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Background Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disorder worldwide, and there is no established treatment for this disease. We conducted a network meta-analysis (NMA) to compare existing treatments, which include four classes of antidiabetic drugs, and examined the optimum treatments for NAFLD. Aim To compare the effectiveness of different treatments for NAFLD. Methods An NMA was conducted using Stata 14.0 (Corporation LLC, College Station, United States) and R (X64 3.6.3 version) in this study. Eligible randomized controlled trials (RCTs) were searched in the PubMed, Cochrane Library, Embase, Medline and Web of Science databases from database inception to April 2021. Two researchers independently screened the available studies in strict accordance with inclusion and exclusion criteria. The Cochrane Risk of Bias tool was used to evaluate the risk of bias of the included studies. The variables with and without dimensional differences were calculated as the standardized mean difference and weighted mean difference, respectively. An inconsistency model and "node-splitting" technique were used to test for inconsistency. Funnel plots were used to evaluate publication bias. Results Twenty-two eligible RCTs involving 1377 participants were eventually included in our analysis. Data were pooled using a random-effects model. Our NMA results revealed that glucagon-like peptide-1 receptor agonists (GLP-1RAs) were the most effective treatment, yielding improvements in hepatic fat content (HFC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum γ-glutamyl transferase (GGT) and body weight [surface under the cumulative ranking curve (SUCRA) = 99.6%, 92.6%, 82.8%, 92.3% and 99.6%, respectively], while thiazolidinediones (TZDs) were the best intervention for reducing the NAFLD activity score (NAS; SUCRA = 98.9%). In addition, moderate performance was observed for the sodium glucose cotransporter-2 inhibitors groups (SUCRA = 25.1%, 66.2%, 63.5%, 58.2% and 71.9% for HFC, ALT, AST, GGT and body weight, respectively). However, metformin performed poorly according to most indicators (SUCRA = 54.5%, 0.3%, 19.5%, 33.7%, 57.7% and 44.3% for HFC, NAS, ALT, AST, GGT and body weight, respectively). Conclusion GLP-1RAs may be the optimum choice for most patients with NAFLD. However, TZDs are considered the most effective therapies in NAFLD patients with histological disease activity.

Chiglitazar (Carfloglitazar) is a novel non-thiazolidinedione (TZD) structured peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies. This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone. Eligible patients were randomly assigned to receive chiglitazar 32 mg (n = 167), chiglitazar 48 mg (n = 166), or placebo (n = 202) once daily. The primary endpoint was the change in glycosylated hemoglobin A1c (HbA1c) at week 24 with superiority of chiglitazar over placebo. The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA1c, and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were −0.87% (95% confidential interval (CI): −1.10 to −0.65; P

Bone morphogenetic proteins (BMPs) are secreted ligands that belong to the transforming growth factor-β (TGF-β) superfamily. BMP7 has been reported to play a role in reversing obesity and regulating appetite in the hypothalamus. Whether BMP9 plays a central role in regulating glucose metabolism and insulin sensitivity remains unclear. Here, we investigated the impact of central BMP9 signaling and possible route of transmission. We performed intracerebroventricular (ICV) surgery and injected adenovirus expressing BMP9 (Ad-BMP9) into the cerebral ventricle of mice. Metabolic analysis, hyperinsulinemic-euglycemic clamp test, and analysis of phosphatidylinositol 3,4,5-trisphosphate (PIP3) formation were then performed. Real-time PCR and Western blotting were performed to detect gene expression and potential pathways involved. We found that hypothalamic BMP9 expression was downregulated in obese and insulin-resistant mice. Overexpression of BMP9 in the mediobasal hypothalamus reduced food intake, body weight, and blood glucose level, and elevated the energy expenditure in high-fat diet (HFD)-fed mice. Importantly, central treatment with BMP9 improved hepatic insulin resistance (IR) and inhibited hepatic glucose production in HFD-fed mice. ICV BMP9-induced increase in hepatic insulin sensitivity and related metabolic effects were blocked by ICV injection of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signaling. In addition, ICV BMP9 promoted the ability of insulin to activate the insulin receptor/phosphoinositide 3-kinase (PI3K)/Akt pathway in the hypothalamus. Thus, this study provides insights into the potential mechanism by which central BMP9 ameliorates hepatic glucose metabolism and IR via activating the mTOR/PI3K/Akt pathway in the hypothalamus.

Background and Objectives. Genome-wide association studies (GWAS) have shown that cartilage intermediate layer protein 2 (CILP2) is associated with blood lipid levels and coronary heart disease (CHD). However, no study has reported whether CILP2 is related to atherosclerosis in humans. The purpose of the current study is to identify the associations between CILP2 and atherosclerosis in vitro and in vivo. Methods and Results. Circulating CILP2 levels (measured by ELISA) were compared to various insulin resistance- and atherosclerosis-related parameters in normal subjects and newly diagnosed CHD patients. THP-1 cells were cultured and treated with indicated stimulators. Western blots and RT-PCR were performed to examine protein and mRNA expressions. The results showed that there were significantly higher circulating CILP2 levels in CHD patients relative to healthy controls. Circulating CILP2 correlated positively with waist-hip ratio (WHR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HbA1c, homeostasis model assessment of insulin resistance (HOMA-IR), and Gensini scores. In an in vitro study, we found that CILP2 increased oxidatively modified LDL-stimulated lipid accumulation in THP-1 macrophages via the upregulation of CD36 expression. Inhibition of PPARγ signaling eliminated the CILP2 regulation of CD36 expression in THP-1 macrophages. CILP2 positively regulated CD36 transcription through PPARγ-mediated action on two peroxisome-proliferator-responsive elements (PPREs) binding sites of CD36 promoter, PPRE-G, and PPRE-J. Conclusions. Our findings have uncovered a novel role for CILP2 in lipid uptake and foam cell formation. This role is mediated by CD36 through the activation of PPARγ pathway.

