Interactions between myoblasts and macrophages under high glucose milieus result in inflammatory response and impaired insulin sensitivity

BACKGROUND Skeletal muscle handles about 80% of insulin-stimulated glucose uptake and become the major organ occurring insulin resistance(IR).Many studies have confirmed the interactions between macrophages and skeletal muscle regulated the inflammation and regeneration of skeletal muscle.However,despite of the decades of research,whether macrophages infiltration and polarization in skeletal muscle under high glucose(HG)milieus results in the development of IR is yet to be elucidated.C2C12 myoblasts are well-established and excellent model to study myogenic regulation and its responses to stimulation.Further exploration of macrophages'role in myoblasts IR and the dynamics of their infiltration and polarization is warranted.AIM To evaluate interactions between myoblasts and macrophages under HG,and its effects on inflammation and IR in skeletal muscle.METHODS We detected the polarization status of macrophages infiltrated to skeletal muscles of IR mice by hematoxylin and eosin and immunohistochemical staining.Then,we developed an in vitro co-culture system to study the interactions between myoblasts and macrophages under HG milieus.The effects of myoblasts on macrophages were explored through morphological observation,CCK-8 assay,Flow Cytometry,and enzyme-linked immunosorbent assay.The mediation of macrophages to myogenesis and insulin sensitivity were detected by morphological observation,CCK-8 assay,Immunofluorescence,and 2-NBDG assay.RESULTS The F4/80 and co-localization of F4/80 and CD86 increased,and the myofiber size decreased in IR group(P<0.01,g=6.26).Compared to Mc group,F4/80+CD86+CD206-cells,tumor necrosis factor-α(TNFα),inerleukin-1β(IL-1β)and IL-6 decreased,and IL-10 increased in McM group(P<0.01,g>0.8).In McM+HG group,F4/80+CD86+CD206-cells,monocyte chemoattractant protein 1,TNFα,IL-1βand IL-6 were increased,and F4/80+CD206+CD86-cells and IL-10 were decreased compared with Mc+HG group and McM group(P<0.01,g>0.8).Compered to M group,myotube area,myotube number and E-MHC were increased in MMc group(P<0.01,g>0.8).In MMc+HG group,myotube area,myotube number,E-MHC,GLUT4 and glucose uptake were decreased compared with M+HG group and MMc group(P<0.01,g>0.8).CONCLUSION Interactions between myoblasts and macrophages under HG milieus results in inflammation and IR,which support that the macrophage may serve as a promising therapeutic target for skeletal muscle atrophy and IR.

Short-Term Effects of Liraglutide versus Vildagliptin on Insulin Secretion and Sensitivity in Type 2 Diabetes: A Single Blinded Randomized Controlled Trial (LIRAVIS Study)

Background: We aimed to evaluate the short-term metabolic effects of a GLP-1a, (liraglutide) versus a DPP-4i, (vildagliptin) in a group of sub-Saharan type 2 diabetes patients. Methods: We conducted a randomized controlled single blinded clinical trial in 14 uncontrolled type 2 diabetes patients (HbA1c ≥ 53 mmol/mol) with mean duration of diabetes of 8 [1 - 12] years and median age of 57 [49 - 61] years. Baseline treatment consisted of metformin in monotherapy or metformin plus sulfonylureas. Participants were randomly allocated to 2 groups of add-on 1.2 mg/day subcutaneous liraglutide in group 1 or 100 mg/day of oral vildagliptin in group 2 for 2 weeks. In all participants, insulin secretion in response to mixed meal tolerance test, insulin sensitivity by 80 mU/m2/min hyperinsulinemic-euglycemic clamp, body composition, and lipid profile were measured before and after intervention. Results: At the end of intervention, insulin sensitivity remained unchanged both with liraglutide from 6.6 [4.2 - 7.9] to 6.9 [4.3 - 10.8] mg/kg/min;p = 0.61 and vildagliptin from 7.1 [5.3 - 9.0] to 6.5 [5.6 - 9.4] mg/kg/min (p = 0.86). The area under the C-peptide curve varied from 5.5 [1.0 - 10.9] to 14.9 [10.8 - 17.2] nmol/L/120min, p = 0.09 in group 1 and from 1.1 [0.5 - 14.1] to 13.0 [9.6 - 16.9] nmol/L/120min (p = 0.17) in group 2. LDL Cholesterol levels decreased significantly with liraglutide from 0.85 g/L [0.51 - 1.02] to 0.54 g/L [0.50 - 0.73] (p = 0.04) but not with Vildagliptin. Body weight tended to decrease in group 1 (−0.6 kg) versus modest increase in group 2 (+1.1 kg). Conclusion: Short-term metabolic effects of Liraglutide and Vildagliptin add-on therapy are comparable in sub-Saharan type 2 diabetes patients with a more favorable trend for Liraglutide on body weight, lipid profile, and insulin secretion.

