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.

Vitamin D, Parathyroid Hormone, Insulin Sensitivity and Islet β-Cell Secretory Function in Diabetic Patients from South Kivu in the Democratic Republic of Congo: Cross-Sectional Study

Background: The role of vitamin D and parathyroid hormone in the metabolic profile of type 2 diabetes mellitus in sub-Saharan Africa has not been adequately assessed. The aim of this study was to determine the prevalence of low vitamin D level and secondary hyperparathyroidism and their association with insulin sensitivity and β-cell secretory function among Congolese type 2 diabetics. Methodology: Fasting glycaemia, fasting insulin, 25OH D3 and human parathyroid hormone (hPTH) were measured in one hundred and eighty-four type 2 diabetic patients followed as outpatients in South Kivu. Levels of 25OH D3 65 pg/ml defined low vitamin D and elevated parathyroid hormone levels, respectively. The HOMA model was used to measure insulin sensitivity and β-cell secretory function. Results: Medians (IQR) were 25.3 (20.4 - 32.4) ng/ml for 25OH D3 and 53.7 (38.4 - 115.7) pg/ml for hPTH. 58.7% of diabetics had insulin resistance, 126 (68.5%) had low vitamin D and 80 (43.5%) had hyperparathyroidism. In multivariate analysis, hPTH (partial r = −0.28;p = 0.0002) and 25OH D3 (partial r = 0.16;p = 0.03) showed an independent association with insulin sensitivity after adjustment for body mass index and waist circumference. Finally, hPTH (partial r = 0.27;p = 0.0002) was the sole determinant of β-cell secretory function. Conclusions: This study confirms the high prevalence of low vitamin D level and secondary hyperparathyroidism and their association with insulin resistance and impaired islet β-cell secretory function among Congolese with type 2 diabetes mellitus. Vitamin D and calcium supplementation should be envisaged for cases of deficiency in this region.

近红外无创血糖浓度的Label Sensitivity算法和支持向量机回归

近红外光谱分析技术在生物医学工程领域具有广阔应用前景。无创且持续性地测量能实时监控人体血糖水平,给糖尿病患者带来极大便利性、提高生存质量、降低糖尿病并发症发生率具有很大的社会效益。无创血糖监测的想法提出较早,但仍然存在预测精度低、预测值与标签值相关性不高等难点,至今没有达到临床要求。近年来,光谱检测技术发展迅猛且机器学习技术在智能信息处理方面具有明显优势,两者结合可以有效提高人体无创血糖医学监测模型的精度和普适性。提出了一种标签敏感度算法(LS),并结合支持向量机方法建立了人体血糖含量预测模型。使用近红外光谱仪采集了4名志愿者食指处动态血液光谱数据(每名志愿者28组数据),并使用多元散射矫正(MSC)方法消除了部分光散射的影响。考虑血糖对不同波长光的吸收有差异,提出了基于血糖浓度标签差的特征波长挑选方法,并构建了标签敏感度支持向量机(LSSVR)预测模型。设计实验,对比该模型与偏最小二乘回归(PLSR)和区分度支持向量机(FSSVR)算法。结果表明,LS算法的最佳特征波长数为32,经特征波长选择后的LSSVR表现最佳,其均方误差降低至0.02 mmol·L^(-1),明显优于全谱段PLSR模型,血糖浓度的预测值与标签值的相关系数提升至99.8%,预测值全部位于可容许误差的克拉克网格A区内。LSSVR模型的优异表现为早日实现血糖的无创监测提供了新思路。

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.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Identification, pathogenicity, and fungicide sensitivity of Eutiarosporella dactylidis associated with leaf blight on maize in China

Maize(Zea mays L.) is an economically vital grain crop that is cultivated worldwide. In 2011, a maize foliar disease was detected in Lingtai and Lintao counties in Gansu Province, China. The characteristic signs and symptoms of this disease include irregular chlorotic lesions on the tips and edges of infected leaves and black punctate fruiting bodies in dead leaf tissues. Given favourable environmental conditions, this disease spread to areas surrounding Gansu. In this study, infected leaves were collected from Gansu and Ningxia Hui Autonomous Region between 2018and 2020 to identify the disease-causing pathogen. Based on morphological features, pathogenicity tests, and multilocus phylogenetic analysis involving internal transcribed spacer(ITS), 18S small subunit rDNA(SSU), 28S large subunit rDNA(LSU), translation elongation factor 1-alpha(TEF), and β-tubulin(TUB) sequences, Eutiarosporella dactylidis was identified as the causative pathogen of this newly discovered leaf blight. Furthermore, an in vitro bioassay was conducted on representative strains using six fungicides, and both fludioxonil and carbendazim were found to significantly inhibit the mycelial growth of E. dactylidis. The results of this study provide a reference for the detection and management of Eutiarosporella leaf blight.

