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Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

Insulin resistance (IR), a metabolic risk factor, is linked to the pathogenetic mechanism of primary hypertension. Detecting IR in the patients with hypertension will help to predict and stratify the added cardiovascular risk, institute appropriate IR management, and manage hypertension optimally. There are many methods for assessing IR, each with distinct advantages and disadvantages. The euglycemic insulin clamp and intravenous glucose tolerance test, gold standards for measuring IR, are used in research but not in clinical practice. Homeostatic model assessment (HOMA‐IR), a method for assessing β‐cell function and IR, is frequently applied presently, particularly in Asia. Besides, the triglyceride–glucose index (TyG) first published by South American authors showed a good correlation with the insulin clamp technique and HOMA‐IR index. This simple, convenient, and low‐cost TyG index is of research interest in many countries in Asia and can be used to screen for IR in the Asian hypertensive community.

Background: Epithelial ovarian cancer (EOC) is the most common gynecological cancer in women. Resistin, an inflammatory adipocytokine, is associated with obesity, insulin resistance, and various cancer types. Materials and Methods: We investigated resistin expression in tissues and its association with the clinicopathological characteristics and prognosis of patients with EOC. The SKOV3 and CAOV3 cell lines were treated with exogenous resistin and rapamycin (resistin inhibitor), and the expression of mTOR in SKOV3 and CAOV3 cells was measured. Cell proliferation was measured using the CCK-8 assay. Western blotting analysis was performed to examine the phosphorylation of P70S6K and mTOR. Wound healing and Transwell analyses were conducted to examine the effect of resistin on the migration of SKOV3 and CAOV3 cells. Results: High resistin expression was positively correlated with the pathological grade (P = 0.017) and lymph node metastasis (P = 0.045). However, resistin expression was not correlated with age, FIGO stage, or residual tumor after initial laparotomy (P > 0.05). Cox multivariate analysis showed that resistin expression was an independent factor for determining disease-free survival, whereas lymph node metastasis, resistin expression, and age (≥55 years) were independent factors affecting overall survival. Exogenous resistin induced ovarian cancer cell proliferation, whereas rapamycin had the opposite effect. Resistin promoted the proliferation of ovarian cancer cells via the mTOR signaling pathway and was associated with phosphorylating P70S6K. Furthermore, resistin promoted the migration of ovarian cancer cells. Conclusions: Resistin may promote the occurrence of ovarian cancer and is related to the prognosis of patients. This protein may also affect the proliferation of EOC cells through the mTOR signaling pathway. Therefore, resistin shows potential as a molecular therapeutic target in ovarian cancer.

Rationale: We recently demonstrated that the Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-Treated astrocytes. The impact of ORY100. An Inhibitor Of The LSD1-CoREST Complex, On Hmg20a Expression, Reactive Astrogliosis And Glucose Metabolism Was Evaluated In Vitro And In Vivo In High-Fat High-Sucrose Fed Mice. Results: We Show That Hmg20a Is Predominantly Expressed In Hypothalamic Astrocytes, The Main Nutrient-Sensing Cell Type Of The Brain. Hmg20a Expression Was Upregulated In Diet-Induced Obesity And Glucose Intolerant Mice, Correlating With Increased Transcript Levels Of Gfap And Il1b Indicative Of Inflammation And Reactive Astrogliosis. Hmg20a Transcript Levels Were Also Increased In Adipose Tissue Of Obese Non-Diabetic Individuals As Compared To Obese Diabetic Patients. Hmg20a Silencing In Astrocytes Resulted In Repression Of Inflammatory, Cholesterol Biogenesis And Epithelial-To-Mesenchymal Transition Pathways Which Are Hallmarks Of Reactive Astrogliosis. Accordingly, Hmg20a Depleted Astrocytes Exhibited Reduced Mitochondrial Bioenergetics And Increased Susceptibility To Apoptosis. Neuron Viability Was Also Hindered In HMG20A-Depleted Astrocyte-Derived Conditioned Media. Ory1001 Treatment Rescued Expression Of Reactive Astrogliosis-Linked Genes In Hmg20a Ablated Astrocytes While Enhancing Cell Surface Area, Gfap Intensity And Stat3 Expression In Healthy Astrocytes, Mimicking The Effect Of Hmg20a. Furthermore, Ory1001 Treatment Protected Against Obesity-Associated Glucose Intolerance In Mice Correlating With A Regression Of Hypothalamic Hmg20a Expression, Indicative Of Reactive Astrogliosis Attenuation With Improved Health Status. Conclusion: Hmg20a Coordinates The Astrocyte Polarization State. Under Physiological Pressure Such As Obesity And Insulin Resistance That Induces Low Grade Inflammation, Hmg20a Expression Is Increased To Induce Reactive Astrogliosis In An Attempt To Preserve The Neuronal Network And Re-Establish Glucose Homeostasis. Nonetheless, A Chronic Metabesity State Or Functional Mutations Will Result In Lower Levels Of Hmg20a, Failure To Promote Reactive Astrogliosis And Increase Susceptibility Of Neurons To Stress-Induced Apoptosis. Such Effects Could Be Reversed By Ory1001 Treatment Both In Vitro And In Vivo, Paving The Way For A New Therapeutic Approach For Type 2 Diabetes Mellitus., The authors are supported by grants from the Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 and PI-0001-2020 to B.R.G.; PI-0085-2013 to P.I.L.; PI-0006-2016 to E.F.M.; PI-0574-2012 to S.Y.R.Z; PI-0247-2016 to F.J.B.S.), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to B.R.G.; CTS.8081 to E.G.F.), the Ministerio de Economía y Competitividad co-funded by Fondos FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P to B.R.G.; PRE2018-084907 to M.E.M.V.G.; PI13/00309; PI17/01004 to F.J.B.S.; BFU2014-5343-P to J.C.R.; and AGL2017-86927-R to F.M.), Vencer el Cancer (B.R.G), DiabetesCero (B.R.G.) and the Juvenile Diabetes Research Foundation (17-2013-372 and 2-SRA-2019-837-S-B to B.R.G.). E.F.M. was a recipient of a Juan de la Cierva Incorporación Fellowship from the Ministerio de Economía y Competitividad (IJCI-2015-26238). S.Y.R.Z is a recipient of a postdoctoral fellowship from Consejería de Salud, Junta de Andalucía (RH-0070-2013). L.L.N. is supported by a Consejeria de Economia, Conocimiento, Empresas y Universidad postdoctoral fellowship (DOC_00652). F.J.B.S. and E.G.F. are recipients of "Nicolás Monardes" research contracts from Consejería de Salud Junta de Andalucía, (C-0070-2012 and C-0031-2016). A.M.M. is supported by CPII19/00023 and PI18/01590 from the Instituto de Salud Carlos III co-funded by Fondos FEDER. CIBERDEM is an initiative of the Instituto de Salud Carlos III. V.C. is supported by a AECC investigator award.