Association of vitamin D and magnesium with insulin sensitivity and their influence on glycemic control

Insulin resistance increases the risk of developing diabetes,and the degree of resistance influences the glycemic control of patients with diabetes.Numerous researchers have focused on improving insulin sensitivity in order to prevent diabetes-related complications and other chronic diseases.Several studies have also linked vitamin D levels to insulin secretion and resistance,given that both vitamin D and its receptor complex play important roles in regulating pancreaticβ-cells.It has been suggested that vitamin D supplementation improves vitamin D levels,but further research is needed to confirm this as neither insulin function nor glycemic control improves when vitamin D levels increase.Magnesium is a cofactor for many enzymes.Although the role of magnesium in the management of diabetes has long been evaluated,it has not yet been determined whether magnesium supplements improve insulin function.However,several researchers have found that patients with good glycemic control have high magnesium levels.Magnesium is closely related to vitamin D and is necessary for the transport and activation of vitamin D in humans.Combined supplementation with vitamin D and magnesium improves glycemic control in patients with diabetes.

Association of point in range withβ-cell function and insulin sensitivity of type 2 diabetes mellitus in cold areas

Background and Objective:Self-monitoring of blood glucose(SMBG)is crucial for achieving a glycemic target and upholding blood glucose stability,both of which are the primary purpose of anti-diabetic treatments.However,the association between time in range(TIR),as assessed by SMBG,andβ-cell insulin secretion as well as insulin sensitivity remains unexplored.Therefore,this study aims to investigate the connections between TIR,derived from SMBG,and indices representingβ-cell functionality and insulin sensitivity.The primary objective of this study was to elucidate the relationship between short-term glycemic control(measured as points in range[PIR])and bothβ-cell function and insulin sensitivity.Methods:This cross-sectional study enrolled 472 hospitalized patients with type 2 diabetes mellitus(T2DM).To assessβ-cell secretion capacity,we employed the insulin secretion-sensitivity index-2(ISSI-2)and(ΔC-peptide_(0-120)/Δglucose_(0-120))×Matsuda index,while insulin sensitivity was evaluated using the Matsuda index and HOMA-IR.Since SMBG offers glucose data at specific point-in-time,we substituted TIR with PIR.According to clinical guidelines,values falling within the range of 3.9-10 mmol were considered"in range,"and the corresponding percentage was calculated as PIR.Results:We observed significant associations between higher PIR quartiles and increased ISSI-2,(ΔC-peptide_(0-120)/Δglucose_(0-120))×Matsuda index,Matsuda index(increased)and HOMA-IR(decreased)(all P<0.001).PIR exhibited positive correlations with log ISSI-2(r=0.361,P<0.001),log(ΔC-peptide_(0-120)/Δglucose_(0-120))×Matsuda index(r=0.482,P<0.001),and log Matsuda index(r=0.178,P<0.001)and negative correlations with log HOMA-IR(r=-0.288,P<0.001).Furthermore,PIR emerged as an independent risk factor for log ISSI-2,log(ΔC-peptide_(0-120)/Δglucose_(0-120))×Matsuda index,log Matsuda index,and log HOMA-IR.Conclusion:PIR can serve as a valuable tool for assessingβ-cell function and insulin sensitivity.

