The triglyceride glucose (TyG) index has been confirmed a predictive value for type 2 diabetes mellitus (T2DM). However, no research has yet confirmed whether there is a linear correlation between the TyG index and MACCEs in DFUs. The present study aimed to delve into the association between the TyG index and the risk of MACCEs in patients with DFUs. A total of 960 inpatients with DFUs were recruited. All participants were followed up every 6 months for 11 years with a median of 83 months. According to the cut-off value of the TyG index acquired from receiver operating characteristic (ROC) analysis, the subjects were divided into two groups: low-level (<9.12, n = 480) and high-level (≥9.12, n = 480). The relationship between the TyG index and MACCEs was evaluated by the multivariable Cox regression model, restricted cubic spline (RCS) model, stratified analysis and the Kaplan-Meier survival analysis. Out of 960 participants, 271 experienced MACCEs (28.22%), of whom 79 (29.15%) died. ROC analysis got the optimal TyG index cut-off value of 9.12. Multivariable Cox regression analysis combined with the RCS model showed that the TyG index was positively associated with MACCEs in an S-shaped non-linear dose-dependent manner within the range of TyG index 7.5-9.5 (p < 0.001). The Kaplan-Meier survival analysis indicated the higher the TyG index, the greater the cumulative incidence of MACCEs (log-rank, p < 0.001). The study first confirmed an S-shaped non-linear dose-dependent positive relationship between the TyG index and the risk of MACCEs in DFUs. Consequently, lowering the TyG index level aids in improving the prognosis of patients with DFUs.

Background As meta-inflammation is a common feature for obesity, type 2 diabetes (T2D), nonalcoholic fatty liver disease and atherosclerosis, we have proposed a new concept, metabolic inflammatory syndrome (MIS), to cluster such diseases. We aimed to characterize MIS and explore its association with coronary heart disease (CHD) among T2D inpatients in China. Methods A total number of 8344 T2D participants were enrolled. Each component of MIS and metabolic syndrome (MS) was analyzed. Their association with the risk of CHD was assessed using a binary logistic analysis. Results Among the T2D inpatients, the detection rate of MIS was much higher than that of MS (93.6 % vs. 53.2 %). Among all the components of MIS and MS, carotid atherosclerosis (71.9 %) was most commonly detected, which increased with aging in subgroups. Surprisingly, the most common combination of MIS was with all 4 components in T2D patients, with a constituent ratio of 30.9 %. According to the odds ratios (ORs), MIS was a better predictor of CHD than MS, especially after adjustment for age, sex, smoking, and alcohol consumption (adjusted OR for MIS: 3.083; for MS: 1.515). The presence of more components of MIS was associated with a higher detection rate of CHD (P < 0.001). Among all the components of MIS and MS, carotid atherosclerosis best predicted the risk of CHD (adjusted OR: 1.787). Conclusions MIS is an independent risk factor for CHD, with a bigger OR value than MS. Carotid atherosclerosis, with the highest detection rate, was the best individual predictor of CHD and thus a critical component of MIS. The concept of MIS represents the understanding of metabolic diseases from the perspective of holistic integrative medicine.

Background The triglyceride glucose (TyG) index has been confirmed to be a novel sensitive predictor of clinical prognosis in patients with endocrine metabolic disorders. However, there is a paucity of research dedicated to delving into the relationship between the TyG index and the risk of major adverse cardio-cerebrovascular events (MACCEs) and all-cause mortality in patients with diabetic foot ulcer (DFU). Methods This study enrolled 1750 inpatients with DFUs based on an ambispective longitudinal cohort with continuous follow-up covering January 2013 to December 2023. All participants were followed up every 6 months for 11 years, for a median of 83 months. A total of 960 participants were eligible for inclusion in the current analysis. According to the median TyG index, the subjects were divided into two groups: low (< 9.12, n = 480) and high (≥ 9.12, n = 480). The present study evaluated the relationships between the TyG index and the risk of MACCEs and all-cause mortality in patients with DFU through receiver operating characteristic (ROC) curve analysis, Cox regression models, restricted cubic splines (RCSs), stratified analysis, and Kaplan‒Meier survival analysis. Results Out of 960 participants, 271 experienced MACCEs (28.22%), 79 (29.15%) of whom died during the follow-up period. ROC curve analysis revealed that the optimal TyG index cutoff values for predicting the risk of MACCEs and all-cause mortality in patients with DFU were 8.97 and 9.01, respectively. After adjusting for confounding factors, the TyG index was positively associated with MACCEs (hazard ratio (HR) = 1.807; 95% CI = 1.402–2.328; P < 0.001) and all-cause mortality (HR = 1.661; 95% CI = 1.039–2.656; P = 0.034) in an S-shaped nonlinear dose-dependent manner. After eliminating the influence of covariates by stratified analysis, Kaplan‒Meier survival analysis was performed, and the results showed that the higher the TyG index was, the greater the cumulative incidence of MACCEs ( P < 0.001) and all-cause mortality ( P = 0.031). Conclusion The present study revealed an S-shaped nonlinear dose‒dependent positive relationship between the TyG index and the risk of MACCEs and all-cause mortality in patients with DFU. Consequently, lowering the TyG index helps improve the clinical prognosis in patients with DFU.