Islet amyloid polypeptide (amylin), consecrated by the pancreatic β-cells with insulin, has a significant role to play in maintaining homeostasis of islet cell hormones. Alzheimer's disease is the predominant source of dementia. However, its etiology remains uncertain; it appears that type 2 diabetes mellitus and other prediabetic states of insulin resistance contribute to the intermittent Alzheimer's disease presence. Amylin is abnormally elevated in Type II diabetes patients, accumulated into amylin aggregates, and ultimately causes apoptosis of the β-cells, and till date, its mechanism remains unclear. Several flavonoids have inhibitory effects on amylin amyloidosis, but its inhibition mechanisms are unknown. Screening a collection of traditional compounds revealed the flavone Chrysin, a potential lead compound. Chrysin inhibits amyloid aggregate formation according to Thioflavin T binding, turbidimetry assay. We report results of molecular interaction analysis of Chrysin with amylin which shows potent binding affinity against amylin. Pharmacokinetics and Drug likeness studies of Chrysin also suggest that it is a potential lead compound. Therefore, Chrysin prevented amylin aggregation.

Although our previous research shows an ameliorated high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in global SND1 transgenic mice, the involvement of SND1 loss-of-function in hepatic metabolism remains elusive. Herein, we aim to explore the potential impact of hepatocyte-specific SND1 deletion on insulin-resistant mice. As SND1 is reported to be linked to inflammatory response, the pathobiological feature of acute liver failure (ALF) is also investigated. Hence, we construct the conditional liver knockout (LKO) mice of SND1 for the first time. Under the condition of HFD, the absence of hepatic SND1 affects the weight of white adipose tissue, but not the gross morphology, body weight, cholesterol level, liver weight, and hepatic steatosis of mice. Furthermore, we fail to observe significant differences in either HFD-induced insulin resistance or lipopolysaccharide/D-galactosamine-induced (LPS/D-GaIN) ALF between LKO and wild type (WT) mice in terms of inflammation and tissue damage. Compared with negative controls, there is no differential SND1 expression in various species of sample with insulin resistance or ALF, based on several gene expression omnibus datasets, including GSE23343, GSE160646, GSE120243, GSE48794, GSE13271, GSE151268, GSE62026, GSE120652, and GSE38941. Enrichment result of SND1-binding partners or related genes indicates a sequence of issues related to RNA or lipid metabolism, but not glucose homeostasis or hepatic failure. Overall, hepatic SND1 is insufficient to alter the phenotypes of hepatic insulin resistance and acute liver failure in mice. The SND1 in various organs is likely to cooperate in regulating glucose homeostasis by affecting the expression of lipid metabolism-related RNA transcripts during stress., Graphical Abstract

Aim of the study To investigate the efficacy and safety of Abexol and atorvastatin in patients with non-alcoholic fatty liver disease (NAFLD). Material and methods: The present study had a monocentric, randomized, double-blinded, comparative design with 4 parallel groups – group 1 (Abexol), group 2 (atorvastatin), group 3 (combined therapy) and group 4 (placebo) – to which dietary recommendations and physical activity practice were provided twice a day, for 24 weeks. Significant changes in the ultrasound analysis of the liver were considered a primary efficacy variable. Insulin resistance improvement (HOMA2-IR) was considered as a co-primary efficacy criterion. Significant changes in the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lipid profile variables and the anthropometric variables were evaluated as secondary variables of effectiveness. Statistical analysis of all data was according to the intention to treat method. Results The groups were statistically homogeneous at baseline conditions. At the end of the 6 months of treatment about 50% of the patients in all groups showed a decrease of at least one degree in echogenicity, while the rest remained the same. There were no significant changes in the values of liver enzymes or anthropometric variables evaluated. Treatment with atorvastatin and combined therapy significantly reduced levels of low-density lipoprotein-cholesterol (LDL-C) and total cholesterol. The treatments were safe and well tolerated, although in the atorvastatin group the number of adverse events reported was greater than in the rest of the groups. Conclusions Abexol and atorvastatin showed comparable efficacy and safety in patients with NAFLD, with advantages for treatment with atorvastatin with respect to its effects on the lipid profile of these patients.

Background: Non-diabetic coronary artery spasm (CAS) without obstructive coronary artery disease increases insulin resistance. We investigated the risk of incident type 2 diabetes (diabetes) associated with CAS. Methods: Patient records were retrospectively collected from the Taiwan National Health Insurance Research Database during the period 2000-2012. The matched cohorts consisted of 12,413 patients with CAS and 94,721 patients in the control group. Results: During the entire follow-up, the incidence of newly-diagnosed diabetes was 22.2 events per 1000 person-years in the CAS group and 13.9 events per 1000 person-years in the control group. The increased risk of CAS-related incident diabetes was observed regardless of sex and length of follow-up. The median time to incident diabetes was 2.9 and 3.5 years in the CAS and the control group (P

In recent years, the role of vaspin as an insulin-sensitizer has been studied widely. This is the investigation that examined the association of vaspin polymorphism rs2236242 on the vaspin level and the risk of type 2 diabetes and insulin-resistant Iranian pre-diabetic/diabetic population.A case-control study was conducted on 160 participants includes 80 participants holding (FBG) fasting blood glucose 3.88-5.55 (mmol/L) in the normal group, and 80 participants holding FBG≥5.55 (mmol/L) in a diabetic/pre-diabetic group. The serum vaspin and insulin were determined with ELISA (enzyme-linked assay) and biochemical variables by standard method. Tetra arms amplification system for the vaspin gene was performed. Statistical analysis was done using SPSS software version 20.The means of age, body mass index (BMI), waist circumference (WC), hip circumference (HC), FBG, and vaspin were significantly different between normal and type 2 diabetic/impaired fasting blood group (P-value0.05). rs2236242 showed association with Hip circumference (P-value0.05). A significant association between allele A of rs2236242 with type 2 diabetes was seen (P-value0.001). The vaspin levels showed a negative correlation with FBG (r =-0.296, P=0.001).Allele A of rs2236242 is a protective risk for type 2 diabetes, but no association of rs2236242 with insulin resistance was seen. The lower level of vaspin is a predictor for the progression of type 2 diabetes.Poslednjih godina dosta je proučavana uloga vaspina kao senzitizatora insulina. Ovo istraživanje je proučavalo povezanost polimorfizma vaspina rs2236242 na nivou vaspina i rizik od dijabetesa tipa 2 kod iranske populacije predijabetičara i dijabetičara rezistentne na insulin.Sprovedena studija je uključivala 160 učesnika. Kod 80 učesnika nivo glukoze u krvi je bio 3,88-5,55 mmol/L - kontrolna grupa koja nije uzimala hranu pre davanja uzoraka (FBG), i 80 učesnika kod kojih je nivo FBG bio ≥ 5,55 mmol/L - grupa dijabetičara / predijabetičara). Serumski vaspin i insulin određeni su ELISA testom i biohemijskim varijablama standardnom metodom. Primenjen je tetra arms sistem za pojačavanje gena vaspina. Statistička analiza je urađena uz pomoć softvera SPSS, verzija 20.Srednje vrednosti životne dobi, indeksa telesne mase (BMI), obima struka (WC), obima kuka (HC), FBG i vaspina su se značajno razlikovale između kontrolne grupe sa normalnim vrednostima i vrednosti u grupi dijabetičara tipa 2 (P vrednost0,05). rs2236242 je pokazao povezanost s obimom kuka (P-vrednost0,05). Primećena je značajna povezanost alela A rs2236242 sa dijabetesom tipa 2 (P-vrednost0,001). Nivoi vaspina pokazali su negativnu korelaciju sa FBG-om (r = -0,296, P = 0,001).Alel A rs2236242 je zaštitni rizik za dijabetes tipa 2, ali nije primećena povezanost rs2236242 sa rezistencijom na insulin. Niži nivo vaspina je prediktor za progresiju dijabetesa tipa 2.