AIM To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. MATERIALS AND METHODS In a multicentred, randomized, double-blinded, placebo-controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%-10.5%, fasting plasma glucose

AIM To assess the efficacy and safety of polyethylene glycol loxenatide (PEX168), a new glucagon-like peptide-1 receptor agonist, as an add-on to metformin therapy in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS This was a multicentre, randomized, double-blind, placebo-controlled phase 3b trial. After metformin monotherapy (≥1500 mg/day) for 8 weeks or more, patients with uncontrolled T2D (HbA1c of 7.0%-10.5%) from 44 sites were randomized (1:1:1) to metformin + placebo, metformin + PEX168 100 μg, and metformin + PEX168 200 μg. The core treatment period lasted for 24 weeks, followed by a 28-week extension period. The primary endpoint was the change in HbA1c levels at week 24. The main secondary endpoint was the proportion of patients with an HbA1c of less than 7.0% at week 24. RESULTS The least-square mean (standard error) change in HbA1c levels was significantly greater (P

Primary aldosteronism (PA) is associated with resistant hypertension and cardiovascular events. There are some limitations of current medical and surgical therapies for PA. To determine the efficacy and safety of catheter‐based adrenal artery ablation for treatment of PA patients who refused both surgery and medical therapy, we performed this prospective cohort study. Thirty‐six PA patients without apparent aldosteronoma were treated by adrenal artery ablation. Primary outcome was postoperative blood pressure and defined daily dose (DDD) of antihypertensive medications after adrenal ablation. Secondary outcome was biochemical success. We assessed outcomes based on Primary Aldosteronism Surgical Outcome (PASO) criteria. Adrenal CT scan, biochemical evaluation, adrenal artery ablation and adrenal venous sampling (AVS) were underwent. After adrenal ablation, complete clinical success (normotension without antihypertensive medication) was achieved in 9/36 (25.0%) patients and partial clinical success (reduction in blood pressure or less antihypertensive medication) in 13/36 (36.1%) patients. Complete biochemical success (correction of hypokalemia and normalization of aldosterone‐to‐renin ratio) was achieved in 16/36 (44.4%) patients. Office‐based and ambulatory blood pressures were reduced by 17/7 and 11/2 mmHg at 6 months after ablation, respectively. The plasma cortisol level in the ablation group decreased slightly, but no patient developed hypoadrenocorticism. Catheter‐based adrenal ablation appears to produce substantial and sustained blood pressure reduction and biochemical improvement, with only minor adverse events in PA patients without apparent aldosteronoma. This therapy could be an important supplement for current PA treatments.

The role of IR and metabolic disorders has become a crucial topic of study in the pathogenesis of PCOS. Adipose tissue is an important target organ of insulin, and adipose IR plays an important role in the occurrence and development of PCOS. This study seeks to investigate the role of adipose IR in the development of PCOS and to examine its relationship with circulating betatrophin levels in women with PCOS. A cross-sectional analysis of a cohort of women with PCOS and healthy women was performed in this study. Serum betatrophin concentrations were measured by ELISA. Adipose IR was calculated using the product of fasting insulin and FFA concentrations, and the relationship between adipose IR, circulating betatrophin, and other parameters was analyzed. Adipose IR in women with PCOS was significantly higher than that in controls. We found that women with PCOS who have adipose IR (adipose IR ≥ 55) have a higher BMI and higher blood glucose, insulin, PRL, FFA, TG, HOMA-IR, AUCglucose, AUCinsulin, VAIfemale, and BAI levels than PCOS-afflicted women without adipose IR, while M-values, and SHBG and LH levels were lower. In women with PCOS, serum betatrophin levels were significantly increased compared with controls. Adipose IR negatively correlated with M values and positively with circulating betatrophin levels in the study population. After metformin treatment, circulating betatrophin levels and adipose IR in women with PCOS were significantly decreased compared with pretreatment. Adipose IR is associated with betatrophin levels in women with PCOS. The combination of adipose IR and circulating betatrophin measurements may be significant for screening patients with PCOS.

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, The present study found that complement‐1q tumor necrosis factor‐α‐related protein isoform 5 (CTRP5) levels were reduced in type 2 diabetes patients and that plasma CTRP5 levels were related to insulin resistance. Furthermore, we found that plasma CTRP5 concentrations further decreased after dapaglifozin treatment, which showed that CTRP5 might play an important role in the development of type 2 diabetes.

Aims Irisin, Betatrophin and Zinc-α2-glycoprotein (ZAG) have been shown to be associated with insulin resistance (IR) and polycystic ovary syndrome (PCOS), respectively. The purpose of this study is to explore the potential accuracy of this combination of three cytokines in screening PCOS. Methods 186 individuals were recruited for this study. Circulating Irisin, Betatrophin and ZAG concentrations were measured by enzyme-linked immunosorbent assay. The association between these serum biomarkers and PCOS was assessed by logistic regression analysis. Receiver operating curve (ROC) analysis was performed to evaluate the diagnostic value of these biomarkers for PCOS women. Results In women with PCOS, serum Irisin and Betatrophin levels were markedly elevated compared to those in healthy controls (p Conclusions When compared to using single cytokine, the analysis of Irisin, ZAG and Betatrophin elevates the accuracy in diagnosing PCOS.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein with anti-angiogenic, antioxidant and anti-inflammatory properties. PEDF is involved in the pathogenesis of diabetic retinopathy, but its exact role in diabetic kidneys remains unclear. P78-PEDF is an active peptide sequence consisting of 44 amino acids with biological activity similar to that of PEDF. The present study aimed to investigate whether PEDF can alleviate renal damage in type 2 diabetic nephropathy mice by inhibiting macrophage infiltration.The db/db mice were randomly divided into a diabetes PEDF intervention group (DM-P78-PEDF), a diabetes empty carrier intervention group (DM-Vehicle), and a diabetes mellitus group (DM). Subsequently, they were injected subcutaneously P78-PEDF (0.3 μg/g/d) and PBS for 6 weeks. The ratio of kidney weight to body weight was observed in the mice. An automatic biochemical analyser was used to determine fasting blood glucose (GLU), blood urea nitrogen (UREA), serum creatinine (CREA), and haemoglobin (Hb) content. Histological and ultrastructural pathological changes in the kidneys were examined through HE and PAS staining. Kidney tissue levels of interleukin-1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) were determined by ELISA. Expression of the macrophage infiltration and typing as well as that of PEDF, NF-kB, and TLR4 was evaluated in the kidneys.PEDF was located in glomeruli, and the expression of PEDF protein and mRNA in the kidney of diabetic mice declined significantly. Compared with diabetic mice treated with vehicle, continuous infusion of P78-PEDF could reduce blood urea nitrogen, serum creatinine (CREA), renal macrophage recruitment, inflammatory cytokines, and histological changes and restore the expression of TLR4/NF-κB signalling pathway-related factors in diabetic mice.These findings highlight the importance of P78-PEDF peptide as a potential treatment in the occurrence and development of diabetic renal injury.