Future changes in precipitation and water availability over the Tibetan Plateau projected by CMIP6 models constrained by climate sensitivity

Precipitation projections over the Tibetan Plateau(TP)show diversity among existing studies,partly due to model uncertainty.How to develop a reliable projection remains inconclusive.Here,based on the IPCC AR6–assessed likely range of equilibrium climate sensitivity(ECS)and the climatological precipitation performance,the authors constrain the CMIP6(phase 6 of the Coupled Model Intercomparison Project)model projection of summer precipitation and water availability over the TP.The best estimates of precipitation changes are 0.24,0.25,and 0.45 mm d^(−1)(5.9%,6.1%,and 11.2%)under the Shared Socioeconomic Pathway(SSP)scenarios of SSP1–2.6,SSP2–4.5,and SSP5–8.5 from 2050–2099 relative to 1965–2014,respectively.The corresponding constrained projections of water availability measured by precipitation minus evaporation(P–E)are 0.10,0.09,and 0.22 mm d^(−1)(5.7%,4.9%,and 13.2%),respectively.The increase of precipitation and P–E projected by the high-ECS models,whose ECS values are higher than the upper limit of the likely range,are about 1.7 times larger than those estimated by constrained projections.Spatially,there is a larger increase in precipitation and P–E over the eastern TP,while the western part shows a relatively weak difference in precipitation and a drier trend in P–E.The wetter TP projected by the high-ECS models resulted from both an approximately 1.2–1.4 times stronger hydrological sensitivity and additional warming of 0.6℃–1.2℃ under all three scenarios during 2050–2099.This study emphasizes that selecting climate models with climate sensitivity within the likely range is crucial to reducing the uncertainty in the projection of TP precipitation and water availability changes.

MEAN SENSITIVITY AND BANACH MEAN SENSITIVITY FOR LINEAR OPERATORS

Let(X,T)be a linear dynamical system,where X is a Banach space and T:X→X is a bounded linear operator.This paper obtains that(X,T)is sensitive(Li-Yorke sensitive,mean sensitive,syndetically mean sensitive,respectively)if and only if(X,T)is Banach mean sensitive(Banach mean Li-Yorke sensitive,thickly multi-mean sensitive,thickly syndetically mean sensitive,respectively).Several examples are provided to distinguish between different notions of mean sensitivity,syndetic mean sensitivi`ty and mean Li-Yorke sensitivity.

Exogenous insulin autoimmune syndrome:A case report and review of literature

BACKGROUND Insulin autoimmune syndrome(IAS)is a severe manifestation of spontaneous hypoglycemia.It is characterized by elevated levels of immune-reactive insulin and highly potent insulin autoantibodies(IAAs),which are induced by endogenous insulin circulating in the bloodstream.It is distinguished by recurring instances of spontaneous hypoglycemia,the presence of IAA within the body,a substantial elevation in serum insulin levels,and an absence of prior exogenous insulin administration.Nevertheless,recent studies show that both conventional insulin and its analogs can induce IAS episodes,giving rise to the notion of nonclassical IAS.Therefore,more attention should be paid to these diseases.CASE SUMMARY In this case report,we present a rare case of non-classical IAS in an 83-year-old male patient who present with symptoms of a psychiatric disorder.Upon symptom onset,the patient exhibited Whipple's triad(including hypoglycemia,blood glucose level less than 2.8 mmol/L during onset,and rapid relief of hypoglycemic symptoms after glucose administration).Concurrently,his serum insulin level was significantly elevated,which contradicted his C-peptide levels.After a comprehensive examination,the patient was diagnosed with exogenous insulin autoimmune syndrome.Considering that the patient had type 2 diabetes mellitus and a history of exogenous insulin use before disease onset,it was presumed that non classical IAS was induced by this condition.The PubMed database was used to search for previous cases of IAS and non-classical IAS to analyze their characteristics and treatment approaches.CONCLUSION The occurrence of non-classical IAS is associated with exogenous insulin or its analogs,as well as with sulfhydryl drugs.Symptoms can be effectively alleviated through the discontinuation of relevant medications,administration of hormones or immunosuppressants,plasma exchange,and lifestyle adjustments.

Characterizing permeability-porosity relationships of porous rocks using a stress sensitivity model in consideration of elastic-structural deformation and tortuosity sensitivity

Clarifying the relationship between stress sensitivities of permeability and porosity is of great significance in guiding underground resource mining.More and more studies focus on how to construct stress sensitivity models to describe the relationship and obtain a comprehensive stress sensitivity of porous rock.However,the limitations of elastic deformation calculation and incompleteness of considered tortuosity sensitivity lead to the fact that the existing stress sensitivity models are still unsatisfactory in terms of accuracy and generalization.Therefore,a more accurate and generic stress sensitivity model considering elastic-structural deformation of capillary cross-section and tortuosity sensitivity is proposed in this paper.The elastic deformation is derived from the fractal scaling model and Hooke's law.Considering the effects of elastic-structural deformation on tortuosity sensitivity,an empirical formula is proposed,and the conditions for its applicability are clarified.The predictive performance of the proposed model for the permeability-porosity relationships is validated in several sets of publicly available experimental data.These experimental data are from different rocks under different pressure cycles.The mean and standard deviation of relative errors of predicted stress sensitivity with respect to experimental data are 2.63%and 1.91%.Compared with other models,the proposed model has higher accuracy and better predictive generalization performance.It is also found that the porosity sensitivity exponent a,which can describe permeability-porosity relationships,is 2 when only elastic deformation is considered.a decreases from 2 when structural deformation is also considered.In addition,a may be greater than 3 due to the increase in tortuosity sensitivity when tortuosity sensitivity is considered even if the rock is not fractured.