Objective: This study aimed to investigate whether the antihypertensive effect of irbesartan (IRB) in spontaneously hypertensive rats (SHR) was achieved through improvement of insulin resistance and adjustment of the LPN–APN imbalance.Methods:SHR rats were divided into SHAM, SHR-A and SHR-I group(8 per group). Homologous Wistar–Kyoto (WKY) rats were used as control group (WKY).The SHR-I group received 30 mg/kg/d IRB, the SHR-A group received 2.5 mg/kg AML. After 8 weeks, systolic blood pressure (SBP) was measured. The concentrations of blood glucose, insulin, LPN and APN were detected. Rat epididymal adipose tissues were collected to analyze the mRNA expression levels ofepididymal LPN and APN using reverse transcription–polymerase chain reaction. In addition, the LPN/APN ratio was calculated. Results:SBP, homeostasis model assessment of insulin resistance (HOMA-IR), LPN concentration, adipose LPN mRNA expression level, and the LPN/APN ratio increased (P

Rationale: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. Methods: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. Results: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. Conclusion: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity.

Background/aim: Previous studies have suggested that the hepatic steatosis index (HSI) and fatty liver index (FLI) can be used as a predictor of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to determine whether non-invasive indices of hepatic steatosis (HSI and FLI) are associated with carotid atherosclerosis in type 2 diabetes mellitus (T2DM). Methods: This was a cross-sectional study conducted in the T2DM patients (n=768). Carotid intima-media thickness (CIMT) was measured by the Color Doppler ultrasound. The HSI was calculated based on gender, body mass index (BMI), and transaminases level. The FLI was based on BMI, waist circumference (WC), triacylglycerols (TG) and g-glutamyl transferase (GGT). Results: Raised HSI and FLI levels was associated with increased CIMT levels in T2DM patients. Patients with greater CIMT had higher HSI (39.10 ± 5.70 vs 36.10 ± 4.18, P < 0.001) and FLI (46.35 (29.96, 65.54) vs 36.93 (18.7, 57.93), P < 0.001) than those with lower CIMT. Subjects with existing carotid plaque had higher HSI (38.28 ± 5.63 vs 35.69 ± 3.45 P < 0.001) and FLI (47.41 (27.77, 66.62) vs 37.19 (17.71, 51.78), P < 0.001) accordingly. HSI (r = 0.343, P < 0.001) and FLI (r = 0.184, P < 0.001) were positively related with the CIMT. In the linear regression, after full adjustment metabolic risk factors, smoking, and measures of insulin resistance, HSI and FLI were independently associated with CIMT (HSI: β = 0.011, FLI: β = 0.001, all P < 0.01). Further, logistic regression analyses showed that higher HSI and FLI had an impact on the risk for carotid atherosclerosis [HSI: OR (95%CI): 1.174 (1.123-1.228), FLI: OR (95%CI): 1.011(1.004-1.019), all P < 0.01]. Overall, increasing values of HSI and FLI were associated with CIMT (P < 0.05) significantly across different categories of age and hypertension. Conclusion: Current data suggest HSI and FLI are independently correlated with carotid atherosclerosis in T2DM. They may be a simple and useful marker for assessing the progression of diabetic macrovascular complications.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver pathology worldwide due to the rising prevalence of obesity. This term includes changes from simple steatosis to steatohepatitis and fibrosis. It was previously thought to be a hepatic manifestation of metabolic syndrome, but recent literature describes this relation as much more complex and bi-directional. Development of NAFLD is associated with other metabolic syndrome components but it can also exacerbate insulin resistance and increase cardiovascular risk. Recently a lot of attention is brought to the role of lipids and lipotoxicity in pathogenesis and progression of non-alcoholic fatty disease. It seems that some lipid classes can be protective against liver injury while others are harmful in excessive amounts. This study presents an overview of the main lipids involved in the pathogenesis of non-alcoholic fatty liver disease and summarizes their association with lipotoxicity, insulin resistance, oxidative stress and other processes responsible for its progression.

Background: Type 2 diabetes mellitus (T2DM) is a complex chronic metabolic disorder triggered by insulin resistance in peripheral tissues. Evidence has shown that lipid metabolism and related genetic factors lead to insulin resistance. Hence, it is meaningful to investigate the association between single-nucleotide polymorphisms (SNPs) in lipid metabolism-related genes and T2DM. Methods: A total of 1,194 subjects with T2DM and 1,274 Non-diabetic subjects (NDM) were enrolled. Five SNPs in three genes (rs864745 in JAZF1, rs35767 in IGF1, and rs4376068, rs4402960, and rs6769511 in IGF2BP2) that contribute to insulin resistance involving lipid metabolism were genotyped using the MassArray method in a Chinese population. Results: The allele and genotypes of rs6769511 in IGF2BP2 were associated with T2DM (P=0.009 and P=0.002, respectively). In inheritance model analysis, compared with the T/T-C/T genotype, the C/C genotype of rs6769511 in IGF2BP2 was a risk factor for the development of T2DM (P

The aim was to assess whether fibroblast growth factor 21 (FGF-21) and adiponectin influence intrahepatic cholestasis of pregnancy (ICP) pathogenesis and whether ursodeoxycholic acid (UDCA) has an impact on their levels. 50 pregnant women with ICP (ICP PW), 50 with uncomplicated pregnancy (HPW) and 50 healthy nonpregnant women (HW) were included. In ICP PW the first blood sample was drawn at the time of diagnosis, while in HPW it was drawn in the 28th week of pregnancy. The next blood samples were drawn in the 32nd and 36th week of pregnancy and one day after delivery. UDCA was administered when ICP was diagnosed. In ICP PW serum FGF-21 concentration was the lowest at the time of diagnosis with an evident increase after UDCA administration. Serum FGF-21 levels were significantly higher in ICP PW than in HPW from the first to the last measurement. There was a negative association between adiponectin and bile acids (BAs) levels in the later stage of pregnancy in ICP PW. Up-regulated FGF-21 serum levels in ICP patients compared to HPW persisted after delivery, suggesting its role in disease pathophysiology. The negative association between serum adiponectin and BAs of the later stage of pregnancy may suggest its role in regulation of BAs concentration. UDCA exerts a beneficial effect on insulin sensitivity and up-regulates FGF-21 in ICP.

Background: Brown adipose tissue (BAT) dissipates chemical energy as heat and has the potential to be a protective strategy to prevent obesity. microRNAs (miRNAs) are emerging as important posttranscriptional factors affecting the thermogenic function of BAT. However, the regulatory mechanism underlying miRNA-mediated energy metabolism in BAT is not fully understood. Here, we explored the roles of miR-22 in BAT thermogenesis and energy metabolism. Methods: Using global and conditional knockout mice as in vivo models and primary brown adipocytes as an in vitro system, we investigated the function of miR-22 in BAT thermogenesis in vivo and in vitro. Results: miR-22 expression was upregulated in BAT in response to cold exposure and during brown preadipocyte differentiation. Both global and conditional knockout mice displayed BAT whitening, impaired cold tolerance, and decreased BAT thermogenesis. Moreover, we found that miR-22 deficiency impaired BAT glycolytic capacity, which is critical for thermogenesis. The mechanistic results revealed that miR-22 activated the mTORC1 signaling pathway by directly suppressing Tsc1 and concomitantly directly suppressing Hif1an, an inhibitor of Hif1α, which promotes glycolysis and maintains thermogenesis. Conclusions: Our findings identify miR-22 as a critical regulator in the control of thermogenesis in BAT and as a potential therapeutic target for human metabolic disorders.

