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Abstract Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet‐induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination‐proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis.

Abstract Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

AbstractBackground Metabolic dysfunction and obesity are closely related to chronic kidney disease (CKD). However, studies on the relationship between various metabolic syndrome-body mass index (MetS-BMI) phenotypes and the risk of CKD in the Chinese population have not yet been explored.Materials and methods Data from the China Health and Retirement Longitudinal Study (CHARLS) 2015 were analyzed in this study. This study enrolled 12,054 participants. Participants were divided into six distinct groups according to their MetS-BMI status. Across the different MetS-BMI groups, the odd ratios (ORs) for CKD were determined using multivariable logistic regression models.Results The prevalence of CKD was higher in metabolically unhealthy groups than in the corresponding healthy groups. Moreover, the fully adjusted model showed that all metabolically unhealthy individuals had an increased risk of developing CKD compared to the metabolically healthy normal weight group (OR = 1.62, p = 0.002 for the metabolically unhealthy normal weight group; OR = 1.55, p

Summary: Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Aims: This study aimed to examine the alterations in the serum CTRP7 and CTRP15 concentrations in patients newly diagnosed with type 2 diabetes mellitus (T2DM) and to assess the diagnostic potential of the log10 (CTRP7+CTRP15) for insulin resistance (IR) and T2DM. Methods: Serum CTRP7, CTRP15, and adiponectin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis was conducted to investigate CTRP7 and CTRP15-related genes and metabolic signaling pathways. Results: Log10 (CTRP7+CTRP15) levels were notably elevated in the impaired glucose tolerance (IGT) and T2DM cohorts compared with those in the normal control (NGT) cohort. Log10(CTRP7+CTRP15) exhibited positive correlations with HOMA-IR, area under the glucose curve (AUCg), HbA1c%, triglyceride (TG), visceral adiposity index (VAI), body mass index (BMI), and free fatty acid (FFA), levels but negative correlations with adiponectin. Multivariate stepwise regression analysis revealed that HOMA-IR, BMI, HbA1c and FFA levels were independent factors affecting the log10 (CTRP7+CTRP15). Logistic regression analysis revealed that log10 (CTRP7+CTRP15) was independently associated with T2DM and significantly associated with increased risk. Receiver operating characteristic (ROC) curve analysis indicated that the predictive value of log10 (CTRP7+CTRP15) for T2DM and IR was superior to that of CTRP7 or CTRP15 alone. Intervention studies demonstrated that insulin, FFAs and acute exercise contribute to the elevation of serum CTRP7 levels, while hyperglycemia inhibited CTRP7 secretion. Short-term changes in blood glucose, insulin, FFA and acute exercise had minimal effects on serum CTRP15 levels. Bioinformatics analysis revealed that CTRP7 and CTRP15 interact with multiple metabolism-related genes and are enriched in glucose and lipid metabolism-related pathways. Conclusion: Log10 (CTRP7+CTRP15) may serve as a valuable diagnostic marker for the management of metabolic-related diseases, particularly T2DM and IR.

Abstract MicroRNAs (miRNAs) play a significant role in the pathogenesis of various diseases throughout biological processes, and the accurate detection of miRNA biomarkers holds great potential for early stage disease diagnosis and treatment. In this study, a novel method is developed to detect miRNA-21, a biomarker for drug-induced liver injury, by combining target sequence recycling with G-quadruplex-based signal production. This approach is highly sensitive and does not require the use of labels. The target sequence facilitates the cyclic exposure of G-rich regions in the detection probe by toehold-mediated strand displacement processes, with the aid of the catalytic chain. The G-quadruplex sequences that have been produced subsequently interact with thioflavin T (ThT), resulting in a significant increase in its fluorescence intensity. This enhanced fluorescence is utilized for the purpose of detecting miRNA-21, with a remarkably low detection limit of 4.4 fM. The suggested technique also allows for the very specific identification of the target miRNA-21. Due to its non-label format, excellent selectivity, and sensitivity, this technology presents a straightforward and versatile approach for detecting a wide range of biomarkers in the early phases of illness detection.

Abstract Background C-reactive protein(CRP), is an inflammatory marker that weaken leptin bioavailability and insulin sensitivity to disturb energy and glucose metabolism. Polycystic ovary syndrome (PCOS) exhibit a metabolic component consisting of higher plasma CRP levels, hyperinsulinemic and hyperleptinemia. The ability of leptin to regulation of hepatic glucose production (HGP) in the absence of CRP in PCOS remain unknown. Methods Dehydroepiandrosterone (DHEA) was used to induce PCOS in rats. We assessed the effects of CRP gene knockout in PCOS model rats on body weight, energy expenditure glucose metabolism and insulin sensitivity. We conducted experiments involving the administration of leptin to both the peripheral and central systems in PCOS model rats with CRP knockout, and studied the effects on changes in glucose kinetics during hyperinsulinemic-euglycemic clamps. Results In female PCOS rats, the lack of CRP resulted in decreased leptin resistance and weight gain, increased energy expenditure, and improved insulin sensitivity. Additionally, the deletion of the CRP gene strengthened the HGP-lowering effects of leptin when administered peripherally or centrally. This effect was accompanied by a decrease in the expression of hepatic gluconeogenic enzymes and an increase in hepatic insulin signaling. Finally, inhibition of glucose production was also enhanced for central leptin administration during lipid infusion in PCOS rats. Conclusions Our findings highlight the therapeutic potential of targeting CRP to restore glucose homeostasis and insulin sensitivity for leptin in PCOS.

Metabolic cardiovascular diseases have become a global health concern, and some of their risk factors are linked to several metabolic disorders. They are the leading causes of death in developing countries. Adipose tissues secrete a variety of adipokines that participate in regulating metabolism and various pathophysiological processes. Adiponectin is the most abundant pleiotropic adipokine and can increase insulin sensitivity, improve atherosclerosis, have anti-inflammatory properties, and exert a cardioprotective effect. Low adiponectin concentrations are correlated with myocardial infarction, coronary atherosclerotic heart disease, hypertrophy, hypertension, and other metabolic cardiovascular dysfunctions. However, the relationship between adiponectin and cardiovascular diseases is complex, and the specific mechanism of action is not fully understood. Our summary and analysis of these issues are expected to contribute to future treatment options.