Purpose: Nuclear receptor subfamily 2 group E member 1 (Nr2e1) has been regarded as an essential regulator in neural stem cells. However, its function is still not clear in hepatocytes. This study aimed to clarify the effects of Nr2e1-deficiency in hepatocytes in lipotoxic conditions. Materials/methods: Nr2e1-knockdown AML12 cells were generated by lentiviral vector transfection. The influences of Nr2e1-deficiency on hepatocyte survival were determined by cell cycle progression and cell apoptosis rate using flow cytometry. Real-time quantitative PCR and Western blot were used to examine the genes and protein expression related to apoptosis, lipid metabolism, and oxidative stress. Meanwhile, RNA sequencing was adopted in liver samples from Nr2e1-knockout (Nr2e1-KO) mice. Results: Nr2e1 expression was observed with a significant decrease in AML12 cells after palmitic acid-stimulation. Knockdown of Nr2e1 in AML12 cells resulted in increased sensitivity to lipotoxicity, evidenced by a partial G0/G1 cell-cycle arrest and higher rates of cell apoptosis. Moreover, Nr2e1-knockdown AML12 cells presented increased gene expressions relative to lipid synthesis but decreased levels of beta-oxidation related genes. Lack of Nr2e1 augmented palmitate-induced oxidative stress in hepatocytes. In vivo, differential genes in Nr2e1-KO mice liver were enriched in pathways associated with liver regeneration and cell proliferation. Conclusions: This study indicated that hepatocytes lacking Nr2e1 were more susceptible to lipotoxic-mediated damage. Nr2e1 may serve as a potential target for the development of novel therapies for lipotoxicity-induced liver injury.

Poricoic acid A (PAA), a major triterpenoid component of Poria cocos with anti-tumor, anti-fibrotic, anti-inflammatory, and immune-regulating activities, has been shown to induce podocyte autophagy in diabetic kidney disease (DKD) by downregulating FUN14 domain containing 1 (FUNDC1). This study aimed to identify the role of adenosine monophosphate-activated protein kinase alpha (AMPKα) in PAA-mediated phosphorylation of FUNDC1 in podocyte injury occurring in the pathogenesis of DKD. A cellular model of renal podocyte injury was established by culturing MPC5 cells under high-glucose (HG) conditions. MPC5 cells were subjected to transfection with small interfering RNA (siRNA) targeting AMPKα or siRNA targeting FUNDC1, an AMPKα activator, or PAA. PAA treatment induced the phosphorylation of AMPKα in HG-cultured podocytes. AMPKα activation was implicated in the inhibitory effect of PAA on FUNDC phosphorylation in HG-cultured podocytes. Treatment targeting the AMPKα activator also significantly augmented proliferation, migration, mitochondrial membrane potential, and autophagy levels, while reducing apoptosis levels, inhibiting oxidative stress, and suppressing the release of proinflammatory factors in HG-cultured MPC5 cells. In contrast, insufficient expression of AMPKα reversed the effects of PAA on the proliferation, migration, and apoptosis of podocytes and further exacerbated the reduction of phosphorylated FUNDC1 expression in podocytes under HG conditions. AMPKα is involved in the regulation of FUNDC1 phosphorylation by PAA in HG-induced podocyte injury. Furthermore, the AMPKα/FUNDC1 pathway plays a crucial regulatory role in HG-induced podocyte injury. These findings support AMPKα, FUNDC1, and the AMPKα/FUNDC1 pathway as targets for PAA intervention.