Insulin Sensitivity of Term Newborns Exposed in Utero to HIV and Antiretrovirals in Yaoundé

Introduction: Antiretrovirals (ARVs) and the human immunodeficiency virus (HIV) are implicated in the onset of insulin resistance. They cross the placental barrier thereby inducing early modifications of the fetal environment. The aim of our study was to assess insulin sensitivity in full-term newborns exposed in utero to HIV and ARVs in Yaoundé. Materials and Methods: We conducted an analytical cross-sectional study in 2 maternities in the city of Yaoundé from November 2021 to June 2022. We generated two groups of newborns (NBs): one group born to HIV positive mothers on ARVs and the other control group born to HIV negative mothers. Clinical data from mothers and NBs were collected. A homeostatic model assessment of insulin resistance (HOMA-IR) like index with C peptide served to assess insulin sensitivity. We used the Spearman correlation to measure the strength of association between insulin sensitivity and the different variables. A p-value Results: Of 70 neonates included, 35 were born to HIV positive mothers on ARVs and 35 to HIV negative mothers. The median age of HIV positive and negative mothers was 30 (27 - 32) and 34 (24 - 47) years, respectively (p = 0.791). The body mass index before pregnancy as well as the average newborn weights were comparable in both groups. The ARV protocol associating Tenofovir, Lamivudine, Efavirenz was used by 97.1% of HIV positive mothers. In the exposed NBs group, C peptide was significantly lower (p < 0.001) and blood glucose significantly higher (p < 0.001). The median values of HOMA-IR were 1.4 (0.8 - 1.9) and 2 (1.4 - 2.6) (p = 0.001) for exposed and unexposed NBs, respectively. Conclusion: Newborns exposed to HIV and ARVs had lower C peptide levels and were more sensitive to insulin. Close metabolic monitoring of these newborns would allow early diagnosis and management of any glucose regulation disorder.

Perspectives on diacylglycerol-induced improvement of insulin sensitivity in type 2 diabetes

Diacylglycerol(DAG)-based edible oils have attracted increasing research interest owing to their healthpromoting properties.Recent animal and human studies showed that an increased 1,2-DAG content in the liver and skeletal muscle may cause insulin resistance.However,earlier studies using animal models or humans reported that dietary DAGs with a 1,2-DAGs to 1,3-D AGs ratio of approximately 3:7 could improve insulin sensitivity in type 2 diabetic patients.This conflict raises the question of whether there is a link between the ingested DAGs and endogenous DAGs during their metabolism.To make a contribution to this field,this review provides an overview of the metabolic pathways of ingested DAGs and biological roles of DAGs(ingested and endogenous)in the change of insulin sensitivity.Accordingly,strategies for further investigations on the metabolism of DAGs are proposed.

Effect of resistance exercise on insulin sensitivity of skeletal muscle

Insulin resistance(IR)is the common pathophysiological basis of many metabolic diseases.IR is characterized by decreased glucose uptake in skeletal muscle and adipose tissue,especially in skeletal muscle.Skeletal muscle is the main target tissue of glucose uptake under insulin stimulation.Glucose uptake by skeletal muscle is complex,and it is controlled by many pathways.The PI3K/AKt/GSK-1 signaling pathway is not only the main pathway for insulin signal transduction but also an important mechanism for regulating blood glucose.From the binding of insulin to its receptors on the surface of target cells to the transportation of glucose from extracellular fluid to skeletal muscle,a series of signal transduction processes is completed,any of which potentially affects the physiological effects of insulin and leads to IR.Resistance exercise(RT)can reduce skeletal muscle IR and effectively improve blood glucose control and glycosylated hemoglobin level in patients with type 2 diabetes mellitus(T2DM).However,the exact mechanism by which RT improves skeletal muscle IR remains unclear.Therefore,this paper discusses the above problems by tracking the progress of the literature to deepen the correlation between RT and skeletal muscle insulin sensitivity and provide further evidence for the application of exercise therapy in IR.In conclusion,RT mainly improves insulin sensitivity of skeletal muscle by increasing muscle mass,microvascular blood flow,and glucose transporter-4 expression in skeletal muscle,as well as by reducing lipid accumulation and inflammation in skeletal muscle.Thus,it is potentially useful in the prevention and treatment of T2DM.