AbstractBackground Although a study found a significant increase in serum hedgehog interacting protein (HHIP) concentrations in impaired fasting blood glucose, impaired glucose tolerance and newly diagnosed T2DM patients, the variation in circulating HHIP levels in obese individuals remains unknown.Patients and methods Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes and signal pathways. The study is comprised of a total of 452 young women, including 248 obese individuals and 204 controls. Circulating HHIP and Adipoq levels were determined with ELISA kits. Euglycemic–hyperinsulinemic clamps (EHC) and oral glucose tolerance test (OGTT) were conducted in every subject. 32 women were given metformin and 49 were given liraglutide treatment for 6 weeks. The study was registered with www.chictr.org.cn (ChiCTR2000032878 and ChiCTR1800019776).Results Obesity was significantly associated with the cAMP signal pathway, and HHIP was a secreted protein related to cAMP signalling, as determined by KEGG analysis. In this population-based cohort study, we found that the level of circulating HHIP was significantly elevated in obese women, and positively correlated with body mass index and blood glucose, blood lipid, insulin, homeostasis model assessment of insulin resistance, dehydroepiandrostenedione sulphate, and luteinizing hormone, while negatively correlated with M-value and Adipoq. Insulin resistance (IR) and ove™rweight/obesity were associated with the higher HHIP concentration. OGTT and EHC tests revealed that the levels of circulating HHIP were regulated by blood glucose but to a less extent by insulin. After therapy with metformin and liraglutide, circulating HHIP levels were decreased, whereas Adipoq levels increased significantly.Conclusions Our findings support HHIP as a potential biomarker for predicting obesity and IR. In addition, drugs targeting HHIP may be a new strategy to treat obesity.

Abstract Background Experiencing a hyperglycaemic crisis is associated with a short- and long-term increased risk of mortality. We aimed to develop an explainable machine learning model for predicting 3-year mortality and providing individualized risk factor assessment of patients with hyperglycaemic crisis after admission. Methods Based on five representative machine learning algorithms, we trained prediction models on data from patients with hyperglycaemic crisis admitted to two tertiary hospitals between 2016 and 2020. The models were internally validated by tenfold cross-validation and externally validated using previously unseen data from two other tertiary hospitals. A SHapley Additive exPlanations algorithm was used to interpret the predictions of the best performing model, and the relative importance of the features in the model was compared with the traditional statistical test results. Results A total of 337 patients with hyperglycaemic crisis were enrolled in the study, 3-year mortality was 13.6% (46 patients). 257 patients were used to train the models, and 80 patients were used for model validation. The Light Gradient Boosting Machine model performed best across testing cohorts (area under the ROC curve 0.89 [95% CI 0.77–0.97]). Advanced age, higher blood glucose and blood urea nitrogen were the three most important predictors for increased mortality. Conclusion The developed explainable model can provide estimates of the mortality and visual contribution of the features to the prediction for an individual patient with hyperglycaemic crisis. Advanced age, metabolic disorders, and impaired renal and cardiac function were important factors that predicted non-survival. Trial Registration Number: ChiCTR1800015981, 2018/05/04.

Abstract G-protein gamma subunit 2 (GNG2) is involved in several cell signaling pathways, and is essential for cell proliferation and angiogenesis. However, the role of GNG2 in tumorigenesis and development remains unclear. In this study, 1321 differentially expressed genes (DEGs) in breast cancer (BC) tissues were screened using the GEO and TCGA databases. KEGG enrichment analysis showed that most of the enriched genes were part of the PI3K-Akt signaling pathway. We identified GNG2 from the first five DEGs, its expression was markedly reduced in all BC subtype tissues. Cox regression analysis showed that GNG2 was independently associated with overall survival in patients with luminal A and triple-negative breast cancers (TNBC). GNG2 over-expression could significantly block the cell cycle, inhibit proliferation, and promote apoptosis in BC cells in vitro. In animal studies, GNG2 over-expression inhibited the growth of BC cells. Further, we found that GNG2 significantly inhibited the activity of ERK and Akt in an MRAS-dependent manner. Importantly, GNG2 and muscle RAS oncogene homolog (MRAS) were co-localized in the cell membrane, and the fluorescence resonance energy transfer (FRET) experiment revealed that they had direct interaction. In conclusion, the interaction between GNG2 and MRAS likely inhibits Akt and ERK activity, promoting apoptosis and suppressing proliferation in BC cells. Increasing GNG2 expression or disrupting the GNG2–MRAS interaction in vivo could therefore be a potential therapeutic strategy to treat BC.

ObjectiveGPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans.MethodsBioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans.ResultsBioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased.ConclusionsOur results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.

BackgroundThe long-term clinical outcome of poor prognosis in patients with diabetic hyperglycaemic crisis episodes (HCE) remains unknown, which may be related to acute organ injury (AOI) and its continuous damage after hospital discharge. This study aimed to observe the clinical differences and relevant risk factors in HCE with or without AOI.MethodsA total of 339 inpatients were divided into an AOI group (n=69) and a non-AOI group (n=270), and their differences and risk factors were explored. The differences in clinical outcomes and prediction models for evaluating the long-term adverse events after hospital discharge were established.ResultsThe mortality among cases complicated by AOI was significantly higher than that among patients without AOI [8 (11.59%) vs. 11 (4.07%), Q = 0.034] during hospitalization. After a 2-year follow-up, the mortality was also significantly higher in patients with concomitant AOI than in patients without AOI after hospital discharge during follow-up [13 (21.31%) vs. 15 (5.8%), Q < 0.001]. The long-term adverse events in patients with concomitant AOI were significantly higher than those in patients without AOI during follow-up [15 (24.59%) vs. 31 (11.97%), Q = 0.015]. Furthermore, Blood β-hydroxybutyric acid (P = 0.003), Cystatin C (P

Abstract Background Congenital disorders of glycosylation (CDG) are a group of metabolic diseases with clinical and genetic heterogeneity, and CDG-IIg is one of the rare reported types of CDG. The aim of this study is to report the clinical manifestations and gene-phenotype characteristics of a rare case of CDG caused by a COG1 gene mutation and review literatures of CDG disease. Case presentation The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg. We treated the patient with glucose infusion and he was recovered from hypoglycemia. Genetic analysis showed that the patient carried the heterozygous intron mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene that was inherited from the mother, and the heterozygous mutation c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited from the father. The genes interacting with COG1 were mainly involved in the transport and composition of the Golgi. The clinical data and laboratory results from a patient diagnosed with CDG-IIg were analyzed, and the causative gene mutation was identified by high-throughput sequencing. The genes and signal pathways related to COG1 were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Conclusions The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may be a potential pathogenetic variant for CDG-IIg. Because of the various manifestations of CDG in clinical practice, multidisciplinary collaboration is important for the diagnosis and treatment of this disease.