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

BackgroundNuclear factor erythroid 2-related factor 2 (Nrf2) is reportedly involved in hepatic lipid metabolism, but the results are contradictory and the underlying mechanism thus remains unclear. Herein we focused on elucidating the effects of Nrf2 on hepatic adipogenesis and on determining the possible underlying mechanism. We established a metabolic associated fatty liver disease (MAFLD) model in high fat diet (HFD) fed Nrf2 knockout (Nrf2 KO) mice; further, a cell model of lipid accumulation was established using mouse primary hepatocytes (MPHs) treated with free fatty acids (FAs). Using these models, we investigated the relationship between Nrf2 and autophagy and its role in the development of MAFLD.ResultsWe observed that Nrf2 expression levels were up-regulated in patients with MAFLD and diet-induced obese mice. Nrf2 deficiency led to hepatic lipid accumulation in vivo and in vitro, in addition to, promoting lipogenesis mainly by increasing SREBP-1 activity. Moreover, Nrf2 deficiency attenuated autophagic flux and inhibited the fusion of autophagosomes and lysosomes in vivo and in vitro. Weakened autophagy caused reduced lipolysis in the liver. Importantly, Chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase assay results proved that Nrf2 bound to LAMP1 promoter and regulated its transcriptional activity. We accordingly report that Nrf2-LAMP1 interaction has an indispensable role in Nrf2-regulated hepatosteatosis. ConclusionsThese data collectively confirm that Nrf2 deficiency promotes hepatosteatosis by enhancing SREBP-1 activity and attenuating autophagy. To conclude, our data reveal a novel multi-pathway effect of Nrf2 on lipid metabolism in the liver, and we believe that multi-target intervention of Nrf2 signaling is a promising new strategy for the prevention and treatment of MAFLD.

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.

Excessive salt consumption leads to cardiovascular diseases. Despite various measures designed to reduce salt intake, daily salt intake remains at a high level. Appropriate salt intake is balanced by salt taste preference triggered by epithelium sodium channel and salt taste aversion evoked by bitter taste sensor, transient receptor potential channel M5 (TRPM5). However, the behavioral mechanism of excessive salt intake remains largely elusive. In this study, wild type and TRPM5 −/− mice were applied to study the influence of high-salt administration on epithelium sodium channel/TRPM5 and the associated behavior to salt consumption. We found that long-term high-salt intake impaired the aversive behavior to high-salt stimulation but did not alter the preference to low salt in mice. The mechanistic evidence demonstrated that high-salt intake blunted the TRPM5-mediated aversive behavior to noxious salt stimulation through inhibiting PKC (protein kinase C) activity and PKC-dependent threonine phosphorylation in the tongue epithelium but did not affect the epithelium sodium channel–dependent salt taste preference. Inhibition of TRPM5 also resulted in an impaired aversive response to high salt, with reduced taste perception in bitter cortical field of mice. TRPM5 −/− mice showed a lowered aversion to high-salt diet and developed salt-induced hypertension. The impaired perception to bitter taste evoked by high-salt intake also existed in hypertensive patients with high-salt consumption. We demonstrate that long-term high-salt consumption impairs aversive response to concentrated salt by downregulating bitter taste sensor TRPM5. It suggests that enhancing TRPM5 function might antagonize excessive salt intake and high salt–induced hypertension.

AIMS Mitochondrial dysfunction is involved in the pathogenesis of type 2 diabetes. Glutathione S-transferase kappa 1 (GSTK1) is critical to maintain mitochondrial function and homeostasis. We aimed to investigate whether a potential link exists between mitochondrial DNA (mtDNA) copy numbers and inflammation, non-esterified fatty acids (NEFA) and GSTK1 expression in type 2 diabetes. METHODS We assessed mtDNA copy numbers in plasma and GSTK1 expression in white blood cells in 123 people with type 2 diabetes and in 121 healthy controls using a quantitative polymerase chain reaction (qPCR). An automatic chemistry or immunoassay analyser was used to determine serum glucose, lipids and inflammatory markers. Multiple linear regression and multivariable logistic regression models were used to evaluate associations and risks. RESULTS Compared with healthy controls, individuals with diabetes showed higher mtDNA copy numbers (t = -3.938, P

Previous cross-sectional studies have established that circulating osteoprotegerin (OPG) levels are associated with nonalcoholic fatty liver disease (NAFLD). However, the role of OPG in metabolic diseases, such as diabetes and NAFLD, is still unclear. In the current study, we demonstrated that hepatic OPG expression was downregulated in NAFLD individuals and in obese mice. OPG deficiency decreased lipid accumulation and expression of CD36 and peroxisome proliferator–activated receptor-γ (PPAR-γ) in the livers of OPG−/− mice and cultured cells, respectively, whereas OPG overexpression elicited the opposite effects. The stimulatory role of OPG in lipid accumulation was blocked by CD36 inactivation in hepatocytes isolated from CD36−/− mice. The overexpression of OPG led to a decrease in extracellular signal–regulated kinase (ERK) phosphorylation in the livers of OPG−/− mice and in cultured cells, while OPG deficiency resulted in the opposite effect. The inhibition of PPAR-γ or the activation of ERK blocked the induction of CD36 expression by OPG in cultured cells. Mechanistically, OPG facilitated CD36 expression by acting on PPAR response element (PPRE) present on the CD36 promoter. Taken together, our study revealed that OPG signaling promotes liver steatosis through the ERK–PPAR-γ–CD36 pathway. The downregulation of OPG in NAFLD might be a compensatory response of the body to dampen excess hepatic fat accumulation in obesity.

Objective Exenatide is a new agent for diabetes therapy, and its use in polycystic ovary syndrome (PCOS) has gradually increased; however, the clinical benefit and metabolic improvement need further evidence. This research aimed to study the changes in whole metabolites before and after exenatide treatment in overweight/obese PCOS patients to gain a better understanding of exenatide for the treatment of PCOS. Methods Sixty-seven women, including 32 with PCOS and 35 age-matched controls, were recruited. The metabolite changes were detected with nontargeted gas chromatography-tandem mass spectrometry (NTGC-MS) before and after exenatide treatment, and changes in clinical biochemical characteristics were also observed. Results A total of 62 metabolites were differentially expressed between the healthy and PCOS groups, and 31 differentially expressed metabolites were detected before and after exenatide treatment. Abnormal lipid metabolism and amino acid metabolism were the main metabolic disorders. Exenatide improved lipid and amino acid metabolism, especially amino acid metabolites. Three types of branched-chain amino acids (valine, leucine and isoleucine), two types of aromatic amino acids (phenylalanine and tyrosine) and lysine are important potential metabolites for the therapeutic efficacy of exenatide. Many abnormal metabolic disorders are related to insulin resistance, oxidative stress and even ovulatory dysfunction. Moreover, in this small sample clinical study, we also found that exenatide improved insulin sensitivity, reduced body weight and improved glycolipid metabolism in PCOS. Conclusions NTGC-MS-based metabolic pathway analysis revealed that exenatide has a beneficial effect on overweight/obese PCOS patients by regulating metabolic disorders, especially amino acid disorders.