Insulin Resistance in Pregnancy Is Correlated with Decreased Insulin Receptor Gene Expression in Omental Adipose: Insulin Sensitivity and Adipose Tissue Gene Expression in Normal Pregnancy

Aims: To determine correlations of insulin sensitivity to gene expression in omental and subcutaneous adipose tissue of non-obese, non-diabetic pregnant women. Methods: Microarray gene profiling was performed on subcutaneous and omental adipose tissue from 14 patients and obtained while fasting during non-laboring Cesarean section, using Illumina HumanHT-12 V4 Expression BeadChips. Findings were validated by real-time PCR. Matusda-Insulin sensitivity index (IS) and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated from glucose and insulin levels obtained from a frequently sampled oral glucose tolerance test, and correlated with gene expression. Results: Of genes differentially expressed in omental vs. subcutaneous adipose, in omentum 12 genes were expressed toward insulin resistance, whereas only 5 genes were expressed toward insulin sensitivity. In particular, expression of the insulin receptor gene (INSR), which initiates the insulin signaling cascade, is strongly positively correlated with IS and negatively with HOMA-IR in omental tissue (r = 0.84). Conclusion: Differential gene expression in omentum relative to subcutaneous adipose showed a pro-insulin resistance profile in omentum. A clinical importance of omental adipose is observed here, as downregulation of insulin receptor in omentum is correlated with increased systemic insulin resistance.

Human skeletal muscle perilipin 2 and 3 expression varies with insulin sensitivity

Background: Impaired insulin sensitivity may partly arise from a dysregulated lipid metabolism in human skeletal muscle. This study investigates the expression levels of perilipin 2, 3, and 5, and four key lipases in human skeletal muscle from the subjects that exhibit a range from normal to very low insulin sensitivity. Methods: 25 middle aged male participants were matched for lean body mass and recruited into three groups;type 2 diabetes patients (T2D), impaired glucose tolerance (IGT), and healthy sedentary controls (CON) according to their glucose tolerance and VO2peak. A muscle biopsy was obtained from vastus lateralis, and a two-step sequential euglycaemic-hyperinsulinaemic clamp was performed. Muscle samples were analyzed by Western blot for expression of perilipin 2, 3, 5, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), endothelial lipase (EL) and lipoprotein lipase (LPL). Results: Perilipin 3 expression was higher in T2D compared to CON. Perilipin 2 expression was higher in CON than T2D. We observed no difference in expression of perili pin 5, ATGL, HSL, EL or LPL between the groups. Conclusions: In the present study the muscle perilipin 3 expression and perilipin 2 expression varied markedly with insulin sensitivity. This difference in perilipin expression may indicate that the lipid droplet function and thus storage and release of fatty acid-vary with insulin sensitivity.

ASSOCIATION OF INSULIN RESISTANCE AND C-REACTIVE PROTEIN WITH CORONARY ARTERY DISEASE IN PATIENTS WITH NORMAL GLUCOSE TOLERANCE