Background: Chronic kidney disease (CKD) is a major risk factor for coronary artery disease and it is often associated with hepatic steatosis. Hepassocin (also known as hepatocyte-derived fibrinogen related protein or fibrinogen-like 1) is a novel hepatokine that causes hepatic steatosis and induces insulin resistance. However, the role of hepassocin in renal function status remains unclear. Our objective was to investigate the association of plasma hepassocin level with fatty liver and renal function status in patients with stable angina. Methods: Plasma hepassocin levels were determined by enzyme-linked immunosorbent assays in 395 consecutive patients with stable angina. Renal function was defined as an estimated glomerular filtration rate (eGFR). Fatty liver was defined by ultrasonography and fibrosis-4 (FIB-4) index. Results: With increasing hepassocin tertiles, patients had higher prevalence of fatty live, an increased waist-to-hip ratio, and neutrophil count, monocyte count, and FIB-4 index, higher levels of uric acid, blood urine nitrogen and higher sensitivity C-reactive protein. They also had incrementally lower eGFR, serum hemoglobin and albumin levels. In multiple linear stepwise regression analysis, only eGFR was significantly independent negatively associated with plasma hepassocin levels. Conclusion: Our results indicate that circulating hepassocin in patients with stable angina is associated with fatty liver and renal function, which suggests that increased plasma hepassocin may be involved in the pathogenesis of fatty liver and CKD.

The intestines have been recognized as important tissues for metabolic regulation, including glycemic control, but their vital role in promoting the anti-diabetic effects of bitter melon, the fruit of Momordica charantia L, has seldom been characterized, nor acknowledged. Evidence suggests that bitter melon constituents can have substantial interactions with the intestinal epithelial cells before circulating to other tissues. We therefore characterized the effects of bitter melon extract (BME) on intestinal epithelial cells. BME was found to contain substantial amounts of carbohydrates, proteins, and triterpenoids. TNF-α induced insulin resistance in an enterocyte cell line of IEC-18 cells, and BME promoted glucose utilization of the insulin-resistant cells. Further analysis suggested that the increased glucose consumption was a result of the combined effects of insulin sensitizing and insulin substitution functions of BME. The functions of insulin substitution were likely generated due to the activation of AMP-activated protein kinase. Meanwhile, BME acted as a glucagon-like peptide 1 (GLP-1) secretagogue on enteroendocrine cells, which may be mediated by the activation of bitter-taste receptors. Therefore, BME possesses insulin sensitizing, insulin substitution, and GLP-1 secretagogue functions upon intestinal cells. These effects of BME on intestinal cells likely play a significant part in the anti-diabetic action of bitter melon.

Background: The triglyceride-glucose (TyG) index has been reported to be a simple and reliable surrogate marker of insulin resistance. The aim of this study was to investigate associations between the TyG index and echocardiographic parameters including left ventricular mass (LVM), left atrial diameter (LAD) and left ventricular ejection fraction (LVEF), and markers of peripheral artery disease, ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV). Methods: A total of 823 (483 males and 340 females) patients were enrolled from 2007 to 2011 at a regional hospital in southern Taiwan. Multivariable stepwise linear regression analysis was performed to identify the factors related to echocardiographic parameters and peripheral artery disease. Results: The patients were stratified into four groups according to TyG index quartile. Multivariable stepwise linear regression analysis showed that a higher TyG index was associated with elevated observed/predicted LVM (p = 0.081), increased LAD (p = 0.004), decreased LVEF (p = 0.003) and lower ABI (p = 0.030), but not observed/predicted LVM and baPWV. Conclusions: A high TyG index was significantly associated with high LAD, low LVEF and low ABI. However, the TyG index was not significantly associated with inappropriate LVM or baPWV. The results suggest that the TyG index, as a simple indicator of insulin resistance, may reflect cardiac remodeling and dysfunction and atherosclerosis.

Pharmacological stimulation of adipose tissue remodeling and thermogenesis to increase energy expenditure is expected to be a viable therapeutic strategy for obesity. Berberine has been reported to have pharmacological activity in adipose tissue to anti-obesity, while the mechanism remains unclear. Here, we observed that berberine significantly reduced the body weight and insulin resistance of high-fat diet mice by promoting the distribution of brown adipose tissue and thermogenesis. We have further demonstrated that berberine activated energy metabolic sensing pathway AMPK/SIRT1 axis to increase the level of PPARγ deacetylation, which leads to promoting adipose tissue remodeling and increasing the expression of the thermogenic protein UCP-1. These findings suggest that berberine that enhances the AMPK/SIRT1 pathway can act as a selective PPARγ activator to promote adipose tissue remodeling and thermogenesis. This study proposes a new mechanism for the regulation of berberine in adipose tissue and offers a great prospect for berberine in obesity treatment.

Dysfunction of adipose tissue could lead to insulin resistance, obesity and type 2 diabetes. Thus, our present study aimed to investigate metabolites alterations in white adipose tissue (WAT) of diabetic GK rats after IT surgery. Ten-week-old male diabetic GK rats were randomly subjected to IT and Sham-IT surgery. Six weeks later, the untargeted metabolomics in WAT of diabetic GK rats was performed. Differential metabolites were selected according to the coefficient of variation (CV) of quality control (QC) sample 1 and P

Background Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from the nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes. Methods Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of LNK on the pathogenesis of PCOS. Results The level of LNK was higher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocyte maturation rate. LNK overexpression in KGN cells inhibited insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice. Conclusions LNK was closely related to insulin resistance and apoptosis of granulosa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.

Flavonoids are a large class of compounds that are widely found in many plants, including plants used in Chinese herbal medicines. Previous studies have revealed that flavonoids possess biomedical activities, including antioxidant, anti-cancer, anti-viral, and anti-inflammatory properties. They also have the functions of lowering lipids, lowering blood sugar, and improving insulin resistance. This article selects four typical compounds of flavonoids, namely baicalin, baicalein, quercetin, and rutin, and reviews their effects and mechanisms of action in improving insulin resistance. With a view for future clinical research on flavonoids as antidiabetic drugs, we therefore provide the theoretical basis for the development and application of flavonoids.

The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.