目的:分析2型糖尿病(T2DM)患者乳酸水平的分布差异和相关因素,并评估其高乳酸血症的风险因素.方法:对1 243例2型糖尿病患者进行回顾性横断面研究,统计血乳酸和其他代谢和临床指标,进行相关性分析和回归分析以确定与乳酸水平相关的因素和高乳酸血症独立危险因素.结果:与乳酸正常组相比,高乳酸血症组体质量指数(BMI)、二甲双胍服用史比例、血尿酸(SUA)、甘油三酯(TG)、胰岛素5时相、胰岛素晚相分泌、胰岛素抵抗指数(HOMA-IR)、胰岛素抵抗程度(TyG)更高,年龄、尿素氮(BUN)、高密度脂蛋白(HDL-C)和酮体更低,代谢综合征和血脂异常的患病率更高,酮症患病率更低.多因素分析显示,BMI(OR=1.050,95％CI:1.008～1.090)、BUN(OR=0.895,95％CI:0.829～0.966)、HDL-C(OR=0.565,95％CI:0.358～0.891)和血酮体(OR=0.824,95％CI:0.718～0.944)是高乳酸血症的独立危险因素.结论:对于T2DM患者,乳酸浓度是一个值得评估的研究因素,T2DM患者高乳酸血症患病率高,血乳酸水平受BMI、血脂、血酮体等多种因素影响,且与代谢综合征、血脂异常等多种糖尿病合并症具有相关性.

Background: In recent years, with the increasing prevalence of diabetes, diabetic nepropathy (DN) has become a serious public health threat. This study investigated the potential role of Nlr family member X1 (NLRX1) in DN and the underlying mechanisms. Methods: Diabetic model of mice were injected intraperitoneally (i.p.) with streptozotocin, and fed with the high fat diet (HFD) as the in vivo model of diabetes-induced kidney injury. Rat mesangial cells (MCs) were exposed with high glucose (30 mmol/L glucose) as in vitro cell model.Results: NLRX1 mRNA (messenger ribonucleic acid) and protein levels were down-regulated in the kidney tissue of diabetic mouse model of kidney injury. NLRX1 protein administration reduced inflammation and prevented kidney injury in the mouse model. NLRX1 inactivated NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome in both the mouse model and in vitro cell model. Further experiments showed that the administration of NLRP3 attenuated the effects of NLRX1 on inflammation of diabetes-induced kidney injury model.Conclusions: In conclusion, NLRX1 attenuates the inflammation in diabetes-induced kidney injury by inhibiting NLRP3 inflammasome, which may serve as be a potent target for preventing the progression of DN through inhibition of NLRP3 inflammasomedependent inflammation.

Protein phosphatase 2A (PP2A) is one of the most common serine/threonine phosphatases in mammalian cells, and it primarily functions to regulate cell signaling, glycolipid metabolism and apoptosis. The catalytic subunit of PP2A (PP2Ac) plays an important role in the functions of the protein. However, there are few reports on the regulatory role of PP2Ac in pancreatic β-cells under lipotoxic conditions. In the present study, mouse insulinoma 6 (MIN6) pancreatic cells were transfected with short hairpin RNAs to generate PP2Ac knockdown cells and incubated with palmitate (PA) to establish a lipotoxicity model. Serine/threonine phosphatase assay system, Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay and western blotting were used to measure PP2A activity, cell viability, apoptosis, oxidative stress and insulin secretion in the cells. In addition, a mouse model of lipotoxicity was established with a high-fat diet (HFD) and the knockdown of PP2Ac using adeno-associated viruses to interfere with PP2Ac expression in the pancreatic tissues. The activity of PP2A in the mouse pancreatic tissue and the serum insulin level were measured. Furthermore, the proliferation of mouse pancreatic β-cells was assessed using pancreatic tissue immunofluorescence. PP2Ac knockdown inhibited lipotoxicity-induced PP2A hyperactivation, increased the resistance of pancreatic β-cells to lipotoxicity and attenuated PA-induced apoptosis in MIN6 cells. It also protected the endoplasmic reticulum and mitochondria, and ameliorated insulin secretion. The results of mRNA sequencing and western blotting analysis suggested that the protective effects of PP2Ac knockdown in MIN6 cells may be mediated via the MAPK pathway. Moreover, the results of the animal experiments suggested that specific knockdown of pancreatic PP2Ac effectively attenuated HFD-induced insulin resistance and reduced the compensatory proliferation of pancreatic β-cells in mice. In summary, the present study revealed the effects of interfering with PP2Ac gene expression on pancreatic β-cells in vivo and in vitro and the underlying mechanisms, which may provide insights for the treatment of type 2 diabetes mellitus in the clinic.