Objective To examine insulin resistance and high sensitivity C-reactive protein （hsCRP） association with clinical and angiographic severity of coronary artery disease （CAD） in patients with normal glucose tolerance. Methods In 638 consecutive patients with normal glucose tolerance, 221 had atypical chest pain and normal coronary artery （control group）, 279 had stable angina and CAD （SAP group ）, and 138 suffered acute myocardial infarction （ MI group）. The degree of CAD was further divided into borderline lesion （ lumen diameter narrowing 50% - 69% ）, significant 1-, 2- or 3-vessel disease （ luminal diameter narrowing 〉I 70% ）. Fasting serum glucose, insulin and hsCRP levels and lipid profiles were measured, and homeostasis model assessment for insulin resistance （ HOMA-IR ） was calculated. Multivariate analysis was performed to assess risk factors for 3-vessel disease or acute MI. Results Serum hsCRP, lipoprotein （a） levels, and insulin resistance index （IRI） were higher in AMI group than those in SAP and control groups. Serum hsCRP level and IRI were also higher in 3-vessel disease than those in other groups. Multivariate regression analysis revealed that insulin resistance, cigarette smoking, serum hsCRP, and lipoprotein （a） levels were independent risk factors for acute MI. Lipoprotein （ a ） elevation was an independent risk factor for 3-vessel disease. Conclusion Insulin resistance and high serum hsCRP level were associated with occurrence of acute MI and angiographic severity of coronary disease in patients with normal glucose tolerance.

Mitochondrial inhibitor as a new class of insulin sensitizer

Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions.These drugs,such as metformin and STZ,inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the.process of A MPK activation.However,chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans.In an early study,we reported that berberine inhibited oxygen consumption in mitochondria,and increased AMP/ATP ratio in cells.The observation suggests an indirect mechanism for AMPK activation by berberine.Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition.The study suggests that mitochondrial inhibition is an approach for AMPK activation.In this review article,literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance,which supports that mitochondria inhibitors represent a new class of AMPK activator.The inhibitors are promising candidates for insulin sensitizers.This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

Modulating Effects of Chlorogenic Acid on Lipids and Glucose Metabolism and Expression of Hepatic Peroxisome Proliferator-activated Receptor-α in Golden Hamsters Fed on High Fat Diet

Objective To examine the effects of chlorogenic acid （CGA） on lipid and glucose metabolism under a high dietary fat burden and to explore the possible role of peroxisome proliferator-activated receptor-α （PPAR-α） in these effects. Methods Twenty male golden hamsters were randomly divided into CGA treatment group （n=10, given peritoneal injection of CGA solution prepared with PBS, 80 mg CGA/kg body weight daily）, and control group （n=10, given PBS i.p. at the average volume of the treatment group）. Animals in both groups were given 15% high fat diet. Eight weeks after treatment with CGA, the level of biochemical parameters in fasting serum and tissues and the expression of hepatic mRNA and protein PPAR-α were determined. Results Eight weeks after treatment with CGA, the levels of fasting serum triglyceride （TG）, free fatty acid （FFA）, total cholesterol （TC）, low density lipoprotein cholesterol （LDL-C）, high density lipoprotein cholesterol （HDL-C）, glucose （FSG）, and insulin （FSI） were significantly lower in the GGA treatment group than in the control group. CGA also led to higher activity of hepatic lipase （HL） lower contents of TG and FFA in liver, and lower activity of lipoprotein lipase （LPL） in skeletal muscle. Furthermore, CGA significantly elevated significantly elevated the expression level of mRNA and protein expression in hepatic PPAR-α. Conclusion CGA can modify lipids and glucose metabolism, which may be attributed to PPAR-α facilitated lipid clearance in liver and improved insulin sensitivity.

Association of traditional Chinese exercises with glycemic responses in people with type 2 diabetes:A systematic review and meta-analysis of randomized controlled trials