ObjectiveTo analyze the related factors of the postpartum thyroid function in women with overt hypothyroidism (OH)/subclinical hypothyroidism (SCH) and explore the effects of vitamin D categories.MethodsThyroid hormones, thyroid autoantibody, and serum 25OHD levels were continuously recorded from the first trimester of pregnancy (T1) to the 12th postpartum month. Logistic regression analysis and Cox regression analysis were used to screen the related factors of postpartum thyroid function, and the Latent Class Growth Model was performed to analyze the trajectory characteristics of serum 25OHD levels.ResultsTotally, 252 pregnant women with OH/SCH were enrolled in the study. In the 12th month postpartum, 36.5% of the patients improved thyroid function, 37.3% continued hypothyroidism, and 26.2% developed thyroid dysfunction. Vitamin D sufficiency, positive TPOAb, and positive TgAb in T1 were independent prognostic factors of postpartum thyroid function. Vitamin D sufficiency in T1 was illustrated as an independent factor of the improved postpartum thyroid function, but the protective effect for the developed postpartum thyroid dysfunction was only confirmed in TPOAb-positive patients. Cox regression analysis further confirmed the effects of vitamin D categories. Notably, the high-level 25OHD trajectory during pregnancy and postpartum could predict improved postpartum thyroid function and decrease the risk of developed postpartum thyroid dysfunction.ConclusionAppropriate vitamin D nutrition during pregnancy and postpartum may be beneficial to postpartum thyroid function.

BackgroundAnimal studies have found that GPHB5 has a similar effect on system metabolism as TSH. However, the relationship between GPHB5 and metabolic diseases remains unknown. This study investigates the relationship between GPHB5 and MetS in young women.MethodsBioinformatics analysis was undertaken to explore the relationship between GPHB5 and metabolic-related genes and signaling pathways. EHC and OGTT were performed on all individuals. Lipid-infusion, physical activity, and cold-exposure tests were performed on healthy individuals. Serum GPHB5 concentrations were measured by an ELISA kit.ResultsPPI network showed that 11 genes interacted with GPHB5, in which POMC and KISS1R were involved in glucose and lipid metabolism. GO analysis showed 56 pathways for BP and 16 pathways for MF, in which OPRM1 and MCR families were related to energy metabolism. KEGG analysis found that GPHB5 is associated with lipolysis and neuroactive ligand-receptor interaction pathways. The levels of circulating GPHB5 were significantly increased, while serum adiponectin levels were lower in MetS women compared with healthy women. Obese/overweight individuals had lower adiponectin levels and higher GPHB5 levels. Circulating GPHB5 levels were positively correlated with BMI, WHR, blood pressure, FBG, 2 h-BG, HbA1c, FIns, 2h-Ins, LDL-C, FFA, HOMA-IR, and AUCg, etc. but negatively correlated with HDL-C, adiponectin, and M-values. Serum GPHB5 levels did not change significantly during the OGTT, EHC, and lipid infusion. Physical activity and cold-exposure tests did not lead to changes in GPHB5 levels. GLP-1RA treatment resulted in a significant decrease in serum GPHB5 levels.ConclusionsGPHB5 may be a biomarker for MetS.

Diabetic nephropathy (DN) is regarded as the leading cause of end-stage renal disease worldwide and lacks novel therapeutic targets. To screen and verify special biomarkers for glomerular injury in patients with DN, fifteen datasets were retrieved from the Gene Expression Omnibus (GEO) database, correspondingly divided into training and testing cohorts and then merged. Using the limma package, 140 differentially expressed genes (DEGs) were screened out between 81 glomerular DN samples and 41 normal ones from the training cohort. With the help of the ConsensusClusterPlus and WGCNA packages, the 81 glomerular DN samples were distinctly divided into two subclusters, and two highly associated modules were identified. By using machine learning algorithms (LASSO, RF, and SVM-RFE) and the Venn diagram, two overlapping genes (PRKAR2B and TGFBI) were finally determined as potential biomarkers, which were further validated in external testing datasets and the HFD/STZ-induced mouse models. Based on the biomarkers, the diagnostic model was developed with reliable predictive ability for diabetic glomerular injury. Enrichment analyses indicated the apparent abnormal immune status in patients with DN, and the two biomarkers played an important role in the immune microenvironment. The identified biomarkers demonstrated a meaningful correlation between the immune cells’ infiltration and renal function. In conclusion, two robust genes were identified as diagnostic biomarkers and may serve as potential targets for therapeutics of DN, which were closely associated with multiple immune cells.

Abstract Fibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase–Akt kinase–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K–Akt–mTOR–70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.