Genetic association studies have implicated that cartilage intermediate layer protein 2 (CILP-2) confers the risk susceptibility for type 2 diabetes (T2DM). However, it is still unknown whether CILP-2 is involved in the regulation of glucose homeostasis and insulin resistance (IR). In the current study, we initially observed that CILP-2 as a secreted protein was detected in both conditioned medium and lysates of cells transfected with an overexpressed vector. We then found that circulating CILP-2 levels had a progressive increase from normal to impaired glucose tolerance (a pre-diabetic status) and then to diabetes, which was correlated positively with waist-to-hip ratio, triglyceride, fasting blood glucose, 2-h blood glucose after glucose overload, HbA1c, fasting insulin, 2-h plasma insulin after glucose overload, and homeostasis model assessment of insulin resistance but negatively with HDL-C. CILP-2 expression was increased in the liver and muscle but decreased in adipose tissues of obese mice or T2DM patients. Furthermore, we demonstrated that CILP-2 circulating levels were affected by OGTT and Exenatide. CILP-2 overexpression resulted in impaired glucose tolerance and hepatic IR in vivo and increased PEPCK expression whereas suppressed phosphorylation of insulin receptor and Akt kinase in vitro. Based on these findings, we have identified a direct interaction between CILP-2 and PEPCK and suggested that CILP-2 plays an important role in the regulation of hepatic glucose production.

Mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high-fat diet [HFD] and db/db). Liver-specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA-sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)-related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)-induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion-induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca2+ chelator 1,2-bis (2-aminophenoxy) ethane N,N,N´,N´-tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, or cyclophilin-D (Cyp-D) knockdown. mGPDH promoting Cyp-D ubiquitination was also observed. Finally, liver-specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion: mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp-D ubiquitination, a key regulator of the mitochondrial Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.

OBJECTIVE This study aimed to evaluate the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids [SZ-A]) in the treatment of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a multicenter, randomized, double-blind, double-dummy, and parallel controlled noninferiority clinical trial that was conducted for 24 weeks. A total of 600 patients were randomly allocated to the SZ-A group (n = 360) or acarbose group (n = 240). The primary efficacy end point was the change of glycosylated hemoglobin (HbA1c) compared with baseline. In addition, adverse events (AEs), severe AEs (SAEs), treatment-related AEs (TAEs), and gastrointestinal disorders (GDs) were monitored. RESULTS After treatment for 24 weeks, the change in HbA1c was –0.93% (95% CI –1.03 to –0.83) (–10.2 mmol/mol [–11.3 to –9.1]) and –0.87% (–0.99 to –0.76) (–9.5 mmol/mol [–10.8 to –8.3]) in the SZ-A and acarbose groups, respectively, and the least squares mean difference was –0.05% (95% CI –0.18 to 0.07) (–0.5 mmol/mol [–2.0 to 0.8]) between the two groups, with no significant difference on the basis of covariance analysis (P > 0.05). The incidence of TAEs and GDs was significantly lower in the SZ-A group than the acarbose group (P < 0.01), but no differences for AEs or SAEs between the two groups were observed (P > 0.05). CONCLUSIONS SZ-A exhibited equivalent hypoglycemic effects to acarbose in patients with T2D. Nevertheless, the incidence of TAEs and GDs was lower following SZ-A treatment than acarbose treatment, suggesting good safety.

Previous studies on serum fetuin-B (fetuin-like protein IRL685) have investigated its association with T2DM; however, the reason for the variation in serum fetuin-B and its regulatory factors in metabolic disease remain unclear. Here, we evaluated serum fetuin-B levels in women with newly diagnosed MetS and performed multiple interventions to investigate the role of fetuin-B in the pathogenesis of MetS. Serum fetuin-B levels were assessed using ELISA. Bioinformatics analysis was performed to analyze fetuin-B-related genes and signaling pathways. Additionally, oxidative stress parameters were measured in the in vitro study. For subgroup analyses, we performed EHC, OGTT, and treatment with a GLP-1RA to investigate the regulatory factors of serum fetuin-B. We found that in comparison with healthy subjects, serum fetuin-B levels were markedly increased in women with MetS. Further, serum fetuin-B showed a positive correlation with WHR, FAT%, TG, FBG, HbA1c, FIns, HOMA-IR, VAI, and LAP. Bioinformatics analysis revealed that most fetuin-B-related core genes were involved in cholesterol metabolism and fat decomposition. Consistent with this finding, multivariate regression analysis showed that triglyceride content and WHR were independently associated with serum fetuin-B. We also observed that serum fetuin-B levels were markedly elevated in healthy subjects after glucose loading and in women with MetS during EHC. In vitro, overexpression of fetuin-B promoted oxidative stress in HepG2 cell. After 6 months of treatment with a GLP-1RA, serum fetuin-B levels in women with MetS decreased following an improvement in metabolism and insulin sensitivity. Therefore, serum fetuin-B is associated with MetS, which may serve as a biomarker of oxidative stress. This trial is registered with ChiCTR-OCC-11001422.

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 effects 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 study. 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 relationship with the MetS components was analyzed. Results In women with MetS components, circulating irisin and betatrophin 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 lower (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 correlated with the circulating levels of these four cytokines (P < 0.001 or Conclusion Serum ZAG, irisin, betatrophin and adiponectin were associated with MetS and might be biomarkers for screening MetS components.

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., Recurrent moderate hypoglycemia disturbs mitochondrial morphology and function in hippocampus by inhibiting TRPC6, leading to neuronal death and cognitive impairment in diabetic mice.