Background： There is increasing evidence showing the health benefits of various forms of traditional Chinese exercises （TCEs） on the glycemic profile in people with type 2 diabetes. However, relatively little is known about the combined clinical effectiveness of these traditional exercises. This study was designed to perform a systematic review and meta-analysis of the overall effect of 3 common TCEs （Tai Ji Quan, Qigong, Ba Duan Jin） on glycemie control in adults with type 2 diabetes. Methods： We conducted an extensive database search in Cochrane Library, EMBASE, PubMed, Web of Science, EBSCO, and China National Knowledge Infrastructure on randomized controlled trials published between April 1967 and September 2017 that compared any of the 3 TCEs with a control or comparison group on glycemic control. Data extraction was performed by 2 independent reviewers. Study quality was evaluated using the Coehrane Handbook for Systematic Reviews of Interventions, which assessed the risk of bias, including sequence generation, allocation concealment, blinding, completeness of outcome data, and selective outcome reporting. The resulting quality of the reviewed studies was characterized in 3 grades representing the level of bias： low, unclear, and high. All analyses were performed using random effects models and heterogeneity was quantified. We a priori specified changes in biomarkers of hemoglobin A1 c （in percentage） and fasting blood glucose （mmol/L） as the main outcomes and triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein-cholesterol, 2-h plasma glucose, and fasting plasma glucose as secondary outcomes.Results： A total of 39 randomized, controlled trials （Tai Ji Quan = 11; Qigong= 6; Ba Duan Jin= 22） with 2917 type 2 diabetic patients （aged 41-80 years） were identified. Compared with a control or comparison group, pooled meta-analyses of TCEs showed a significant decrease in hemoglobin Alc （mean difference （MD）= -0.67%; 95% confidence interval （CI）：-0.86% to-0.48%; p 〈 0.00001） and fasting blood glucose （MD = -0.66 mmol/L; 95%CI： -0.95 to -0.37 mmol/L; p 〈 0.0001）. The observed effect was more pronounced for interventions that were medium range in duration （i.e., 〉3-〈 12 months）. TCE interventions also showed improvements in the secondary outcome measures. A high risk of bias was observed in the areas of blinding （i.e., study participants and personnel, and outcome assessment）. Conclusion： Among patients with type 2 diabetes, TCEs were associated with significantly lower hemoglobin Alc and fasting blood glucose. Further studies to better understand the dose and duration of exposure to TCEs are warranted.2018 Published by Elsevier B.V. on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license. （http：//creativecommons.org/licenses/by-nc-nd/4.0/）.

Non-alcoholic fatty liver disease:Epidemiology,pathophysiology and an update on the therapeutic approaches

Non-alcoholic fatty liver disease(NAFLD)denotes a spectrum of fatty liver disease in individuals without significant alcohol consumption.NAFLD is set to be the most common etiology of serious liver diseases in numerous nations when accompanied by obesity and type 2 diabetes.It is further histologically categorized into the non-alcoholic fatty liver(NAFL;steatosis without hepatocellular injury)and non-alcoholic steatohepatitis(NASH)which is characterized by the coexistence of hepatic steatosis and inflammation and is accompanied by hepatocyte injury(ballooning),either with or without fibrosis.NAFL is considered the benign and reversible stage arising from the excessive accumulation of triglycerides in hepatocytes.However,NASH is a more progressive stage of NAFLD,due to the increased risks of evolving more serious diseases such as cirrhosis,hepatocellular carcinoma.This concept,however,has been lately challenged by a hypothesis of multiple parallel hits of NAFLD,in which steatosis and NASH are separate entities rather than two points of the NAFLD spectrum,not only from a set of histological patterns but also from a pathophysiological perspective.The current review highlights the epidemiology and pathophysiology of NAFLD,and its progression towards steatohepatitis,with special focus on the novel imminent therapeutic approaches targeting the molecular aspects and the pathogenic pathways involved in the development,and progression of NAFLD.

Sterols and Terpenoids from Viburnum odoratissimum

A new stigmasterol type natural product,viburodorol A(1),along with eleven known sterols and terpenoids(2–12),were isolated from the aerial parts of Viburnum odoratissimum.The structure of 1 was elucidated on the basis of comprehensive spectroscopic analysis.It’s noteworthy that compound 2,the major constituent of this plant,can signifi-cantly stimulate glucose absorption in insulin resistant HepG2 cells without affecting cell viability.Furthermore,this compound can also restore the glucose absorption in DXMS-induced insulin resistant 3T3-L1 cells.