Background Diabetic muscle infarction (DMI), which is also referred to as diabetic myonecrosis, is a rare and long-term complication of poorly controlled diabetes mellitus, while we found that acute diabetes decompensation, such as diabetic ketoacidosis (DKA), could also stimulate the occurrence and development of DMI. Case presentation A 23-year-old woman with type 1 diabetes presented with a 10-day history of nausea, vomiting, pain, and swelling of her left leg. Her urine ketone test was positive. The 3-beta-hydroxybutyrate and leukocyte counts and creatine kinase levels were elevated. Magnetic resonance imaging of the left thigh revealed extensive deep tissue oedema and an increase in the T2 signal in the involved muscles. Once the diagnosis of DMI was made, she was managed with rest, celecoxib, clopidogrel and aggressive insulin therapy. Three months after treatment, the patient reported complete resolution of symptoms. Conclusion DMI is a rare DM complication with a high recurrence rate, commonly presenting with chronic complications, while our case report shows that acute diabetes decompensation, such as DKA, can stimulate the occurrence and development of DMI. Timely diagnosis and appropriate treatment could shorten the recovery time.

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

Background and aims The liver plays a central role in controlling glucose and lipid metabolism. IDH2, a mitochondrial protein, controls TCA cycle flux. However, its role in regulating metabolism in obesity is still unclear. This study intends to investigate the impact of hepatic IDH2 expression on overnutrition-regulated glucose and lipid metabolism. Methods Hepatic IDH2 was knocked-out in mice by the approach of CRISPR-Cas9. Mice were subjected to starvation and refeeding for hepatic glucose and lipid studies in vivo. Primary hepatocytes and mouse normal liver cell line, AML12 cells were used for experiments in vitro. Results This study found that IDH2 protein levels were elevated in the livers of obese people and mice with high-fat diet consumption or hepatic steatosis. Liver IDH2-deletion mice (IDH2LKO) were resistant to high-fat diet-induced body weight gain, with lower serum glucose and TG levels, increased insulin sensitivity, and higher FGF21 secretion, despite the higher TG content in the liver. Consistently, overexpression of IDH2 in hepatocytes promoted gluconeogenesis and enhanced glycogenesis. By performing mass spectrometry and proteomics analyses, we further demonstrated that IDH2-deficiency in hepatocytes accelerated ATP production by increasing forward TCA cycle flux, thus promoting glycolysis pathway and decreasing glycogen synthesis at refeeding state, and inhibiting hepatic gluconeogenesis, increasing β-oxidation during starvation. Moreover, experiments in vivo demonstrated that IDH2-knockout might not exacerbate hepatic inflammatory responses in the NASH model. Conclusions Elevated hepatic IDH2 under over-nutrition state contributes to elevated gluconeogenesis and glycogen synthesis. Inhibition of IDH2 in the liver could be a potential therapeutic target for obesity and diabetes.

Introduction The purpose of this study was to evaluate the clinical characteristics of carotid atherosclerotic disease in patients with type 2 diabetes mellitus, investigate its risk factors, and develop and validate an easy-to-use nomogram. Methods 1049 patients diagnosed with type 2 diabetes were enrolled and randomly assigned to the training and validation cohorts. Multivariate logistic regression analysis identified independent risk factors. A method combining least absolute shrinkage and selection operator with 10-fold cross-validation was used to screen for characteristic variables associated with carotid atherosclerosis. A nomogram was used to visually display the risk prediction model. Nomogram performance was evaluated using the C index, the area under the receiver operating characteristic curve, and calibration curves. Clinical utility was assessed by decision curve analysis. Results Age, nonalcoholic fatty liver disease, and OGTT3H were independent risk factors associated with carotid atherosclerosis in patients with diabetes. Age, nonalcoholic fatty liver disease, smoke, HDL-C, and LDL-C were characteristic variables used to develop the nomogram. The area under the curve for the discriminative power of the nomogram was 0.763 for the training cohort and 0.717 for the validation cohort. The calibration curves showed that the predicted probability matched the actual likelihood. The results of the decision curve analysis indicated that the nomograms were clinically useful. Discussion A new nomogram was developed and validated for assessing the incident risk of carotid atherosclerotic in patients with diabetes; this nomogram may act as a clinical tool to assist clinicians in making treatment recommendations.