AIM Follistatin-like-1 (FSTL-1) is considered to be a novel cytokine, and it is associated with metabolic diseases. However, it is necessary to investigate further the association of FSTL-1 with metabolic syndrome (MetS) and insulin resistance (IR). We performed a cross-sectional study to investigate the associated of circulating FSTL-1 with the MetS. MATERIALS AND METHODS A cross-sectional study was performed in 487 Chinese people, including 231 control subjects and 256 patients with MetS. Bioinformatics analysis was used to determine the protein and pathways associated with FSTL-1. The protein and protein interaction (PPI) network was constructed and analysed. Serum FSTL-1 concentrations were determined by an ELISA assay. The association of FSTL-1 with MetS components and IR was assessed. RESULTS Serum FSTL-1 levels were markedly higher in patients with newly diagnosed MetS than in controls (7.5 [5.6-9.2] vs 5.8 [5.0-7.7] μg/L, P

Background: Previous studies have investigated circulating fetuin-B and its association with type 2 diabetes mellitus (T2DM). However, the variation and regulatory factors of serum fetuin-B levels in individuals with metabolic syndrome (MetS) have not been explained. This study evaluated circulating fetuin-B concentrations in newly diagnosed individuals with MetS and analyzed the impacts of blood glucose, insulin, and glucagon-like peptide-1 receptor agonists (GLP-1RA) treatment on circulating fetuin-B in vivo.Methods: A total of 377 women (192 MetS and 185 healthy subjects) were recruited for cross-sectional study. The euglycemic-hyperinsulinemic clamp (EHC) and oral glucose tolerance test (OGTT) were implemented in healthy women and those with MetS. Serum fetuin-B were examined by an ELISA kit. For the GLP-1RA intervention experiment, twenty-four women with MetS were treated with Liraglutide for 6 months. Results: Serum fetuin-B levels were markedly higher in women with MetS as compared to healthy women. Circulating fetuin-B reflected a positive correlation with body mass index, waist hip ratio (WHR), the percentage of fat in vivo (FAT%), triglyceride, fasting blood glucose, 2-hour blood glucose after glucose overload, glycosylated hemoglobin, fasting plasma insulin, 2-hour plasma insulin after glucose overload, homeostasis model assessment of insulin resistance (HOMA-IR), visceral adiposity index (VAI), and lipid accumulation product (LAP). Multivariate linear regression analyses demonstrated that triglyceride and WHR were independently related factors of serum fetuin-B. Serum fetuin-B levels were related to MetS by binary logistic regression analysis. In fact, serum fetuin-B was markedly elevated in healthy women after glucose loading and in MetS women during the EHC. After six months of GLP-1RA intervention, serum fetuin-B levels in MetS subjects decreased following improvement of metabolism and insulin sensitivity. Conclusions: Serum fetuin-B levels were associated with MetS and its components and regulated by glucose and insulin. GLP-1RA treatment can reduce serum fetuin-B levels in women with MetS. Clinical Trial Registration Number: ChiCTR-OCS-13003185. Registered 02/01 2016, http://www.chictr.org.cn/showproj.aspx?proj=6374

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 mm2), au-PRP group (14.31 ± 18.28 mm2), and CWT group (9.90 ± 8.51 mm2) 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

Background and Aims Follistatin-like protein-1 (FSTL-1) is considered to be an adipokine or myokine that could be a potential regulator of metabolism. Our purpose is to investigate the relationship between circulating FSTL-1 levels and insulin resistance (IR) in type 2 diabetes mellitus (T2DM) and to identify the regulatory factors. Methods FSTL-1 expression in C57BL/6J and db/db mice was examined by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR) and Western blots. Serum FSTL-1 levels were measured by enzyme-linked immunosorbent assay in 298 T2DM patients and 202 healthy controls. Changes in the circulating FSTL-1 level were observed during the oral glucose tolerance test, EHC (euglycemic-hyperinsulinemic clamp), lipid infusion, acute exercise, and cold-exposure test. Results We found that FSTL-1 protein expression in the adipose tissue of db/db mice was significantly higher than that of wild-type mice. Importantly, circulating FSTL-1 levels in T2DM and overweight/obese participants were higher than those in healthy and lean individuals, and was related to HOMA-IR, adiponectin, and obesity- and metabolism-related parameters. In the intervention study, 45 minutes of physical activity was found to significantly increase the circulating FSTL-1 concentration in young, healthy participants. Further, FSTL-1 protein expression in adipose tissue rose dramatically in response to physical activity in mice. Hyperinsulinemia during EHC and acute elevated FFA induced by lipid infusion resulted in a significant decrease in the circulating FSTL-1 levels. However, no change was found in the circulating FSTL-1 levels in response to the oral glucose challenge or cold-exposure test. Conclusions FSTL-1 may be an adipomyokine associated with insulin resistance and physical activity, and circulating FSTL-1 levels are increased in patients with T2DM.

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 Conclusion Blood Fetuin-A may be a useful biomarker for screening women for PCOS and IR.

Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism. This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin’s central effect and hypothalamic signalling.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel neurotrophic factor. Although recent studies have suggested that MANF appeared to be associated with insulin resistance, the results have been inconsistent. The aim of our study was to determine the serum MANF levels in women with PCOS and controls, to investigate their relationship to insulin resistance, and to evaluate circulating MANF changes with metformin intervention in PCOS women. We conducted a series of cross-sectional and interventional studies in 90 newly diagnosed patients with PCOS and 60 age- and gender-matched controls. Oral glucose tolerance test and euglycemic-hyperinsulinemic clamps were performed to assess the glucose tolerance and insulin sensitivity. Forty-three women with PCOS were randomly assigned to six months of oral metformin therapy. Serum MANF levels were significantly lower in women with PCOS than in controls. Serum MANF levels were positively correlated with M-value and negatively correlated with body mass index (BMI), body fat percentage (FAT), homeostatic model assessment of insulin resistance (HOMA-IR), and free androgen index (FAI). Multivariate stepwise regression demonstrated that serum MANF levels were independently associated with M-value and FAI. After six months of metformin treatment, there was a significant increase in serum MANF levels in PCOS women. Serum MANF levels are decreased in women with PCOS, and are reversely related to insulin resistance and hyperandrogenism. Metformin treatment elevates serum MANF levels and alleviates insulin resistance and hyperandrogenism in PCOS women.