Background: The purpose of this study was to investigate the relationship between circulating zinc α 2-glycoprotein (ZAG), irisin, betatrophin and adiponectin concentrations and metabolic syndrome (MetS) components and to analyze the effe cts of blood glucose and insulin on these cytokine concentrations in vivo. Methods: A total of 196 young women, including 78 healthy women and 118 women with MetS components, were recruited for this cross-sectional s tudy. An oral glucose tolerance test and euglycemic-hyperinsulinemic clamp (EHC) were performed in healthy subjects and women with MetS components. An ELISA kit was used to measure serum ZAG, irisin, betatrophin, and adiponectin levels, and their rel ationship with the MetS components was analyzed. Results: In women with MetS components, circulating irisin and betatroph in levels were significantly higher than those in the healthy women ((207 (150– 248) vs 178 (147–228); P < 0.05) for irisin; (0.51 (0.38–0.63) vs 0.38 (0.23–0.52); P < 0.001) for betatrophin), but circulating ZAG and adiponectin levels were significantly lo wer (39.8 (26.4–50.4) vs (46.7 (40.6–63.0); P < 0.001) for ZAG; (36.5 (22.0–47.6) vs 41.2 (35.7–54.7); P < 0.01) for adiponectin). FBG, WC, and triglyceride were significantly corre lated with the circulating levels of these four cytokines (P < 0.001 or

Currently, the most effective strategy for dealing with Alzheimer’s disease (AD) is delaying the onset of dementia. Severe hypoglycemia is strongly associated with dementia; however, the effects of recurrent moderate hypoglycemia (RH) on the progression of cognitive deficits in patients with diabetes with genetic susceptibility to AD remain unclear. Here, we report that insulin-controlled hyperglycemia slightly aggravated AD-type pathologies and cognitive impairment; however, RH significantly increased neuronal hyperactivity and accelerated the progression of cognitive deficits in streptozotocin-induced (STZ-induced) diabetic APP/PS1 mice. Glucose transporter 3–mediated (GLUT3-mediated) neuronal glucose uptake was not significantly altered under hyperglycemia but was markedly reduced by RH, which induced excessive mitochondrial fission in the hippocampus. Overexpression of GLUT3, specifically in the dentate gyrus (DG) area of the hippocampus, enhanced mitochondrial function and improved cognitive deficits. Activation of the transient receptor potential channel 6 (TRPC6) increased GLUT3-mediated glucose uptake in the brain and alleviated RH-induced cognitive deficits, and inactivation of the Ca2+/AMPK pathway was responsible for TRPC6-induced GLUT3 inhibition. Taken together, RH impairs brain GLUT3-mediated glucose uptake and further provokes neuronal mitochondrial dysfunction by inhibiting TRPC6 expression, which then accelerates progression of cognitive deficits in diabetic APP/PS1 mice. Avoiding RH is essential for glycemic control in patients with diabetes, and TRPC6/GLUT3 represents potent targets for delaying the onset of dementia in patients with diabetes.

Abstract Background Insulin resistance (IR) is a common characteristic of women with polycystic ovary syndrome (PCOS). It has been reported that circulating Fetuin-A levels were associated with IR and type 2 diabetes mellitus (T2DM). However, previous reports were inconsistent. Methods Two hundred seven subjects were screened for PCOS according to the diagnostic guideline of the Rotterdam consensus criterion. Serum Fetuin-A levels were measured using an ELISA kit. An independent t-test or Nonparametric test was used to detect differences between PCOS and control groups. Spearman’s correlation analysis was used to examine the association of the serum Fetuin-A with other parameters. Results Our findings showed that circulating Fetuin-A concentration ranged from 196.6 to 418.2 μg/L for most women without PCOS (95%). Women with PCOS had higher circulating Fetuin-A levels than healthy women (437.9 ± 119.3 vs. 313.8 ± 60.5 μg/L; p

Abstract Aims/Introduction As a member of the tumor necrosis factor‐α‐related protein family, complement‐1q tumor necrosis factor‐α‐related protein isoform 5 (CTRP5) has been found to be associated with obesity and insulin resistance (IR). Previous studies in humans and animals have reported contradictory results related to the association between CTRP5 and IR. The purpose of the present study was to explore the relationship between CTRP5 and IR through a cross‐sectional study and drug intervention study of type 2 diabetes patients. Materials and Methods A cross‐sectional study was carried out with 118 newly diagnosed patients with type 2 diabetes and 116 healthy adults. In an interventional study, 78 individuals with newly diagnosed type 2 diabetes received sodium–glucose cotransporter 2 inhibitor (dapagliflozin) treatment for 3 months. Circulating CTRP5 concentrations were measured by enzyme‐linked immunosorbent assay. Results Serum CTRP5 concentrations were markedly reduced in patients with type 2 diabetes when compared with those of healthy individuals (P

BackgroundPrevious animal studies have revealed that CTRP7 is related to energy metabolism. However, little is known regarding the relationship between CTRP7 and metabolic diseases in humans. Hence, this study was designed to explore the association between CTRP7 and MetS through a cross-sectional study and multiple intervention studies.MethodsA total of 624 individuals were enrolled in this study. The levels of CTRP7 and APN were determined by ELISA kit. HEC, OGTT and lipid infusion were performed in heathy individuals to investigate the association of CTRP7 and glucose, insulin and FFA. Bioinformatics analysis was then undertaken to identify genes and signaling pathways associated with CTRP7. The relationship between CTRP7 with MetS components was also evaluated.ResultsIn MetS patients, serum CTRP7 concentrations were significantly higher than in healthy controls, and was positively correlated with WC, BP, FBG, 2h-BG and TG, but negatively correlated with HDL-C and APN. Multivariate logistic regression analysis uncovered that CTRP7 was strongly correlated with the occurrence of MetS. In addition, circulating levels of CTRP7 in patients with two or more MetS components were higher than those with one MetS component. In the intervention studies, OGTTs resulted in a significant reduction in serum CTRP7 concentration. However, the increase in insulin levels caused by EHC and the increase of FFA caused by lipid-infusion led to the significant increase of serum CTRP7 concentration. Meanwhile, bioinformatics analysis revealed that CTRP7 was strongly associated with metabolism-related genes and signal pathways, which further illustrate the association of CTRP7 with whole-body metabolism.ConclusionsSerum CTRP7 is increased in MetS patients, which may be a biomarker related to metabolic diseases.Clinical Trial Registration NumberChiCTR2000032878