LDL,LDL receptors,and PCSK9 as modulators of the risk for type 2 diabetes:a focus on white adipose tissue

Type 2 diabetes(T2D) and cardiovascular disease(CVD) share many risk factors such as obesity,unhealthy lifestyle,and metabolic syndrome,whose accumulation over years leads to disease onset.However,while lowering plasma low-density lipoprotein cholesterol(LDLC) is cardio-protective,novel evidence have recognised a role for common LDLC-lowering variants(e.g.in HMGCR,PCSK9,and LDLR) and widely used hypocholesterolemic drugs that mimic the effects of some of these variants(statins) in higher risk for T2D.As these conditions decrease plasma LDLC by increasing tissue-uptake of LDL,a role for LDL receptor(LDLR)pathway was proposed.While underlying mechanisms remain to be fully elucidated,work from our lab reported that native LDL directly provoke the dysfunction of human white adipose tissue(WAT) and the activation of WAT NLRP3(Nucleotide-binding domain and Leucine-rich repeat Receptor,containing a Pyrin domain 3)inflammasome,which play a major role in the etiology of T2D.However,while elevated plasma numbers of apolipoprotein B(apoB)-containing lipoproteins(measured as apoB,mostly as LDL) is associated with WAT dysfunction and related risk factors for T2D in our cohort,this relation was strengthened in regression analysis by lower plasma proprotein convertase subtilisin/kexin type 9(PCSK9).This supports a central role for upregulated pathway of LDLR and/or other receptors regulated by PCSK9 such as cluster of differentiation 36(CD36) in LDL-induced anomalies.Targeting receptor-mediated uptake of LDL into WAT may reduce WAT inflammation,WAT dysfunction,and related risk for T2D without increasing the risk for CVD.

Effects of pioglitazone on proliferation and differentiation of human preadipocytes

Objective： To explore the effects of thiazolidinediones （TZDs） pioglitazone on proliferation and differentiation of human preadipocytes. Methods：Omental adipose tissue biopsies were obtained from 15 patients who were undergoing elective open-abdominal surgery. The primary culture and differentiated induction of human preadipocytes were performed, and the human preadipo-cytes were treated with pioglitazone at different concentrations at proper moments. Dynamic morphological changes of the human preadipocytes were observed, and their proliferation and differentiation were assessed with Colorimetric MTT Assay and Oil Red O Staining. Results：After 24 hours and 72 hours with pioglitazone, 0.1 μmol/L （μmol/ml） pioglitazone increased the MTT values of the human preadipocytes by 25.3% and 34.8%,respectively（P 〈 0.05）, while 1 μmol/L pioglitazone by 27.4% and 26.6%（P 〈 0.05）, compared with the control group without pioglitazone. The human preadipocytes with pioglitazone cumulated more adipose in the endochylema than those without pioglitazone obviously. 0.1 μmol/L pioglitazone increased the differentiation degree of the human preadipocytes differentiated for 8-10 days by 44.81% and 1 μmol/L pioglitazone by 53.76%（P 〈 0.05）. Conclusion：Thi- azolidinediones pioglitazone may significantly promote the proliferation and differentiation of the human omental preadipocytes.

Conundrum of vitamin D on glucose and fuel homeostasis

As an endocrine hormone,vitamin D plays an important role in bone health and calcium homeostasis.Over the past two decades,the non-calcemic effects of vitamin D were extensively examined.Although the effect of vitamin D on beta cell function were known for some time,the effect of vitamin D on glucose and fuel homeostasis has attracted new interest among researchers.Yet,to date,studies remain inconclusive and controversial,in part,due to a lack of understanding of the threshold effects of vitamin D.In this review,a critical examination of interventional trials of vitamin D in prevention of diabetes is provided.Like use of vitamin D for bone loss,the benefits of vitamin D supplementation in diabetes prevention were observed in vitamin D-deficient subjects with serum 25-hydroxyvitamin D<50 nmol/L(20 ng/mL).The beneficial effect from vitamin D supplementation was not apparent in subjects with serum 25-hydroxyvitamin D>75 nmol/L(30 ng/mL).Furthermore,no benefit was noted in subjects that achieved serum 25-hydroxyvitamin D>100 nmol/L(40 ng/mL).Further studies are required to confirm these observations.