Background : Type 2 Diabetes mellitus is characterized by impaired glucose metabolism and insulin resistance with increasing risk of specific complication, including central neuropathy. Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to regulate hyperglicemia through increasing the half-life of incretins. Although they are administered orally, their effects on central neuropathy and gut microbiota remain unclear. Our objective was aimed to identify the impact of the DPP-4 inhibitor sitagliptin on gut microbiota and central neuropathy in a rat model of streptozotocin (STZ)-induced diabetes Methods: Diabetic rats were induced by a high-fat diet and streptozotocin injection. Diabetic rats were orally administered a dose of sitagliptin (10mg/kd/d), and normal diet for 12 weeks. Fecal DNA extraction and sequencing based on analysis of 16S rRNA genes was used to determine the overall structure of microbiota in fecal samples. Then rats were killed, of which the brain tissue sections were observed for changes of neurons in the hippocampus by HE staining. Results: Sequencing of the V3-V4 regions of 16S rRNA genes revealed that sitagliptin significantly altered the gut microbiota. Compared to the diabetic group, Shannon index and the abundance of phylum Bacteroidetes decreased significantly, whereas the proportion of phylum Firmicutes increased significantly in the sitagliptin-treated rats. Moreover, higher abundance of a few putative short-chain fatty acid-producing bacteria, including Clostridium and Fusobacterium was observed remarkably after sitaglitin treatment. Genera Lactobacillus , Streptococcus and Clostridium, which could produce some neurotransmitters, were also found increased substantially in the sitagliptin-treated rats. Notably, we found that sitagliptin treatment could ameliorate the abnormal changes of pyramidal neurons in hippocampus with HE staining. Conclusions: Our study demonstrated that sitagliptin prevented the neuronal damage of hippocampus in type 2 diabetic rats, accompanied by changes of gut microbiome. It indicated that sitagliptin might alleviate diabetic central neuropathy through triggering “microbiota-gut-brain” axis.

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.

Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.

C1q/tumor necrosis factor-related protein-6 (CTRP6) is a novel adipokine and has emerged as an important mediator for lipid and glucose metabolism. However, to date, the relationship between CTRP6 and T2DM in humans has not been demonstrated. Our objective is to investigate the association of circulating CTRP6 with T2DM in a cross-sectional study. 118 patients with newly diagnosed T2DM, 98 subjects with impaired glucose tolerant (IGT) and 132 healthy subjects were recruited for this study. OGTT were performed in 48 healthy individuals to investigate the association of CTRP6 with glucose, insulin and other adipokines. Circulating CTRP6, TNF-α and Adipoq were measured by ELISA. IGT and T2DM individuals had higher serum CTRP6 levels than healthy controls (406.2 ± 136.6 and 539.1 ± 169.7 vs. 354.3 ± 117.2 ng/mL; both P

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

Lysosome associated membrane protein 3 (LAMP3), a highly glycosylated protein, is one member of the LAMPs family. LAMPs family plays a critical role in the autolysosome fusion process. Autophagy was recently confirmed to regulate hepatic lipolysis. However, the physiological function of LAMP3 in lipid metabolism is not clear. In the current study, we discovered that the LAMP3 expression level was higher in the liver tissues of non-alcoholic fatty liver disease (NAFLD) patients and high-fat diet and ob/ob mice than in the matched control groups. LAMP3 expression was also obviously increased in hepatocellular carcinoma (HCC) cells treated with free fatty acids. Moreover, marked accumulation of intracellular lipid droplets and triglycerides (TG) was observed after LAMP3 overexpression in HCC cells. Further study showed that LAMP3 overexpression activated Akt and upregulated the expression of the lipogenic enzymes FASN and SCD-1 in HepG2 cells. Additionally, the increased TG content induced by LAMP3 overexpression was attenuated by treatment with a PI3K/Akt pathway inhibitor. Our findings demonstrated that LAMP3 is an important regulator of hepatic lipid metabolism, which provides a line of evidence for taking LAMP3 as a drug target in lipid metabolism disorder-associated diseases, such as NAFLD and obesity.

It has been demonstrated that bone morphogenetic protein-9 (BMP-9) may have an important role in vascular development and stability. However, the association of circulating BMP-9 with essential hypertension (HTN) has not been established in humans. The objective of this study is to observe the changes of circulating BMP-9 levels in patients with HTN and to investigate the association of circulation BMP-9 and insulin resistance (IR) in a cross-sectional study. Two hundred twenty-five individuals, including 132 patients with hypertension, and 93 healthy controls, were included in the present study. Circulating BMP-9 concentrations were measured with an ELISA kit. The association of circulating BMP-9 with other parameters was analyzed. When compared with healthy subjects, circulating BMP-9 concentrations were markedly lower in HTN patients (46.20 [31.85-62.80] vs. 77.21 [39.33-189.15], P .01) and correlated negatively with blood pressure and the homeostasis model assessment of insulin resistance (P .05 or P .01). Decreasing levels of BMP-9 were independently and markedly related to HTN. In a multiple linear regression analysis, only systolic blood pressure and free fatty acid concentrations were independently associated with circulating BMP-9. Our findings suggest that BMP-9 may be a serum biomarker for HTN and IR.

Introduction To investigate the effects of pioglitazone (PIO) on insulin resistance and first phase insulin secretion among obese and lean Chinese people with type 2 diabetes mellitus (T2DM). Methods Sixty-eight drug-naïve patients with T2DM were treated with PIO for 16 weeks. Before and after the treatment, insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test. Plasma insulin levels at 0, 3, 5, 7, and 10 min during intravenous glucose tolerance test were determined to calculate the first phase insulin secretion and pancreatic β-cell function. Circulating adiponectin levels were quantified. Results In both the lean and the obese patients with T2DM, the reduction of HbA1c following the PIO treatment was more than 1% (P

Context Myonectin has been identified as a myokine, expressed predominantly in skeletal muscle. However, its clinical implications are largely unknown. Objective The aim of this study is to investigate the relationship between myonectin (C1q tumor necrosis factor-α-related protein isoform 15) and type 2 diabetes mellitus (T2DM) in cross-sectional and interventional studies. Design In a separate study, oral glucose tolerance tests, a 45-minute bout of exercise, lipid infusions, and euglycemic-hyperinsulinemic clamps (EHCs) were performed to investigate the association of myonectin with homeostasis model assessment of insulin resistance (HOMA-IR) and T2DM. Circulating myonectin was measured by enzyme-linked immunosorbent assay. Patients One hundred four newly diagnosed T2DM (nT2DM), 109 impaired glucose tolerance (IGT), and 128 healthy individuals were recruited for this study. Results nT2DM and IGT subjects had higher circulating myonectin concentrations than normal subjects (82.3 ± 47.6 and 68.9 ± 46.6 vs. 45.2 ± 23.5 µg/L, P < 0.05 or P < 0.01). It was also found that in nT2DM individuals, circulating myonectin was higher than in IGT subjects. Plasma myonectin correlated positively with waist/hip ratio, percentage of body fat, triglyceride, fasting blood glucose, 2-hour blood glucose after glucose overload, fasting insulin, hemoglobin A1c, and HOMA-IR and negatively with the insulin sensitivity index in all of the study population. Multivariate logistic regression analysis revealed that circulating myonectin levels were significantly correlated with IGT and T2DM. A 45-minute bout of exercise did not change circulating myonectin levels in healthy, young individuals. Circulating myonectin levels were not significantly altered in response to an oral glucose challenge or EHC. In addition, acute elevated free fatty acid levels induced by lipid infusion had no effects on circulating myonectin. Conclusions These data suggest that myonectin may be a useful marker in predicting the development of prediabetes and diabetes.

