cell viability in 12 h, and lower cell viability from 48 h. The FG group showed cell apoptosis accompanied by a significant MDA level increase and SOD activity decrease in 48 h. More importantly, glucose fluctuation could aggravate oxidative stress in glomerular mesangial cells. Furthermore, the P-AKT level was lower, and increased P-GSK-3ß and cleaved caspase-3 levels were higher in the FG group than in the HG group. CONCLUSIONS: Glucose fluctuation aggravates mesangial cell apoptosis, which may be partly induced by activating oxidative stress and inhibiting the AKT signaling pathway.

Fasting plasma glucose variability levels and risk of adverse outcomes among patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis assessed the association between fasting plasma glucose (FPG) variability levels and the risk of retinopathy and all-cause mortality in patients with type 2 diabetes. METHODS: PubMed and EMBASE were searched to identify studies that evaluated the association between FPG variability and retinopathy and all-cause mortality in patients with type 2 diabetes mellitus. The hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled with the random-effects model. RESULTS: Eight studies were included in our meta-analysis. Five studies evaluated the impact of FPG variability on all-cause mortality and showed that high FPG variability was associated with the risk of all-cause mortality (HR 1.28, 95% CI 1.12-1.46; three studies). For median or mean FPG variability levels under 20%, the relationship between all-cause mortality and FPG variability was not significant. Three studies evaluated FPG variability and the risk of diabetic retinopathy and showed that high FPG variability was strongly associated with the risk of retinopathy (odds ratio (OR) = 3.68; 95% CI 1.01-13.4). CONCLUSION: High FPG variability levels were positively associated with the risk of retinopathy and all-cause mortality in patients with type 2 diabetes.

Zeaxanthin improved diabetes-induced anxiety and depression through inhibiting inflammation in hippocampus.

It is generally accepted that inflammation plays a key role in anxiety and depression induced by diabetes. However, the underlying mechanism and effective treatment method of these diabetes-associated behavior disorders remain to be determined. In the present study, we attempted to illuminate the implication of zeaxanthin in anxiety, depression and neuroinflammation caused by hyperglycemia, and further elaborate the relevant mechanism under these neuropsychiatric disorders. In the current work, diabetic rats were induced by high glucose and fat diet followed by a single intraperitoneal injection of streptozocin, and zeaxanthin was orally administration every day (From 6th to 19th week). Diabetes-associated anxiety and depression were assessed using open field test (OFT) and Forced swimming test (FST) respectively. Moreover, the levels of interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in hippocampus were tested using ELISA and WB. Data showed that long-term zeaxanthin treatment improve diabetic symptoms and alleviate anxiety and depression in diabetic rats. Furthermore, excessive production of IL-6, IL-1ß and TNF-α could be reduced with zeaxanthin treatment. In conclusion, we suggested that zeaxanthin can ameliorate diabetes-associated anxiety and depression, inhibit inflammation in diabetic rats. Our results could provide a potential therapeutic approach for the treatment of abnormal behavior induced by hyperglycemia.