BackgroundBreast cancer (BC) is the most frequent cancer in women. The tumor microenvironment (TME), consisting of blood vessels, immune cells, fibroblasts, and extracellular matrix, plays a pivotal role in tumorigenesis and progression. Increasing evidence has emphasized the importance of TME, especially the immune components, in patients with BC. Nevertheless, we still lack a deep understanding of the correlation between tumor invasion and TME status.MethodsTranscriptome and clinical data were retrieved from The Cancer Genome Atlas (TCGA) database. ESTIMATE algorithm was applied for quantifying stromal and immune scores. Then we screened out the differentially expressed genes (DEGs) through the intersection analysis. Furthermore, the establishment of protein-protein interaction (PPI) network and univariate COX regression analysis were utilized to determine the core genes in DEGs. In addition, we also performed Gene Set Enrichment Analysis (GSEA) and CIBERSORT analysis to distinguish the function of crucial gene expression and the proportion of tumor-infiltrating immune cells (TICs), respectively.ResultsA total of 1178 samples (112 normal samples and 1066 tumor samples) were extracted from TCGA for calculation, and 226 DEGs were obtained from this assessment. Further intersection analysis revealed eight key genes, including ITK, CD3E, CCL19, CD2, SH2D1A, CD5, SLAMF6, SPN, which were proven to correlate with BC status. Moreover, ITK was picked out for further study. The results illustrated that high expression of BC patients had a more prolonged overall survival (OS) time than ITK low expression BC patients (p = 0.009), and ITK expression also presented the statistical significance in age, TNM staging, tumor size classification, and metastasis classification. Additionally, GSEA and CIBERSORT analysis indicated that ITK expression had an association with immune activity in TME.ConclusionITK may be a potential indicator for prognosis prediction in patients with BC, and its biological behavior may promote our understanding of the molecular mechanism of tumor progression and targeted therapy.

Background and Aims Fetuin-B has been reported to be involved in glucose and lipid metabolism and associated with the occurrence of diabetes. The main purpose of this study is to explore the changes of circulating fetuin-B in young women with pre-diabetes and to analyze the relationship between fetuin-B and the occurrence and development of IR. Methods A total of 304 women were enrolled in this study and subjected to both OGTT and EHC. A subgroup of 26 overweight/obese womenwas treated with Lira for 24 weeks. serum fetuin-B concentrations were measured by ELISA. Results In IGT and IR-NG groups, serum fetuin-B levels were higher than those in the NGT group. The serum fetuin-B levels in the IGT group were higher than those in the IR-NG group. serum fetuin-B was positively correlated with BMI, WHR, 2h-BG, FIns, HbA1c, and HOMA2-IR, but negatively correlated with the M-value in all study populations. Multiple stepwise regression analysis showed that the M-value was independently and inversely associated with serum fetuin-B. Logistic regression analysis showed that serum fetuin-B was independently associated with IGT and significantly increased the risk of IGT. During the OGTT, serum fetuin-B increased significantly in the NGT group, but there were no significant changes in other groups. During the EHC, serum fetuin-B increased in the IGT group, but there was no change in other groups. After Lira intervention, serum fetuin-B decreased significantly in IGT women. Conclusions serum fetuin-B levels are elevated in young women with IR or IGT and may be associated with IR.

Background: Increasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and α-glucosidase inhibitor in modulating the gut microbiota. Methods: 16S-rDNA sequencing was performed to analyse the effects of DPP-4i and acarbose on the gut microbiota in mice fed a high-fat diet (HFD). Fecal microbiota transplantation (FMT) from type 2 diabetes patients to germ-free mice was performed to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics was also analysed by untargeted and targeted GC–MS systems. Findings: Although DPP-4i and α-glucosidase inhibitor both altered the gut microbial composition, only the microbiome modulation of DPP-4i contributed to its hypoglycemic effect. Specifically, the changes of 68.6% genera induced by HFD were rescued by DPP-4i. FMT showed that the DPP-4i-altered microbiome improved glucose tolerance in colonized mice, while acarbose did not. Moreover, DPP-4i increased the abundance of Bacteroidetes, and also promoted a functional shift in the gut microbiome, especially increasing the production of succinate. Interpretation: Our findings demonstrate an important effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and an additional benefit of it. Furthermore, modulating the microbial composition, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. Fund: This work was supported by grants from the National Natural Science Foundation of China (No. 81700757, No. 81471039, No. 81700714 and No. 81770434), the National Key R&D Program of China (No. 2017YFC1309602, No. 2016YFC1101100, No. 2017YFD0500503 and No. 2017YFD0501001), and the Natural Science Foundation of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518). Keywords: DPP-4i, Gut microbiota, Glucose tolerance, GF mice

Abstract Background Bone morphogenetic protein9 (BMP9) has been reported to have a role in vascular development. However, there is still a lack of information regarding the association between circulating BMP9 levels and cardiovascular disease in humans. The goal of this study is to measure circulating BMP9 concentrations in patients with essential hypertension (HTN), coronary heart disease (CHD) and HTN + CHD, and evaluates the relationship between circulating BMP9 and these cardiovascular diseases. Methods A total of 417 individuals were recruited for this cross-sectional study from June 2015 to December 2017. These subjects were screened for HTN and CHD. Circulating BMP9 concentrations were measured by ELISA. Results Circulating BMP9 concentrations were significantly low in HTN, CHD and HTN + CHD individuals relative to those of the healthy individuals. Circulating BMP9 correlated negatively with SBP, FIns and HOMA-IR in HTN patients and correlated negatively with FBG and 2 h-BG in CHD patients. In both HTN and CHD patients, circulating BMP9 correlated negatively with BMI, WHR, FAT%, BP and TG. Multivariate logistic regression analysis showed that circulating BMP9 levels were associated with HTN, HTN + CHD and CHD. Individuals with low quartile of circulating BMP9 had a significantly high risk of HTN or/and CHD as compared with those in high quartile. Conclusions BMP9 is likely to be a biomarker for cardiovascular disease in humans, and it may play a role in the progression of cardiovascular disease. Trial registration ChiCTR-OPC-14005324.