Objective The present study aims to assess for temporal changes in tibial subchondral bone and cartilage in WNIN/Gr-Ob rats (portraying obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, hypertension) in comparison with Wistar controls (WNIN) using anthropometry, micro-computed tomography (micro-CT), scanning electron microscopy (SEM), histopathology, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Design Body weight, abdominal circumference, body mass index (BMI), lean/fat mass, serum tumor necrosis factor (TNF)-α levels were measured (ELISA), followed by ultrastructural analysis of tibial subchondral bone (micro-CT) and cartilage architecture (histopathology and SEM) in WNIN/Gr-Ob and WNIN rats with age (3, 6 and 9 months). Additionally, primary cultures of articular chondrocytes isolated from 6-month-old WNIN/Gr-Ob and WNIN rats were assessed for matrix metalloproteinase (MMP)-13 and Collagen type II (COL2A1) by immunofluorescence. Results WNIN/Gr-Ob rats exhibited frank obesity with increased BMI, lean and fat mass vis-à-vis significantly higher levels of serum TNF-α (6>9>3 months) as compared with the controls. With an increase in BMI, WNIN/Gr-Ob rats presented with tibial cartilage fibrillation, erosion, osteophyte formation (6 months) and subchondral bone cyst (9 months) confirmed by histology and SEM. An increase in subchondral trabecular bone volume (sclerosis with decreased plate porosity) was observed in all ages in WNIN/Gr-Ob rats compared to their Control. Gaining insights, primary cultures of articular chondrocytes complemented with altered cellular expressions of COL2A1 and MMP-13 from WNIN/Gr-Ob rats, indicating osteoarthritis (OA) progression. Conclusion Multiple metabolic perturbations featured in WNIN/Gr-Ob rats were effective to induce spontaneous OA-like degenerative changes affecting knee joints akin to human OA.

The miR-17-92 cluster (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92a) contributes to the occurrence and development of various diseases by inhibiting multiple target genes. Here, we explored the effects of miR-18a on insulin sensitivity. Quantitative real-time PCR indicated that serum miR-18a levels were lower in type 2 diabetes mellitus patients than in healthy controls, suggesting that miR-18a may influence blood glucose levels. Global overexpression of miR-18a in transgenic mice increased their glucose tolerance and insulin sensitivity, while it reduced expression of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) in their skeletal muscle and adipose tissue. Western blotting indicated that overexpressing miR-18a in 3T3-L1 and C2C12 cells enhanced insulin-stimulated AKT phosphorylation and suppressed PTEN expression, while inhibiting miR-18a had the opposite effects. These results suggest that miR-18a improves insulin sensitivity by downregulating PTEN. This makes miR-18a a potentially useful target for the treatment of diabetes mellitus in the future.

Both hepatitis C virus (HCV) infection and retinol-binding protein 4 (RBP4) might contribute to insulin resistance (IR), how RBP4 links to IR in HCV infection remain elusive. A joint study of a prospective cohort of 842 chronically HCV-infected (CHC) patients (with 842 controls) and a line of HCV core transgenic mice was conducted. Of 842 patients, 771 had completed anti-HCV therapy and 667 had sustained virological responses (SVRs). Compared with controls, CHC patients had lower RBP4 levels. At baseline, age (95% CI β: −0.87~−0.317), BMI (0.516~2.036), triglycerides (0.03~0.127), neutrophil-to-lymphocyte ratio (NLR) (1.561~7.327), and estimated glomerular filtration rate (eGFR) (−0.342~−0.149) levels were associated with RBP4 levels in CHC patients. At 24-week post-therapy, male sex (0.652~8.129), BMI (0.199~1.254), triglycerides (0.039~0.088), uric acid (0.599~3.067), eGFR (−0.247 ~−0.14) levels, and fibrosis-4 (−3.602~−0.039) scores were associated with RBP4 levels in SVR patients; compared with baseline, except genotype 3 HCV-infected patients, SVR patients had increased RBP4 levels, which were comparable with controls, while no HOMA-IR index alteration was noted after SVR. The HCV core transgenic mice exhibited nonobese hepatic steatosis, had higher hepatic RBP4 expression, higher serum levels of RBP4 and triglycerides, but comparable HOMA-IR levels than non-transgenic littermates. In conclusion, steatosis, sex, age, uric acid, NLR, and FIB-4 levels were associated with HCV-related RBP4 levels; BMI, triglycerides, and eGFR levels were associated with non-HCV-related RBP4 levels. Reversal of low RBP4 levels after SVR was evident in non-genotype 3 HCV-infected patients. Steatosis and inflammation linked with metabolic alteration other than IR, determined RBP4 levels in HCV-infected patients.

The endocannabinoid system is found in tissues that regulate the glycemia, including adipose tissue, muscle, and pancreatic islets. Diet-induced metabolic syndrome changes the expression of the CB receptors in muscle, adipose tissue, and liver. However, it is poorly understood whether metabolic syndrome (MetS) affects the expression of CB receptors in pancreatic β cells. We analyzed the expression of CB receptors in pancreatic β cells under chronic high-sucrose diet (HSD)-induced MetS. Wistar rats fed an HSD as a model of MetS were used to investigate changes in cannabinoid receptors. After 8 weeks of treatment, we evaluated the appearance of the following MetS biomarkers: glucose intolerance, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and an increase in visceral adiposity. To determine the presence of CB1 and CB2 receptors in pancreatic β cells, immunofluorescence of primary cell cultures and pancreatic sections was performed. For whole-islet quantification of membrane-bound CB1 and CB2 receptors, western-blotting following differential centrifugation was conducted. Our results revealed that an HSD treatment closely mimics the alterations seen in MetS. We observed that in primary cell culture, CB1 and CB2 receptors were expressed at a higher level in pancreatic β cells compared with non-β cells. MetS resulted in a reduction of CB1 in the islet, whereas abundant CB2 was observed after the treatment. CB1 and CB2 receptors are differentially expressed in pancreatic β cells during MetS development.

The contribution of dysregulated mitochondrial gene expression and consequent imbalance in biogenesis is not well understood in metabolic disorders such as insulin resistance and obesity. The ribosomal RNA maturation protein PTCD1 is essential for mitochondrial protein synthesis and its reduction causes adult-onset obesity and liver steatosis. We used haploinsufficient Ptcd1 mice fed normal or high fat diets to understand how changes in mitochondrial biogenesis can lead to metabolic dysfunction. We show that Akt-stimulated reduction in lipid content and upregulation of mitochondrial biogenesis effectively protected mice with reduced mitochondrial protein synthesis from excessive weight gain on a high fat diet, resulting in improved glucose and insulin tolerance and reduced lipid accumulation in the liver. However, inflammation of the white adipose tissue and early signs of fibrosis in skeletal muscle, as a consequence of reduced protein synthesis, were exacerbated with the high fat diet. We identify that reduced mitochondrial protein synthesis and OXPHOS biogenesis can be recovered in a tissue-specific manner via Akt-mediated increase in insulin sensitivity and transcriptional activation of the mitochondrial stress response.

Many studies suggest that Epigallocatechin-3-Gallate (EGCG) has many protective effects. But little is known about its protective effects against chronic restraint stress-induced damage in rats. The aim was to demonstrate the potential protective effects of EGCG against harmful pancreatic damage to the immobilization stress in the rat model. Forty rats, 2 months old, were divided into four groups (n = 10): control group; EGCG group, rats received EGCG by gavage (100 mg/kg /day) for 30 days; stressed group, rats exposed to immobilization stress; and stressed with EGCG group, rats exposed to immobilization stress and received EGCG for 30 days. Glycemic status parameters, corticosterone, and inflammatory markers were investigated on the first day, 15th day, and the 30th day of the experiment. Pancreatic oxidative stress markers and cytokines were evaluated. Histological, immunohistological, and statistical studies were performed. On the 15th day, fasting blood glucose (FBG), fasting plasma insulin (FPI), homeostatic model assessment for insulin resistance (HOMA-IR), and fasting plasma corticosterone were significantly higher in the stressed group when compared with first and 30th day in the same group as well as when compared with control and stressed with EGCG groups. The stressed group revealed significantly higher pancreatic IL-1β, IL-6, TNF-α, MDA, and NO, serum amylase and serum lipase, and significantly lower GSH, SOD, and CAT when compared to control and stressed with EGCG groups. EGCG treatment attenuated the pancreatic stress-induced cellular degeneration, leucocytic infiltration, and cytoplasmic vacuolations; significantly decreased area percentage of collagen fibers; and significantly increased mean area percentage of insulin immunopositive cell as compared with stressed group. EGCG is a protective agent against immobilization stress because of its anti-diabetic, anti-inflammatory, and and anti-oxidative stress properties, as confirmed by biochemical and histological alterations.