// Han Wang 1,* , Lin Du 1,* , Tong Wu 2 , Gangyi Yang 2 , Wenjing Hu 2 , Hansheng Wang 1 , Mengliu Yang 2 , Dongfang Liu 2 , Harvest F. Gu 3,4 , Zhiming Zhu 5 , Hongting Zheng 6 and Ling Li 1 1 The Key Laboratory of Laboratory Medical Diagnostics in The Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China 2 Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China 3 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden 4 Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Solna, Stockholm, Sweden 5 Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China 6 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China * These authors have contributed equally to this project Correspondence to: Ling Li, email: // Keywords : betatrophin; insulin resistance; metabolic disorders; interventional study; cell cross-talk; Gerotarget Received : August 15, 2017 Accepted : October 05, 2017 Published : October 16, 2017 Abstract Betatrophin has a closely relationship with metabolism. However, its effect on metabolism disorder remains unclear. This study was comprised of a series of cross-sectional and interventional studies in vivo and vitro . PCOS women with IR and healthy women were recruited from the general population and outpatients. Plasma betatrophin levels were measured with ELISA. Insulin sensitivity was assessed with EHC. Gene expressions at mRNA and protein levels were determined with RT-PCR and Western blotting. Influences of insulin, metformin, rosiglitazone and over- or knockdown-expression of betatrophin were analyzed ex vivo . Our results indicated that IR women had higher betatrophin levels compared with the controls. Circulating betatrophin was positively correlated with BMI, WHR, Fat%, triglyceride, total cholesterol, LDL-C, AUC glucose and AUC insulin , luteinizing Hormone, FAI and HOMA-IR but negatively with M-value. Metformin treatment in PCOS women with IR led to a reduction of betatrophin levels. Insulin stimulation in hepatocytes increased betatrophin expression. Metformin or rosiglitazone led to a reduction of betatrophin expression in insulin-stimulated hepatocytes. In hepatocytes/macrophages co-culture systems, betatrophin expression was significantly increased, whereas this increase was eliminated by rosiglitazone. In hepatocytes, overexpression and knockdown of betatrophin decreased or increased insulin-stimulated insulin receptor, protein kinase B and insulin receptor substrate-1 phosphorylation respectively. Serum from metformin-treated women with IR decreased betatrophin expression and reinforced insulin signals. Thus, the present study provides the in vivo and in vitro evidence, suggesting that there is a cell cross-talking between hepatocytes with macrophages for the regulating betatrophin and it may be a useful marker for IR and metabolic disorders.

// Yang Peng 1, * , Guo-Chao Zhong 2, * , Qiao Mi 1, * , Kejia Li 1 , Ao Wang 1 , Ling Li 3 , Hua Liu 4 and Gangyi Yang 1 1 Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, Chongqing, China 2 Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China 3 Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China 4 Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA * These authors contributed equally to this work Correspondence to: Gangyi Yang, email: gangyiyang@163.com Ling Li, email: liling31@hotmail.com Keywords: potassium, type 2 diabetes mellitus, systematic review, meta-analysis, dose-response Received: July 28, 2017 Accepted: September 23, 2017 Published: October 11, 2017 ABSTRACT Objective: To clarify the relationship between serum, dietary, and urinary potassium and the risk of type 2 diabetes mellitus (T2DM). Materials and Methods: We searched PubMed and EMBASE through January 6, 2017 for studies reporting risk estimates on the association of potassium measurements and the risk of T2DM. The summary risk estimates were obtained through a random-effects model. Dose-response analysis was conducted. Results: Eight studies involving 5,053 cases and 119,993 individuals were included. A trend toward significance was found in the highest versus lowest meta-analysis on serum potassium and T2DM risk (RR = 0.79; 95% CI 0.60–1.04); moreover, the RR per 1 mmol/L increase in serum potassium was 0.83 (95% CI 0.73–0.95). A non-significant association of dietary potassium and T2DM risk was detected (RR for the highest versus lowest category: 0.93; 95% CI 0.81–1.06; RR for every 1000mg increase per day: 1.00, 95% CI 0.96–1.05). A similar non-significant association was found for urinary potassium and T2DM risk (RR for the highest versus lowest category: 0.83; 95% CI 0.39–1.75; RR per 10 mmol increase: 1.00; 95% CI 0.95–1.05). Evidence of a linear association between serum, dietary, and urinary potassium and the risk of T2DM was found (all P non-linearity > 0.05). Conclusions: Low serum potassium increases the risk of T2DM in a linear dose-response manner; nevertheless, neither dietary potassium nor urinary potassium shows any association with the risk of T2DM. However, these findings should be interpreted with caution due to limited studies.

Bone morphogenetic protein 9 (BMP-9) has been demonstrated to improve glucose homoeostasis in diabetic mice. However, no report has demonstrated the relationship of circulating BMP-9 levels with insulin resistance (IR) or Type 2 diabetes mellitus (T2DM) in humans. The objective of the present study was to investigate the relationship between BMP-9 and IR in cross-sectional and interventional studies. Circulating BMP-9 levels were analysed by ELISA in 280 well-characterized individuals. Two-hour oral glucose tolerance test (OGTT) and euglycaemic–hyperinsulinaemic clamp (EHC) were performed in 20 healthy subjects. Acute IR was induced by lipid infusion for 4 h in 20 healthy volunteers. Real-time (RT)-PCR and Western blotting were used to assess mRNA and protein expression of BMP-9. The effect of a glucagon-like peptide-1 (GLP-1) receptor agonist (PEX168) on circulating BMP-9 was investigated in a 24-week treatment trial. Circulating BMP-9 levels were significantly higher in healthy subjects than in newly diagnosed patients with T2DM. Circulating BMP-9 negatively correlated with HbA1c, fasting blood glucose (FBG), OGTT, the area under the curve for glucose (AUCglucose) and homoeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression analyses showed that BMP-9 levels were independently associated with non-esterified fatty acid (NEFA) and AUCglucose. Both hyperinsulinaemia and lipid infusion decreased circulating BMP-9 levels. BMP-9 mRNA and protein expressions were significantly decreased in muscle and adipose tissues of T2DM patients. In the placebo treated group, BMP-9 levels continued to decline over time, whereas in the PEX 168 treated groups BMP-9 levels remained stable. Our data suggest that BMP-9 is likely to play an important role in IR in humans.