Abstract Background This study aimed to evaluate the safety and feasibility of subaxial cervical pedicle screw (CPS) insertion by comparing the morphological parameters between developmental canal stenosis (DCS) and non-developmental canal stenosis (NDCS) patients. Methods A total of 120 Chinese patients who had undergone cervical spinal multiplanar CT imaging from September 2010 to December 2014 were included in this study. According to the Pavlov ratio (PR), participants were classified into a DCS group (PR

Abstract Background Ghrelin modulates many physiological processes. However, the effects of intestinal ghrelin on hepatic glucose production (HGP) are still unclear. The current study was to explore the roles of intestinal ghrelin on glucose homeostasis and insulin signaling in the liver. Methods The system of intraduodenal infusion and intracerebral microinfusion into the nucleus of the solitary tract (NTS) in the normal chow-diet rats and pancreatic-euglycemic clamp procedure (PEC) combined with [3-3H] glucose as a tracer were used to analyze the effect of intestinal ghrelin. Intraduodenal co-infusion of ghrelin, tetracaine and Activated Protein Kinase (AMPK) activator (AICAR), or pharmacologic and molecular inhibitor of N-methyl-D-aspartate receptors within the dorsal vagal complex, or hepatic vagotomy in rats were used to explore the possible mechanism of the effect of intestinal ghrelin on HGP. Results Our results demonstrated that gut infusion of ghrelin inhibited duodenal AMP-dependent protein kinase (AMPK) signal pathways, increased HGP and expression of gluconeogenic enzymes, and decreased insulin signaling in the liver of the rat. Intraduodenal co-infusion of ghrelin receptor antagonist [D-Lys3]-GHRP-6 and AMPK agonist with ghrelin diminished gut ghrelin-induced increase in HGP and decrease in glucose infusion rate (GIR) and hepatic insulin signaling. The effects of gut ghrelin were also negated by co-infusion with tetracaine, or MK801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, and adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shNR1) within the dorsal vagal complex, and hepatic vagotomy in rats. When ghrelin and lipids were co-infused into the duodenum, the roles of gut lipids in increasing the rate of glucose infusion (GIR) and lowering HGP were reversed. Conclusions The current study provided evidence that intestinal ghrelin has an effect on HGP and identified a neural glucoregulatory function of gut ghrelin signaling.

Background/Aims: Alarin has been reported to be related with increased food intake and body weight. The relationship of circulating Alarin with insulin resistance or metabolic syndrome (MetS), however, is unknown. This study aimed to investigate the physiological role of Alarin and its association with MetS in humans. Methods: Newly diagnosed MetS patients (n=237) and age-matched healthy subjects (n=192) were recruited for this study. Oral glucose tolerance test, treadmill exercise, lipid infusions and euglycemic-hyperinsulinemic clamp (EHCs) were performed. Circulating Alarin and TNFα levels were measured by ELISA. Results: Circulating Alarin levels were significantly higher in MetS patients compared with healthy subjects (0.46 ± 0.22 vs. 0.41 ± 0.14 µg/L, P < 0.01). In all studied subjects, circulating Alarin levels were positively correlated with WC, blood pressure, FBG, triglyceride, HbA1c, HOMA-IR, AUCglucose, and TNFα (P < 0.05 or P < 0.01). Multivariate logistic regression analyses revealed that circulating Alarin levels were correlated with MetS and insulin resistance. There was no significant change of circulating Alarin levels in the subjects with treadmill exercise for 45 min. In healthy individuals, however, glucose challenge, acute hyperglycemia and lipid infusions resulted in increased circulating Alarin levels, while acute hyperinsulinaemia transiently decreased circulating Alarin levels. Conclusion: The present study provides the evidence that circulating Alarin levels are associated with MetS and insulin resistance.

Abstract Background Recurrent moderate hypoglycemia (RH), a major adverse effect of hypoglycemic therapy in diabetic patients, is one of the main risk factors for cognitive impairment and dementia. Transient receptor potential canonical channel 6 (TRPC6) is a potential therapeutic target for Alzheimer's disease (AD) and its expression is highly regulated by glucose concentration. Objective To investigate whether RH regulates the expression of TRPC6 in brain and whether TRPC6 dysfunction can drive hypoglycemia‐associated cognitive impairment in diabetes, and reveal the underlying mechanism. Methods Histological staining, in vivo two‐photon Ca2+ imaging, and behavioral tests were used to measure neuronal death, brain network activity, and cognitive function in mice, respectively. High‐resolution respirometry and transmission electron microscope were used to assess mitochondrial structure and function. Intracellular calcium measurement and molecular biology techniques were conducted to uncover the underlying mechanism. Results Here, we report that the expression of TRPC6 in hippocampus was specifically repressed by RH in streptozocin‐induced type 1 diabetic mice, but not in nondiabetic mice. TRPC6 knockout directly leads to neuron loss, neuronal activity, and cognitive function impairment under diabetic condition, the degree of which is similar to that of RH. Activation of TRPC6 with hyperforin substantially improved RH‐induced cognitive impairment. Mechanistically, TRPC6 inhibited mitochondrial fission in the hippocampus of diabetic mice undergoing RH episodes by activating adenosine 5‘‐monophosphate‐activated protein kinase, and TRPC6‐mediated cytosolic calcium influx was required for this process. Clinically, dysfunction of TRPC6 was closely associated with cognitive impairment in type 2 diabetic patients with RH. Conclusions Our results indicate that TRPC6 is a critical sensitive cation channel to hypoglycemia and is a promising target to prevent RH‐induced cognitive impairment by properly orchestrating the mitochondrial dynamics in diabetic patients.

Autologous platelet-rich plasma (au-PRP) has been widely used for the management of refractory chronic wounds. However, patients with diabetic lower extremity ulcers (DLEUs) usually have complicated clinical conditions, and the utility of au-PRP is limited. In this study, the feasibility, effectiveness, and safety of allogeneic platelet-rich plasma (al-PRP) and au-PRP were investigated and compared in the treatment of DLEUs. A total of 75 in-patients with type 2 diabetes were assigned to the al-PRP group ( n = 20), au-PRP group ( n = 25), and conventional wound therapeutic (CWT) group ( n = 30) matched by the ankle brachial index and ulcer size from December 2015 to August 2018. Based on metabolic and nutritional regulation, infective control, and topical wound management, al-PRP, au-PRP, and CWT were administered to each group, respectively. Evaluation of treatment outcomes was determined by the parameters of wound healing and adverse reactions. The therapeutic times and average concentration of platelets were not significantly different between the au-PRP and al-PRP groups. The wound healing times of the al-PRP group (56.9 ± 29.22 d) and au-PRP group (55.6 ± 33.8 d) were significantly shorter than those of the CWT group (88.0 ± 43.4 d) ( P < 0.01), but there was no significant difference between the groups with PRP treatment. Although there was no significant difference in the daily healing area among all groups ( P > 0.05), the trend of the healing rate in the al-PRP group (16.77 ± 12.85 mm 2 ), au-PRP group (14.31 ± 18.28 mm 2 ), and CWT group (9.90 ± 8.51 mm 2 ) gradually decreased. No obvious adverse reactions (fever, edema, pain, skin itching, rash, or other sensory abnormalities) were observed in either the au-PRP or the al-PRP groups. Both al-PRP and au-PRP could effectively and safely promote wound healing in patients with DLEUs. Alternatively, al-PRP could be used for DLEUs as an off-the-shelf solution when au-PRP is limited. Registration number of clinical trials: ChiCTR1900021317