Level of dietary energy and 2,4-thiazolidinedione alter molecular and systemic biomarkers of inflammation and liver function in Holstein cows

Background： The objective of the study was to evaluate the effect of overfeeding a moderate energy diet and a2,4-thiazolidinedione（TZD） injection on blood and hepatic tissue biomarkers of lipid metabolism, oxidative stress,and inflammation as it relates to insulin sensitivity.Results： Fourteen dry non-pregnant cows were fed a control（CON） diet to meet 100% of NRC requirements for3 wk, after which half of the cows were assigned to a moderate-energy diet（OVE） and half of the cows continued on CON for 6 wk. All cows received an intravenous injection of 4 mg TZD/kg of body weight（BW） daily from 2 wk after initiation of dietary treatments and for 2 additional week. Compared with CON cows and before TZD treatment, the OVE cows had lower concentration of total protein, urea and albumin over time. The concentration of cholesterol and tocopherol was greater after 2 wk of TZD regardless of diet. Before and after TZD, the OVE cows had greater concentrations of AST/GOT, while concentrations of paraoxonase, total protein, globulin, myeloperoxidase, and haptoglobin were lower compared with CON cows. Regardless of diet, TZD administration increased the concentration of ceruloplasmin, ROMt, cholesterol, tocopherol, total protein, globulin, myeloperoxidase and beta-carotene. In contrast,the concentration of haptoglobin decreased at the end of TZD injection regardless of diet. Prior to TZD injection, the mR NA expression of PC, ANGPTL4, FGF21, INSR, ACOX1, and PPARD in liver of OVE cows was lower compared with CON cows. In contrast, the expression of HMGCS2 was greater in OVE compared with CON cows. After 1 wk of TZD administration the expression of IRS1 decreased regardless of diet; whereas, expression of INSR increased after 2 wk of TZD injection. Cows fed OVE had lower overal expression of TNF, INSR, PC, ACOX1, FGF21, and PPARD but greater HMGCS2 expression. These differences were most evident before and after 1 wk of TZD injection, and by 2 wk of TZD differences in expression for most genes disappeared.Conclusions： Based on molecular and blood data, administration of TZD enhanced some aspects of insulin sensitivity while causing contradictory results in terms of inflammation and oxidative stress. The bovine liver is TZD-responsive and level of dietary energy can modify the effects of TZD. Because insulin sensitizers have been proposed as useful tools to manage dairy cows during the transition period, further studies are required to investigate the potential hepatotoxicity effect of TZD（or similar compounds） in dairy cattle.

Effect of Frey's procedure on islet cell function in patients with chronic calcific pancreatitis

Background: Frey’s procedure involves both drainage and resection of the pancreas in subjects with chronic calcific pancreatitis(CCP). The procedure may affect the pancreatic endocrine function after surgery. The present study was to evaluate the effect of Frey’s procedure on both beta and alpha cell function in CCP patients.Methods: Thirty CCP patients who underwent Frey’s procedure were included. According to the glycemic status, patients were divided into the diabetes mellitus(DM), prediabetes, and normal glucose tolerance(NGT) groups. Islet cell function was assessed before and 3 months after surgery.Results: At baseline, there was a significant difference in beta cell function among the three groups [NGT group 1.71(1.64–2.07) vs prediabetes group1.50(0.83–1.61) vs DM group 0.33(0.12–0.55), P < 0.0001], but the insulin resistance was not different among them. Post glucose hyperglucagonemia representing alphacell dysfunction during oral glucose tolerance test was present in all of them, but showed no significant difference [NGT group 0.15(0.06–0.31) vs prediabetes group 0.32(0.05–0.70) vs DM group 0.07(0.02–0.18), P = 0.20]. Frey’s procedure did not change beta cell function and insulin resistance. However, alphacell dysfunction deteriorated after surgery [0.10(0.03–0.27) vs 0.33(0.09–0.68), P = 0.004].Conclusions: Although Frey’s procedure does not affect the beta cell function and insulin resistance in CCP patients, the alpha-cell dysfunction deteriorates after surgery.