Up to now, there has not yet been guidance or consensus from Chinese experts in the field of personalized prevention and treatment of type 2 diabetes. In view of the above, the endocrinology diabetes Professional Committee of Chinese Non-government Medical Institutions Association, the integrated endocrinology diabetes Professional Committee of the integrated medicine branch of Chinese Medical Doctor Association, and the diabetes education and microvascular complications group of the diabetes branch of the Chinese Medical Association organized relevant experts to discuss and reach the "Chinese expert consensus on strengthening personalized prevention and treatment of type 2 diabetes" for reference in clinical practice.

ObjectiveTo evaluate the clinical value of glycosylated hemoglobin (HbA1c) in newly diagnosed ketosis-prone type 2 diabetes (KPD).MethodsA total of 330 patients with newly diagnosed type 2 diabetes (T2DM) hospitalized in our department with an average age of 48.72 ± 13.07 years old were selected and divided into T2DM group (193 cases) and KPD group (137 cases) according to whether they were combined with ketosis. According to the quartile level of HbA1c, they were divided into group A (HbA1c < 8.90%, 84 cases), group B (8.90%≤HbA1c < 10.70%, 86 cases), group C (10.70%≤HbA1c ≤ 12.40%, 85 cases) and group D (HbA1c > 12.40%, 75 cases). The general clinical features, laboratory indicators and islet function of each group were compared. Spearman correlation analysis was used to explore the correlation between HbA1c and β- Hydroxybutyric acid (β- HB) and islet function. ROC curve was used to analyze the sensitivity and specificity of HbA1c in diagnosing KPD, and the optimal tangent point was obtained.ResultsHbA1c, β-HB, FFA, RBG, insulin dosage, GSP, OGTT (0, 0.5, 1, 2, 3h) in KPD group were significantly higher than those in T2DM group (P< 0.001). HDL-C, IRT (0, 0.5, 1, 2, 3h), HOMA-β, HOMA-IR, HOMA-IS, ΔC30/ΔG30, AUC insulin were significantly lower than those in T2DM group (P< 0.001). With the increase of HbA1c level, the incidence of ketosis, β-HB, FFA and insulin dosage increased, while IRT (0, 0.5, 1, 2, 3h), ΔC30/ΔG30, AUC insulin, HOMA-β and HOMA-IS decreased accordingly (P< 0.001). In all newly diagnosed T2DM patients, Spearman correlation analysis showed that HbA1c was positively correlated with β-HB (r=0.539, P < 0.001), and was negatively correlated with HOMA-β (r=-0.564, P < 0.001), HOMA-IS (r=-0.517, P < 0.01, P < 0.001), HOMA-IR (r=-0.177, P < 0.001), ΔC30/ΔG30 (r=-0.427, P < 0.01) and AUC insulin (r=-0.581, P < 0.001). In ROC curve analysis, the optimal threshold for the diagnosis of KPD was 10.15%, Youden index was 0.616, area under the curve (AUC) was 0.882, sensitivity = 92.70%, specificity = 70.50%.ConclusionIn newly diagnosed T2DM patients, if HbA1c > 10.15%, it is more likely to develop KPD. Monitoring HbA1c level is conducive to timely detection of high-risk individuals with KPD and taking appropriate measures to prevent the occurrence and development of the disease.