Aim. Adult growth hormone deficiency (AGHD) is associated with an increased risk of fractures. The interactions between various body composition and bone are known to be complex in nature. However, very few studies have examined this crosstalk in AGHD. In this study, we sought to investigate the relationship between various parameters of body composition and bone mineral density (BMD) as well as determine the role of visceral fat in determining the bone mass in patients with AGHD. Methods. We conducted a cross-sectional study on 57 patients with AGHD. Anthropometry, biochemistry, and analysis of body composition and BMD were performed according to standard protocols. Male and female patients were classified into those with osteoporosis and those without osteoporosis (normal subjects and patients with osteopenia). Further, we analyzed the correlation between the BMD and measurements obtained for various body composition parameters in male and female AGHD patients. Results. Our findings indicated that among female AGHD patients, those with osteoporosis had a significantly higher levels of fat mass (FM) and visceral adipose tissue mass (VATM) (both, P

Background. Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR). Methods. The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA. Results. Serum Fetuin-B and TNF-α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF-α, while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR. Conclusion. Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901.

Summary: High salt intake is one independent risk factor for cardiac hypertrophy. Polycystic kidney disease 2-like 1 (PKD2L1, also called TRPP3) acts as a sour sensor in taste cells, and its possible role in the cardiovascular system is unknown. Here, we report that knockout of PKD2L1 exacerbated high-salt diet (HSD)-induced cardiac hypertrophy and fibrosis, accompanied by cardiac dysfunction and reduced cardiac mitochondrial oxidative phosphorylation and enzyme activity. Furthermore, knockdown of PKD2L1 led to more serious mitochondrial Ca2+ overload and reduced Ca2+ uptake in cardiomyocytes on high salt loading. Mechanistically, PKD2L1 deficiency increased p300-mediated acetylation of histone 3 lysine 27 on the promoter of sodium/calcium exchange 1 (NCX1) by repressing AMP-activated protein kinase (AMPK) activity, resulting in NCX1 overexpression and mitochondrial Ca2+ overload. These results reveal an inhibitory effect of PKD2L1 on cardiac hypertrophy and provide a mechanistic insight into the link between mitochondrial Ca2+ homeostasis and cardiac hypertrophy. : Lu et al. reveal a role of a mitochondria-localized TRPP member, PKD2L1, in high salt-induced cardiac hypertrophy. PKD2L1 knockout leads to overexpression of NCX1 through increasing the acetylation level of histone 3 lysine 27 on NCX1 promoter and thus exacerbates mitochondrial calcium overload by activating the reverse mode of NCX1 in cardiomyocytes. Keywords: high-salt diet, cardiac hypertrophy, PKD2L1, mitochondria, NCX1

Abstract Background Zinc-α2-glycoprotein (ZAG) is a novel adipokine that reduces insulin resistance, protecting against type 2 diabetes. However, past studies have been contradictory. This cross-sectional study aims to investigate the association of circulating ZAG with metabolic syndrome (MetS) in middle-aged and older Chinese adults. Methods Four hundred eighty nine individuals (234 healthy controls and 255 MetS patients) were examined. All individuals were screened for MetS according to the diagnostic guidelines of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Circulating ZAG and ADI levels were measured by ELISA. Blood fat, glucose and insulin were measured with a commercial kit. Circulating ZAG levels were compared with various parameters in study subjects. Results Plasma ZAG levels were lower in MetS patients compared to those of the healthy controls (35.0 ± 11.7 vs. 46.1 ± 18.6 mg/L, P

Background. ANGPTL8 has been reported to be a regulator of lipid metabolism, and it is associated with insulin resistance (IR) and metabolic syndrome (MetS). We investigated whether ANGPTL8 plays a role in MetS. Methods. ANGPTL8 and adiponectin concentrations were measured in PCOS patients with or without MetS and in their corresponding healthy controls. The association of circulating ANGPTL8 with adiponectin and other parameters was also examined. Results. Circulating ANGPTL8 concentrations were higher in PCOS women with MetS than in those without MetS and in the controls (P

Abstract While adult mammalian skeletal muscle is stable due to its post‐mitotic nature, muscle regeneration is still essential throughout life for maintaining functional fitness. During certain diseases, such as the modern pandemics of obesity and diabetes, the regeneration process becomes impaired, which leads to the loss of muscle function and contributes to the global burden of these diseases. However, the underlying mechanisms of the impairment are not well defined. Here, we identify mGPDH as a critical regulator of skeletal muscle regeneration. Specifically, it regulates myogenic markers and myoblast differentiation by controlling mitochondrial biogenesis via CaMKKβ/AMPK. mGPDH−/− attenuated skeletal muscle regeneration in vitro and in vivo, while mGPDH overexpression ameliorated dystrophic pathology in mdx mice. Moreover, in patients and animal models of obesity and diabetes, mGPDH expression in skeletal muscle was reduced, further suggesting a direct correlation between its abundance and muscular regeneration capability. Rescuing mGPDH expression in obese and diabetic mice led to a significant improvement in their muscle regeneration. Our study provides a potential therapeutic target for skeletal muscle regeneration impairment during obesity and diabetes.

Objective. C1q/TNF-related protein5 (CTRP5) is a member of the C1q/tumor necrosis factor α- (TNF-α-) related protein family and has been reported to be associated with the regulation of glucose and lipid metabolism. However, the clinical association between CTRP5 and metabolic syndrome (MetS) has not been reported. The aim of the current study is to investigate the association between CTRP5 and MetS by a cross-sectional study. Methods. We performed a cross-sectional study in a Chinese population including 89 controls and 88 MetS individuals. Serum CTRP5 concentrations were determined by ELISA. The relationship between circulating CTRP5 and MetS and insulin resistance (IR) was assessed by Spearman’s correlation and multiple stepwise regression analysis. Results. Circulating CTRP5 concentrations were markedly decreased in MetS individuals relative to normal adults. Overweight/obese individuals (BMI ≥ 25 kg/m2) showed a lower serum CTRP5 level than lean subjects (BMI

As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.