The aim of this study was to elucidate mechanisms whereby bile acids exert beneficial metabolic effects, using the Cyp8b1−/- mouse as model. These mice are unable to synthesize cholic acid, resulting in increased synthesis of chenodeoxycholic acid and enlarged bile acid pool. Cyp8b1−/- mice were found to be protected against high-fat diet induced obesity. Bomb calorimetry measurements showed increased faecal energy output in Cyp8b1−/mice. Indirect calorimetry measurements demonstrated increased energy expenditure in Cyp8b1−/- mice. Meal tolerance tests revealed no differences in glucose disposal, but the insulin response was lower in Cyp8b1−/- mice. Intravenous glucose tolerance tests, as well as static incubations of isolated islets, showed no difference between the groups, whereas insulin tolerance tests demonstrated improved insulin sensitivity in Cyp8b1−/- mice. The genes encoding mitochondrial transcription factor A (TFAM) and type 2-iodothyronine deiodinase were upregulated in brown adipose tissue of Cyp8b1/- mice and Western blot analyses showed increased abundance of TFAM, and a trend towards increased abundance of UCP1. The upregulation of TFAM and UCP1 was accompanied by increased mitochondrial density, as shown by transmission electron microscopy. White adipocytes of Cyp8b1−/- mice exhibited increased responsiveness to both catecholamines and insulin in lipolysis experiments and increased insulin-stimulated lipogenesis. In conclusion, increased energy expenditure, mitochondrial density of brown adipocytes and faecal energy output may all contribute to the protection against diet-induced obesity of Cyp8b1−/- mice. Enhanced insulin sensitivity of Cyp8b1−/- mice is accompanied by increased hormonal responsiveness of white adipocytes.

Introduction Obese woman with hirsutism have increased risk for developing insulin resistance and diabetes mellitus. Aim To evaluate patients with hirsutism, report the hormone levels, body mass index (BMI), insulin resistance and diabetes in our study population and compare our results with those of similar research conducted in other countries. Material and methods Hormones were measured with radioimmunoassay/immunoradiometric assay methods. Oral glucose tolerance test was done only in a selected group of women (with positive anamnesis for diabetes, women with polycystic ovary syndrome (PCOS) and overweight/obese women). The level of blood glucose was measured after drinking the liquid containing 75 g glucose. Blood was taken to measure glucose, insulin and C-peptide levels after 30 min, 60 min and 3 h. Results Women with PCOS (27.4%) had higher BMI than women with other causes of hirsutism. Among 135 of the women with hirsutism, 9.6% were underweight, 60% were with normal weight, 20.7% were overweight and 9.6% were obese. Obesity was more frequent in PCOS and hyperandrogenism groups. Women with hirsutism had higher levels of androstenedione, dehydroepiandrosterone sulfate (DHEAS), total testosterone, free testosterone, lower levels of sex hormone-binding globulin (SHBG). Insulin resistance was present in 20 (14.8%) women and diabetes in 2 (1.4%) women. Conclusions Obesity was associated with increased hirsutism. In our study we found that insulin resistance should be assessed in hirsute women with PCOS regardless of their BMI as insulin resistance was found in hirsute women irrespective of whether they were overweight, obese, of normal weight or underweight. Groups at risk (hirsute, obese, diabetes) should be identified and treated.

Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-βGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from β-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.

Background Gestational diabetes mellitus (GDM) is a metabolic disease that can have long-term adverse effects on the cognitive function of mothers. In our study, we explored the changes in metabolic health and cognitive function in mice of middle- and old- age after exposure to GDM, and whether metformin therapy during pregnancy provided long-term benefits. Results Mice with GDM demonstrated significant cognitive impairment in old age, which was associated with insulin resistance. Gestational metformin therapy was shown to increase insulin sensitivity and improve cognition. The ovarian aging rate was also accelerated in mice exposed to GDM during pregnancy, which may be related to fatty acid metabolism in the ovaries. Conclusion Treatment with metformin during pregnancy was shown to improve fatty acid metabolism in ovarian tissues. Method During pregnancy, mice were fed with a high-fat diet (GDM group) or a low-fat diet (Control group), and a third group received metformin while receiving a high-fat diet (Treatment group). At 12 months old, the mice completed an oral glucose tolerance test, insulin tolerance test, Morris water maze test, female sex hormones were measured, and metabolite profiles of tissue from the ovaries, hypothalamus, and pituitary glands were analysed using gas chromatography-mass spectrometry.

Numerous epidemiological studies have reported that moderate alcohol drinking has beneficial effects. However, few studies have focused on the beneficial effects of ethanol, the common component in alcoholic beverages. Here we fed the C57BL/6 mice with 3.5% v/v ethanol as drinking water substitute to investigate the effects of long-term low-dose ethanol intake in vivo. We evaluated the metabolic rate and mitochondrial function of the long-term low-dose ethanol-intake (LLE) mice, assessed the exercise ability of LLE mice, and fed the LLE mice with a high-fat diet to investigate the potential impact of ethanol on it. The LLE mice showed improved thermogenic activity, physical performance, and mitochondrial function, as well as resistance against the high-fat diet-induced obesity with elevated insulin sensitivity and subdued inflammation. Our results suggest that long-term low-dose ethanol intake can improve healthspan and resist high-fat diet-induced obesity in mice. It may provide new insight into understanding the protective effects of moderate alcohol drinking.

In this study, we investigated the mechanisms underlying the altered hepatic glucose metabolism and enhanced diabetes risk in individuals with the TCF7L2 rs290487 C allele. Analysis of 195 cirrhotic patients revealed a higher insulin resistance index and incidence of hepatogenous diabetes in patients with the rs290487 C/C genotype compared to those with the C/T or T/T genotype. The in vitro experiments using targeted mutant PLC-PRF-5 cell line showed that cells with the rs290487 C/C genotype (C/C cells) had higher glucose production, lower glucose uptake, and lower TCF7L2 mRNA and protein levels than those with the C/T genotype (C/T cells). Integrated multi-omics analysis of ChIP-seq, ATAC-seq, RNA-seq, and metabolomics data showed genome-wide alterations in the DNA binding affinity of TCF7L2 in the C/C cells, including gain (e.g., PFKP and PPARGC1A) and loss (e.g., PGK1 and PGM1) of binding sites in several glucose metabolism-related genes. These allele-specific changes in transcriptional regulation lead to increased expression of gluconeogenesis-related genes (PCK1, G6PC and PPARGC1A) and their downstream metabolites (oxaloacetate and β-D-fructose 2,6-bisphosphate). These findings demonstrate that the TCF7L2 rs290487 C allele enhances gluconeogenesis through allele-specific changes in transcription and chromatin binding.