The role of central juxtaposed with another zinc finger gene 1 (JAZF1) in glucose regulation remains unclear. Here, we activated mediobasal hypothalamus (MBH) JAZF1 in high-fat diet (HFD)-fed rats by an adenovirus expressing JAZF1 (Ad-JAZF1). We evaluated the changes in the hypothalamic insulin receptor (InsR)-PI3K-Akt-AMPK pathway and hepatic glucose production (HGP). To investigate the impact of MBH Ad-JAZF1 on HGP, we activated MBH JAZF1 in the presence or absence of ATP-dependent potassium (KATP ) channel inhibition, hepatic branch vagotomy (HVG), or an AMPK activator (AICAR). In HFD-fed rats, MBH Ad-JAZF1 decreased body weight and food intake, and inhibited HGP by increasing hepatic insulin signaling. Under insulin stimulation, MBH Ad-JAZF1 increased InsR and Akt phosphorylation, and phosphatidylinositol 3, 4, 5-trisphosphate (PIP3) formation; however, AMPK phosphorylation was decreased in the hypothalamus. The positive effect of MBH JAZF1 on hepatic insulin signaling and HGP was prevented by treatment with a KATP channel inhibitor or HVG. The metabolic impact of hypothalamic JAZF1 was also blocked by MBH AICAR. Ad-JAZF1 treatment in SH-SY5Y cells resulted in an elevation of InsR and Akt phosphorylation following insulin stimulation. Our findings show that hypothalamic JAZF1 regulates HGP via the InsR-PI3K-Akt-AMPK pathway and KATP channels.

Background: Applying the hyperinsulinemic-euglycemic clamp to estimate insulin resistance (IR) is accurate but time-consuming, so identifying a simple and effective index for IR is vitally...

Bone morphogenetic protein (BMP)-9 has been reported to regulate energy balance in vivo. However, the mechanisms underlying BMP9-mediated regulation of energy balance remain incompletely understood. Here, we investigated the role of BMP9 in energy metabolism. In the current study, we found that hepatic BMP9 expression was down-regulated in insulin resistance (IR) mice and in patients who are diabetic. In mice fed a high-fat diet (HFD), the overexpression of hepatic BMP9 improved glucose tolerance and IR. The expression of gluconeogenic genes was down-regulated, whereas the level of insulin signaling molecule phosphorylation was increased in the livers of Adenovirus-BMP9-treated mice and glucosamine-treated hepatocytes. Furthermore, BMP9 overexpression ameliorated triglyceride accumulation and inhibited the expression of lipogenic genes in both human hepatocellular carcinoma HepG2 cells treated with a fatty acid mixture as well as the livers of HFD-fed mice. In hepatocytes isolated from sterol regulatory element-binding protein (SREBP)-1c knockout mice, the effects of BMP9 were ablated. Mechanistically, BMP9 inhibited SREBP-1c expression through the inhibition of liver X receptor response element 1 activity in the SREBP-1c promoter. Taken together, our results show that BMP9 is an important regulator of hepatic glucose and lipid metabolism.-Yang, M., Liang, Z., Yang, M., Jia, Y., Yang, G., He, Y., Li, X., Gu, H. F., Zheng, H., Zhu, Z., Li, L. Role of bone morphogenetic protein-9 in the regulation of glucose and lipid metabolism.

Chiglitazar showed favorable effect on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to further compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes inadequately controlled with lifestyle interventions (ClinicalTrials.gov NCT02121717). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or placebo once daily. After 24-week treatment, patients in placebo group were randomly assigned to receive chiglitazar 32 mg or 48 mg, while others remained on the planned treatment till to 52 weeks. The primary endpoint was change in HbA1c at week 24 with superiority of each chiglitazar dose versus placebo. Analysis was done in all randomized patients who received at least one dose of study drug (n= 535). Chiglitazar was superior to placebo in HbA1c reduction at 24 weeks (LS mean difference -0.87% [95% CI -1.10 to -0.65] and -1.05% [95% CI -1.29 to -0.81] for 32 mg and 48 mg, respectively) and achieved sustainable effect till to 52 weeks. Overall adverse events were comparable across groups. The incidences of weight gain, edema, and hypoglycemia were relatively higher in chiglitazar groups. Chiglitazar showed superior and sustainable HbA1c lowering effect with well tolerated safety profile in patients with type 2 diabetes. Disclosure L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. W. Song: None. H. Fang: None. W. Li: None. J. Geng: None. Y. Xu: None. Y. Wang: None. L. Guo: None. H. Cai: None. T. Yang: None. H. Li: None. G. Yang: None. Q. Li: None. K. Liu: None. S. Li: None. Y. Liu: None. F. Shi: None. X. Li: None. X. Gao: None. Q. Ji: None. H. Tian: None. Q. Su: None. Z. Zhou: None. W. Wang: None. Z. Zhou: None. X. Li: None. Y. Xu: None. Z. Ning: None. X. Lu: None. W. Jia: None. Funding Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)

The whitening and loss of brown adipose tissue (BAT) during obesity and aging promote metabolic disorders and related diseases. The imbalance of Ca2+ homeostasis accounts for the dysfunction and clearance of mitochondria during BAT whitening. Capsaicin, a dietary factor activating TRPV1, can inhibit obesity induced by high-fat diet (HFD), but whether capsaicin inhibits BAT loss and the underlying mechanism remain unclear. In this study, we determined that the inhibitory effects of capsaicin on HFD-induced obesity and BAT whitening were dependent on the participation of SIRT3, a critical mitochondrial deacetylase. SIRT3 also mediated all of the beneficial effects of capsaicin on alleviating reactive oxygen species generation, elevating mitochondrial activity, and restricting mitochondrial calcium overload induced by HFD. Mechanistically, SIRT3 inhibits mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium overload by reducing the H3K27ac level on the MCU promoter in an AMPK-dependent manner. In addition, HFD also inhibits AMPK activity to reduce SIRT3 expression, which could be reversed by capsaicin. Capsaicin intervention also inhibited aging-induced BAT whitening through this mechanism. In conclusion, this study emphasizes a critical role of the AMPK/SIRT3 pathway in the maintenance of BAT morphology and function and suggests that intervention in this pathway may be an effective target for preventing obesity- or age-related metabolic diseases.