Objective:To investigate the effect and mechanism of glucose-regulated protein 75 (Mortalin) on palmitic acid-induced lipotoxicity in MIN6 cells.Methods:Twenty 6-8 weeks male C57BL/6J (20-24 g) with specific pathogen free (SPF) mice were randomly divided into standard diet (SD) and high-fat diet (HFD) groups, with 10 mice in each group. Mortalin expression levels in pancreatic tissues were detected by immunofluorescence and immunohistochemistry. Mortalin knockdown stable cell lines were constructed by lentivirus transfection using MIN6 cells, and cells were divided into Mortalin short hairpin (Sh-Mortalin) group, Mortalin knockdown and null group (ShNC-Mortalin group), Sh-Mortalin+PA group, and ShNC-Mortalin+PA group according to whether they were treated with bovine serum albumin (BSA) or palmitic acid (PA). Moreover, cells were divided into Sh-Mortalin+dimethyl sulfoxide (DMSO) group, Sh-Mortalin+PA+DMSO group, Sh-Mortalin+U0126 group, and Sh-Mortalin+PA+U0126 group according to whether the extracellular regulated protein kinase (ERK) inhibitor U0126 or DMSO was applied. Cell proliferation rate was then measured using 5-ethynyl-2′-deoxyuridine (EdU). Apoptosis rate and reactive oxygen species (ROS) levels were measured by flow cytometry, and insulin levels were measured by enzyme-linked immunosorbent assay. Expression levels of ERK pathway-related proteins [phosphorylated extracellular regulatory protein kinase 1/2 (p-ERK1/2), phosphorylated v-raf-leukemia viral oncogene 1 (p-Raf-1)] were detected by Western blotting. The t-test was used for comparisons between two groups, and one-way analysis of variance (ANOVA) was used for comparisons between multiple groups. Results:The results of in vivo experiments showed that Mortalin expression was significantly increased in the pancreas of mice in the HFD group compared with the SD group ( P<0.01). The results of in vitro experiments showed that compared with the ShNC-Mortalin+PA group, the Sh-Mortalin+PA group showed significantly higher proliferation levels, lower apoptosis rates, lower ROS levels and higher insulin levels ( P<0.05). Western blotting results showed that the p-ERK1/2 and p-Raf-1 protein levels decreased in a PA-time gradient in all cells, and the p-ERK1/2 protein level was higher in the Sh-Mortalin group compared with the ShNC-Mortalin group ( P<0.05). Compared with the Sh-Mortalin+DMSO group, EdU positivity and p-ERK1/2 levels were significantly lower in the Sh-Mortalin+U0126 group, and cellular lipotoxic damage was significantly increased ( P<0.05). Conclusion:Mortalin is involved in regulating the process of lipotoxic damage in MIN6 cells and Mortalin knockdown attenuates PA-induced lipotoxic injury in MIN6 cells by activating the Raf-1/ERK signaling pathway.

Insulin resistance and many metabolic disorders are causally linked to mitochondrial dysfunction or defective mitochondrial quality control. Mitophagy is a highly selective mechanism that recognizes and removes damaged mitochondria to maintain mitochondrial homeostasis. Here, we addressed the potential role of FUNDC1, a mediator of mitophagy, in pancreatic β-cell dysfunction under lipotoxicity. In pancreatic MIN6 cells, FUNDC1 deficiency aggravated palmitate-induced mitochondrial dysfunction, which led to cell death and insulin insensitivity. Interestingly, FUNDC1 overexpression prevented these cellular harms brought on by palmitate. In mice models, pancreatic-specific FUNDC1 overexpression alleviated high-fat diet (HFD)-induced insulin resistance and obesity. Mechanistically, pancreatic-specific overexpression of FUNDC1 ameliorated mitochondrial defects and endoplasmic reticulum (ER) stress upon HFD. Our research indicates that FUNDC1 plays an essential role in apoptosis and dysfunction of pancreatic β-cells via modulating lipotoxicity-induced mitochondrial defects.

Diabetic kidney disease (DKD) is a devastating complication of diabetes mellitus (DM) and is the most prevalent chronic kidney disease (CKD). Poricoic acid A (PAA), a component isolated from Traditional Chinese Medicine (TCM) Poria cocos, has hypoglycaemic and anti-fibrosis effects. However, the role of PAA in DKD remains largely unclear. To mimics an in vitro model of DKD, the mouse podocyte MPC5 cells were treated with high glucose (25 mM; HG) for 24 h. CCK-8 and flow cytometry assays were conducted for assessing MPC5 cell viability and apoptosis. Meanwhile, streptozotocin (STZ) was used to induce experimental DKD in mice by intraperitoneal injection. PAA notably inhibited the apoptosis and inflammation, reduced the generation of ROS, and elevated the MMP level in HG-treated MPC5 cells. Moreover, PAA obviously reduced blood glucose and urine protein levels, inhibited renal fibrosis in DKD mice. Meanwhile, PAA markedly increased LC3 and ATG5 levels and declined p62 and FUNDC1 levels in HG-treated MPC5 cells and in the kidney tissues of DKD mice, leading to the activation of cell mitophagy. Furthermore, the downregulation of FUNDC1 also inhibited apoptosis, inflammation, and promoted mitophagy in HG-treated MPC5 cells. As expected, the knockdown of FUNDC1 further enhanced the protective role of PAA in MPC5 cells following HG treatment, indicating that induction of mitophagy could attenuate podocyte injury. Collectively, PAA could exert beneficial effects on podocyte injury in DKD by promoting mitophagy via downregulating FUNDC1. These findings suggested that PAA may have great potential in alleviating kidney injury in DKD.