In this study, mice with type 2 diabetes mellitus (T2DM) induced by high-fat diet were used to investigate the antidiabetic effect and mechanism of action of peanut skin extract (PSE). Results revealed that the fasting blood glucose, body weight, and food intake of mice with T2DM significantly decreased after they were given PSE. The effects of 80 mg/kg PSE were similar to those of 140 mg/kg metformin (MET). The glucose tolerance and insulin sensitivity of the mice also improved. The composition of intestinal microflora in the mice significantly changed after PSE administration. In particular, no Actinobacteria was detected in the PSE-treated group, and the ratio of Firmicutes to Bacteroidetes was remarkably reduced. PSE also increased the abundance of gut microbiota involved in fatty acid biosynthesis, lipid biosynthesis, and sucrose metabolism. The abundance of gut microbiota related to aminoacyl-tRNA biosynthesis also decreased. Lipopolysaccharide, interleukin (IL)-6, IL-1β and tumor necrosis factor-α in the blood, liver and adipose tissue were reduced by PSE. Similarly, the mRNA expression levels of IkappaB kinase and nuclear factor kappaB in the hypothalamus were reduced by PSE. These results suggested that PSE and MET elicited significant antidiabetic effects by maintaining gut microbiota and inhibiting inflammation.

Senescent cells accumulate with obesity in the white adipose tissue of mice and humans. These senescent cells enhance the pro-inflammatory environment that, with time, contributes to the onset of glucose intolerance and type 2 diabetes. Glucose intolerance in mouse models of obesity has been successfully reversed by the elimination of senescent cells with the senolytic compounds navitoclax or the combination of dasatinib and quercetin (D/Q). In this work, we generated obese mice by high-fat diet feeding, and treated them with five consecutive cycles of navitoclax or D/Q during 16 weeks. We observed an efficient reduction in the white adipose tissue of the senescence markers senescence-associated β-galactosidase activity, Cdkn2a-p16 and Cdkn2a-p19 at the end of the 5 cycles. Mice treated with both navitoclax and D/Q showed an improvement of their insulin sensitivity and glucose tolerance during a short period of time (cycles 3 and 4), that disappeared at the fifth cycle. Also, these mice tended to increase the expression at their adipose tissue of the adipogenic genes Pparg and, Cebpa, as well as their plasma adiponectin levels. Together, our work shows that two different senolytic treatments, acting through independent pathways, are transiently effective in the treatment of obesity-induced metabolic disorders.

Objective:To propose cut-off points for the TAG–glucose (TyG) index in Brazilian children and evaluate the link to cardiometabolic risk.Design:A cross-sectional study with children from a municipality in Minas Gerais, Brazil. Anthropometric (weight, height, waist circumference and waist:height ratio), biochemical (lipid and glucose profile) and blood pressure (BP) tests were performed. Using the receiver operating characteristic curve, cut-off points for the TyG index were proposed according to sex using homoeostasis model of assessment – insulin resistance (IR) as the reference method.Setting:Viçosa, MG, Brazil.Participants:Children aged 4–9 years (n 515).Results:The TyG index cut-off points to identify the risk of IR were 7·9 and 8·1 for boys and girls, respectively. We observed that 48·7 % of the children had an increased TyG index. The increased TyG index was associated with overweight, total body and central fat, increased BP and altered lipid profile. Children with an increased TyG index had a higher accumulation of cardiometabolic risk factors.Conclusions:According to the cut-off points proposed by the current study, children at risk of IR estimated by the TyG index presented a higher cardiometabolic risk, including isolated risk factors, as to the higher accumulation of these.

SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway. In vivo, lycorine ameliorates high-fat diet-induced hyperlipidemia, hepatic steatosis, and insulin resistance in mice. Our study demonstrated that the inhibition of SCAP through the SMAILD pathway could be employed as a useful therapeutic strategy for treating metabolic diseases. Abbreviation: 25-OHD: 25-hydroxyvitamin D; 3-MA: 3-methyladenine; ABCG5: ATP binding cassette subfamily G member 5; ABCG8: ATP binding cassette subfamily G member 8; ACACA: acetyl-CoA carboxylase alpha; AEBSF: 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride; AHI: anhydroicaritin; AKT/protein kinase B: AKT serine/threonine kinase; APOE: apolipoprotein E; ATF6: activating transcription factor 6; ATG: autophagy-related; BAT: brown adipose tissue; CD274/PD-L1: CD274 molecule; CETSA: cellular thermal shift assay; CMA: chaperone-mediated autophagy; COPII: cytoplasmic coat protein complex-II; CQ: chloroquine; DDIT3/CHOP: DNA damage inducible transcript 3; DNL: de novo lipogenesis; EE: energy expenditure; EGFR: epithelial growth factor receptor; eMI: endosomal microautophagy; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FADS2: fatty acid desaturase 2; FASN: fatty acid synthase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvate transaminase; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS1: 3-hydroxy-3-methylglutaryl-CoA synthase 1; HSP90B1/GRP94: heat shock protein 90 beta family member 1; HSPA5/GRP78: heat hock protein family A (Hsp70) member 5; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INSIG1: insulin induced gene 1; LAMP2A: lysosomal associated membrane protein 2A; LDLR: low density lipoprotein receptor; LyTACs: lysosome targeting chimeras; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MBTPS1: membrane bound transcription factor peptidase, site 1; MEF: mouse embryonic fibroblast; MST: microscale thermophoresis; MTOR: mechanistic target of rapamycin kinase; MVK: mevalonate kinase; PROTAC: proteolysis targeting chimera; RQ: respiratory quotient; SCAP: SREBF chaperone; SCD1: stearoyl-coenzemy A desaturase 1; SMAILD: sequestosome 1 mediated autophagy-independent lysosomal degradation; SQSTM1: sequestosome 1; SREBF: sterol regulatory element binding transcription factor; TNFRSF10B/DR5: TNF receptor superfamily member 10b; TRAF6: TNF receptor associated factor 6; UPR: unfolded protein response; WAT: white adipose tissue; XBP1: X-box binding protein 1

Studies have shown that diabetes is an important risk factor for cognitive dysfunction, also called diabetic encephalopathy (DE). Quercetin has been reported to be effective in improving cognitive dysfunction in DE. But its detailed mechanism is still ambiguous. In this study, we used db/db mice to investigate whether quercetin could activate SIRT1 and inhibit ER pathways to improve DE. Behavioral tests (Morris water maze and new objects) showed that quercetin (70 mg/kg) can effectively improve the learning and memory ability in db/db mice. OGTT and ITT tests indicated that quercetin could alleviate impaired glucose tolerance and insulin resistance in db/db mice. Western blot analysis and Nissl staining showed that quercetin can improve the expression of nerve and synapse-associated proteins (PSD93, PSD95, NGF and BDNF) and inhibit neurodegeneration. Meanwhile, quercetin up-regulates SIRT1 protein expression and inhibits the expression of ER signaling pathway-related proteins (PERK, IRE-1α, ATF6, eIF2α, BIP and PDI). In addition, oxidative stress levels were significantly reduced after quercetin treatment. In conclusion, current experimental results indicated that SIRT1/ER stress is a promising mechanism involved in quercetin-treated diabetic encephalopathy.