Serum cystatin C (CysC) has been identified as a possible potential biomarker in a variety of diabetic complications, including diabetic peripheral neuropathy and peripheral artery disease. We aimed to examine the association between CysC and diabetic foot ulceration (DFU) in patients with type 2 diabetes (T2D). 411 patients with T2D were enrolled in this cross-sectional study at a university hospital. Clinical manifestations and biochemical parameters were compared between DFU group and non-DFU group. The association between serum CysC and DFU was explored by binary logistic regression analysis. The cut point of CysC for DFU was also evaluated by receiver operating characteristic (ROC) curve. The prevalence of coronary artery disease, diabetic nephropathy (DN), and DFU dramatically increased with CysC (P

Objective. To determine the trends of serum lipid levels and dyslipidemia in adults newly diagnosed with type 2 diabetes mellitus during 2003–2012 in Southwest China. Methods. Serum lipid measurements of 994 adults were obtained from 5 independent, cross-sectional studies (2003-2004, 2005-2006, 2007-2008, 2009-2010, and 2011-2012). The main outcome measures were mean serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels; body mass index; hemoglobin A1C level; and the percentages of patients with dyslipidemia, hypertension, coronary heart disease, and cerebrovascular disease. Results. The mean total cholesterol and low-density lipoprotein cholesterol levels increased from 4.92 ± 1.15 to 5.30 ± 1.17 mmol/L (P = 0.039) and 2.72 ± 0.83 to 3.11 ± 1.09 mmol/L (P = 0.004), respectively, and the mean HDL cholesterol level declined from 1.22 ± 0.30 to 1.06 ± 0.24 mmol/L (P < 0.001). The percentages of patients with dyslipidemia increased gradually. The incidence of coronary heart and cerebrovascular diseases increased from 8.2% to 19.1% and 6.6% to 15.3%, respectively (P < 0.05). Conclusion. Unfavorable upward trends were observed in serum lipid levels and the prevalence of dyslipidemia, coronary heart disease, and cerebrovascular disease in adults newly diagnosed with type 2 diabetes mellitus in Southwest China during 2003–2012.

BackgroundAldose reductase inhibitors (ARIs) can block the metabolism of the polyol pathway, and have been used to slow or reverse the progression of diabetic cardiovascular autonomic neuropathy (DCAN). The purpose of this study was to review the effectiveness and safety of ARIs in the treatment of DCAN as determined by five cardiac autonomic neuropathy function tests.MethodsCENTRAL, MEDLINE, EMBASE, Scopus databases (inception to May 2012) were searched to identify randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) investigating ARIs for the treatment of DCAN with an English-language restriction. The data were analyzed using RevMan 5.0, and the heterogeneity between the trials was evaluated using the Cochrane's Q-test as well as the I² test. The type of model (random or fixed) used for analysis was based on heterogeneity. Weighted mean differences (WMD) with 95% confidence intervals (CI) were computed for the five cardiac automatic neuropathy function tests to evaluate the effects.ResultsTen articles met the prerequisites for this review. Analysis of the results showed that ARIs significantly improved function in at least three of the five automatic neuropathy tests, including the resting heart rate variation coefficients (WMD = 0.25, 95%CI 0.02 to 0.48, P = 0.040); the 30∶15 ratio (WMD = 0.06, 95%CI 0.01 to 0.10, P = 0.010) and the postural systolic blood pressure change (WMD = -5.94, 95%CI -7.31 to -4.57, P = 0.001). The expiration/inspiration ratio showed a marginally significant benefit (WMD = 0.05, 95%CI 0.00 to 0.09, P = 0.040). Glycaemic control was not significantly affected by ARIs. Adverse effects of ARIs except for Tolerestat were minimal.ConclusionsBased on these results, we conclude that ARIs could ameliorate cardiac automatic neuropathy especially mild or asymptomatic DCAN but need further investigation.

BACKGROUND: Treatment of diabetes mellitus with Traditional Chinese Medicine has a long history. The aim of this study is to establish the safety and efficacy of traditional Chinese medicine combined with glibenclamide to treat type 2 diabetes mellitus. METHODS: In a controlled, double blind, multicentre non-inferiority trial, 800 patients with unsatisfactory glycemic control (fasting glucose 7-13 mmol/L and HbA1c 7-11%) were randomly assigned to receive Xiaoke Pill, a compound of Chinese herbs combined with glibenclamide, or Glibenclamide in two study groups - drug naive group, and patients previously treated with metformin monotherapy (metformin group). Outcome measures at 48 weeks were the incidence and rate of hypoglycemia, mean difference in HbA1c, and proportion of patients with HbA1c

BACKGROUND: Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE(-/-) mice with adiponectin (Acrp30) knockdown. METHOD: HFD-fed ApoE(-/-) mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes. RESULTS: The combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1) and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals. CONCLUSION: These findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be partly mediated via increased FGF-21 and its receptors action.

BACKGROUND: To investigate the effects of short-term continuous subcutaneous insulin infusion (CSII) on plasma fibroblast growth factor-21 (FGF-21) levels in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). METHOD: Sixty-eight patients with nT2DM (nT2DM group), and 52 gender-, age- and body mass index (BMI) -matched normal glucose tolerance (NGT group) controls participated in the study. 30 nT2DM patients with FBG ≥ 14.0 mmol/L were treated with CSII for 2 weeks, and were underwent a euglycemic-hyperinsulinemic clamp pre- and post-treatment. Plasma FGF-21 concentrations were measured with a commercial ELISA kit. The relationship between plasma FGF-21 levels and metabolic parameters was also analyzed. RESULTS: Fasting plasma FGF-21 levels were higher in the nT2DM group than in NGT groups (1.60 ± 0.08 vs. 1.13 ± 0.26 µg/L, P