Sigma-1 receptor (Sig-1R) is a class of orphan receptors, the potential role of which in pancreatic islet cells remains poorly understood. The present study aimed to investigate the role of Sig-1R in islet β-cell proliferation and examine the effects of Sig-1R on islet β-cell injury under lipotoxic conditions. Sig-1R-overexpressing MIN6 cells were generated by lentiviral vector transfection. The effect of Sig-1R overexpression on cell proliferation detected by EdU staining, cell cycle progression by propidium iodide (PI), apoptosis by Annexin V-APC/PI, mitochondrial membrane potential by Mitolite Red and cytoplasmic Ca2+ levelsby Fura-2/AM in islet β-cells were measured by flow cytometry. Western blot analysis was used to measure protein expression levels of endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 and C/EBP homologous protein, mitochondrial apoptotic proteins Bcl-2-associated X and Bcl-2 and cytochrome c. In addition, ATP levels and insulin secretion were separately measured using ATP Assay and mouse insulin ELISA. Mitochondria-associated ER membrane (MAM) structures in MIN6 cells were then detected using transmission electron microscopy. Protein disulfide isomerase expression and possible colocalization between inositol 1,4,5-trisphosphate receptor and voltage-dependent anion channel 1 were examined using immunofluorescence. Sig-1R overexpression was found to promote β-cell proliferation by accelerating cell cycle progression. Furthermore, Sig-1R overexpression ameliorated the apoptosis rate whilst impairing insulin secretion induced by palmitic acid by relieving ER stress and mitochondrial dysfunction in MIN6 cells. Sig-1R overexpression also promoted Ca2+ transport between mitochondria and ER by increasing the quantity of ER adjacent to mitochondria in the 50-nm range. It was concluded that Sig-1R overexpression conferred protective effects on β-cells against lipotoxicity as a result of the promotion of cell proliferation and inhibition of ER stress and oxidative stress, by regulating the structure of MAM.

*These authors contributed equally to this work Background: Type 2 diabetes (T2D) is characterized by progressive β-cell dysfunction. Regulatory microRNAs (miRNAs) may be associated with this. Methods: Serum miR-26a-5p and RNF6 levels were detected in T2D patients and healthy volunteers via qRT-PCR. Subsequently, the role of specific dysregulated miR-26a-5p or RNF6 in regulating insulin content, cell proliferation, and apoptosis was studied in INS-1 cells. The targeting correlation between miR-26a-5p and RNF6 was detected using a luciferase assay. Results: RNF6 expression was significantly decreased in T2D individuals and INS-1 cells treated with high glucose, while miR-26a-5p expression was increased. In INS-1 cells, RNF6 overexpression or miR-26a-5p downregulation significantly increased insulin content and secretion, induced proliferation, and inhibited apoptosis. RNF6 has been identified as an miR-26a-5p target, which negatively regulates RNF6 to worsen INS-1 cell function. Conclusion: RNF6 promoted insulin secretion and induced cell proliferation in INS-1 cells. This may be related to miR-26a-5p targeting and negatively regulating T2D pathogenesis.

Background Type 2 diabetes (T2D) is characterized by progressive β-cell dysfunction. Regulatory microRNAs (miRNAs) may be associated with this. Methods Serum miR-26a-5p and RNF6 levels were detected in T2D patients and healthy volunteers via qRT-PCR. Subsequently, the role of specific dysregulated miR-26a-5p or RNF6 in regulating insulin content, cell proliferation, and apoptosis was studied in INS-1 cells. The targeting correlation between miR-26a-5p and RNF6 was detected using a luciferase assay. Results RNF6 expression was significantly decreased in T2D individuals and INS-1 cells treated with high glucose, while miR-26a-5p expression was increased. In INS-1 cells, RNF6 overexpression or miR-26a-5p downregulation significantly increased insulin content and secretion, induced proliferation, and inhibited apoptosis. RNF6 has been identified as an miR-26a-5p target, which negatively regulates RNF6 to worsen INS-1 cell function. Conclusion RNF6 promoted insulin secretion and induced cell proliferation in INS-1 cells. This may be related to miR-26a-5p targeting and negatively regulating T2D pathogenesis.