Objective:Waist-to-height ratio has been shown to be an important indicator of cardiometabolic risk. There are few studies evaluating this measure against existing measures of adiposity and cardiometabolic markers in early childhood. The objectives were: (i) to determine in young children the ability of waist-to-height ratio, BMI z-score, weight for length, and sum of skin fold thickness to predict cardiometabolic risk and (ii) to examine this association at ages 1, 3 and 5 years.Design:Prospective cohort study.Setting:A university hospital in Toronto, Ontario.Participants:Infants at 1 (n 406), 3 (n 112) and 5 years of age (n 94) born to mothers with and without gestational diabetes mellitus.Results:Weight for length and BMI z-score demonstrated the strongest correlations with biochemical measures compared to waist-to-height ratio, including leptin (at 5 years, weight for length z-score: ρ = 0·65, P < 0·001; BMI z-score: ρ = 0·67, P < 0·001) and measures of insulin resistance (at 3 years, weight for length z-score: ρ = 0·25, P = 0·02; BMI z-score: ρ = 0·24, P = 0·02). The magnitude of associations between anthropometric measures and biochemical measures strengthened over time. Weight for length and BMI z-scores were moderately correlated with overall measures of fat mass as measured by dual-energy X-ray absorptiometry (ρ = 0·65, P = 0·00; ρ = 0·61, P = 0·01).Conclusions:Waist-to-height ratio was not superior to existing measures in predicting cardiometabolic risk in young children. BMI z-score is a preferred measure of adiposity between birth and 5 years of age.

Insulin resistance (IR) contributes to diabetes and aging. Ultraconserved elements (UCEs) are a class of long noncoding RNAs (lncRNAs) that are 100% conserved in humans, mice, and rats. We identified the lncRNA uc.333 using an lncRNA microarray and then used quantitative real-time polymerase chain reaction to analyze its expression in the livers of nonalcoholic fatty liver disease (NAFLD) patients, db/db mice, high-fat diet-fed mice, IL-6-treated mice, and TNF-α-treated mice. The underlying mechanisms of uc.333 in IR were investigated using fluorescence in situ hybridization, Western blot, and miRNA microarray analyses. The results revealed that uc.333 expression was decreased in liver tissues from NAFLD patients and treated mice. Furthermore, overexpression of uc.333 decreased IR, whereas knocking down uc.333 increased IR. We also confirmed that uc.333 binds to miR-223 and that the levels of miR-223 were increased in the livers of patients and treated mice. These findings showed that uc.333 improves IR by binding to miR-223; thus, uc.333 may be a useful target for the treatment and prevention of IR.

Low estrogen levels may predispose women to increased bodyweight and dyslipidemia. Previous studies from our laboratory suggest an involvement of depressed heat shock response (HSR) in this scenario because estrogen potently stimulates HSR. As heat treatment induces the expression of the anti-inflammatory heat shock proteins of the 70-kDa family (HSP70) and its accompanying HSR, we aimed to investigate whether chronic heat treatment promotes beneficial effects on biometric, lipid profile, oxidative stress, and HSR in ovariectomized rats. Wistar adult female rats (n = 32) were divided into four groups: control (C, n = 7), ovariectomized (OVX, n = 9), heat-treated (HT, n = 9), and heat-treated ovariectomized rats (OVX+HT, n = 7). HT and OVX+HT rats were anesthetized and submitted to heat treatment (once a week for 12 weeks) in a water bath (41 °C) to increase rats’ rectal temperature up to 41 °C for 15 min, while C and OVX animals were submitted to a 36 °C water bath. HT attenuated the weight gain induced by OVX and increased HDL cholesterol and triglyceride serum levels. Also, OVX rats showed increased total cholesterol and LDL cholesterol levels that were not influenced by HT. Interestingly, it was found that an overall trend for HT to decrease tissue catalase and superoxide dismutase antioxidant activities was paralleled by a decrease in malondialdehyde levels (indicative of lower lipoperoxidation), especially in the skeletal muscle. Surprisingly, OVX was not able to depress intracellular HSP70 expression in the skeletal muscle, as expected, and this remained unchanged with HT. However, chronic HT did enhance intracellular HSP70 contents in white adipose tissue of OVX animals. As both glucose and insulin tolerance tests were not affected by OVX, which was not modified by HT, we suppose that estrogen absence alone is not sufficient to determine a state of insulin resistance associated with low intramuscular HSP70 content. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12192-020-01087-z) contains supplementary material, which is available to authorized users.

Obesity is a medical condition in which excess body fat has accumulated to a serious extent. It is a chronic disease that can lead to dyslipidemia, insulin resistance, and type 2 diabetes. In the present study, we investigated the anti-obesity effects of Sicyos angulatus (SA) extract on a high-fat diet (HFD)-induced C57BL/6J obese mice. The mice were divided into vehicle and three SA groups (25, 50, and 100 mg/kg body weight). The mice were fed a HFD with or without SA for 12 weeks. The oral administration of SA reduced body and adipose tissue weight in HFD-fed mice compared to those in the vehicle group (p

Antioxidant signaling/communication is among the most important cellular defense and survival pathways, and the importance of redox signaling and homeostasis in aging has been well-documented. Intracellular levels of glutathione (GSH), a very important endogenous antioxidant, both govern and are governed by the Nrf2 pathway through expression of genes involved in its biosynthesis, including the subunits of the rate-limiting enzyme (glutamate cysteine ligase, GCL) in GSH production, GCLC and GCLM. Mice homozygous null for the Gclm gene are severely deficient in GSH compared to wild-type controls, expressing approximately 10% of normal GSH levels. To compensate for GSH deficiency, Gclm null mice have upregulated redox-regulated genes, and, surprisingly, are less susceptible to certain types of oxidative damage. Furthermore, young Gclm null mice display an interesting lean phenotype, resistance to high fat diet-induced diabetes and obesity, improved insulin and glucose tolerance, and decreased expression of genes involved in lipogenesis. However, the persistence of this phenotype has not been investigated into old age, which is important in light of studies which suggest aging attenuates antioxidant signaling, particularly in response to exogenous stimuli. In this work, we addressed whether aging compromises the favorable phenotype of increased antioxidant activity and improved glucose homeostasis observed in younger Gclm null mice. We present data showing that under basal conditions and in response to cadmium exposure (2 mg/kg, dosed once via intraperitoneal injection), the phenotype previously described in young (, Graphical abstract Image 1, Highlights • Young Gclm-/- mice have lower body weight, more insulin sensitivity, and glucose tolerance relative to young Gclm+/+ mice. • The improved glucose homeostasis in young Gclm-/- mice under basal conditions and cadmium treatment are maintained in old age. • Gclm-/- mice have increased Nrf2-regulated genes and beta oxidation; and decreased gluconeogenesis and fatty acid synthesis.

Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock‐in mouse model, AppNL−F/NL−F , which accumulates Aβ plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6‐month‐old male AppNL−F/NL−F and wild‐type mice were fed a regular or high‐fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild‐type and AppNL−F/NL−F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD‐fed AppNL−F/NL−F mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8‐oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aβ binding protein transthyretin (TTR) in AppNL−F/NL−F mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD‐fed AppNL−F/NL−F mice., Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD). In this paper, we showed that type 2 diabetic conditions induced by chronic high‐fat diet treatment exacerbated pre‐existing AD pathology such as Aβ deposition, microgliosis, and oxidative DNA damage in a knock‐in mouse model of AD, App NL‐F/NL‐F. This was accompanied by decreased expression of transthyretin, a protein that can bind to the Aβ peptide, suppress its aggregation, and promote its clearance.