Association between glucose-lowering drugs and circulating insulin antibodies induced by insulin therapy in patients with type 2 diabetes

BACKGROUND Insulin antibodies(IAs)affect blood glucose control in patients receiving insulin therapy.AIM To investigate the relationship between different hypoglycemic treatments and IAs in patients with type 2 diabetes mellitus(T2DM).METHODS This cross-sectional,retrospective study included 1863 patients with T2DM who were receiving exogenous insulin therapy.All patients received stable antidiabetic therapy in the last 3 months and IA levels were measured using an iodine-125 array.RESULTS A total of 1863 patients were enrolled.There were 902(48.4%)patients who had positive IAs(IA level>5%),with a mean IA level of 11.06%(10.39%-11.72%).IA levels were positively correlated with high fasting blood glucose(odds ratio=1.069,P<0.001).The proportion of positive IAs was lowest in patients using glargine only(31.9%)and highest in patients using human insulin only(70.3%),P<0.001.The IA levels in patients using sulfonylureas/glinides(8.3%),metformin(9.6%),and dipeptidyl peptidase-4 inhibitors(8.2%)were all lower than in patients without these drugs(all P<0.05).CONCLUSION Nearly half of patients on insulin therapy have positive IA antibodies,and IA antibody levels are associated with blood glucose control.Insulin glargine and a combination of oral glucose-lowering drugs were correlated with lower IA levels.

Dynamics in the Prevalence of Insulin Resistance between 2005 and 2023 in Type 2 Diabetics in South Kivu in the East of the Democratic Republic of Congo: Cross-Sectional Studies

Aim: Sub-Saharan Africa is undergoing an epidemiological transition responsible for a change in the metabolic profile in favour of insulin resistance. The aim of this study was to assess the dynamics of the prevalence of insulin resistance and associated risk factors in diabetic patients in the Democratic Republic of Congo between 2005 and 2023. Method: We measured fasting blood glucose and insulin levels and looked for metabolic syndrome parameters (2009 criteria) in type 2 diabetes patients in 2005-2008 (n = 176) and in 2018-2023 (n = 303). The HOMA model was used to measure insulin sensitivity and islet β-cell secretory function. Results: Between 2005 and 2013, the trend was towards an increase in the prevalence of insulin resistance (from 13.1% to 50.8%;p Conclusion: This present study shows an increase in insulin resistance in Congolese urban areas and a persistence of atypical diabetes mellitus in Congolese rural areas, confirming the particularity of the pathophysiology of the disease in African areas currently influenced by the epidemiological transition. Further studies using an appropriate methodology are required.

Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR

Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.

Epinephrine also acts on beta cells and insulin secretion

In a recent review examining neurotransmitter modulation of insulin secretion,the significant impact of epinephrine was not addressed.Its primary action involves inhibiting insulin release via alpha-adrenergic receptors,thereby reducing the response to insulin secretion stimulators,through the activation of K+channels and resulting in membrane hyperpolarization in beta cells.

High-Precision Flow Numerical Simulation and Productivity Evaluation of Shale Oil Considering Stress Sensitivity

Continental shale oil reservoirs,characterized by numerous bedding planes and micro-nano scale pores,feature significantly higher stress sensitivity compared to other types of reservoirs.However,research on suitable stress sensitivity characterization models is still limited.In this study,three commonly used stress sensitivity models for shale oil reservoirs were considered,and experiments on representative core samples were conducted.By fitting and comparing the data,the“exponential model”was identified as a characterization model that accurately represents stress sensitivity in continental shale oil reservoirs.To validate the accuracy of the model,a two-phase seepage mathematical model for shale oil reservoirs coupled with the exponential model was introduced.The model was discretely solved using the finite volume method,and its accuracy was verified through the commercial simulator CMG.The study evaluated the productivity of a typical horizontal well under different engineering,geological,and fracture conditions.The results indicate that considering stress sensitivity leads to a 13.57%reduction in production for the same matrix permeability.Additionally,as the fracture half-length and the number of fractures increase,and the bottomhole flowing pressure decreases,the reservoir stress sensitivity becomes higher.

Sensitivity and resistance risk analysis of Didymella bryoniae populations to fluopyram

Fluopyram is an succinate dehydrogenase inhibitors(SDHI)fungicide that has been registered in China to control gummy stem blight(GSB)in watermelons for many years.However,whether the field pathogens of GSB are still sensitive to fluopyram or not is unknown.Therefore,we collected 69 Didymella bryoniae isolates from the fields that usually use fluopyram to control GSB to determine the sensitivity change.The EC_(50)(50%inhibition effect)values of fluopyram against D.bryoniae ranged from 0.0691 to 0.3503μg mL^(–1) and the variation factor was 5.07.The mean EC_(50) value was(0.1579±0.0669)μg mL^(–1) and the curve of sensitivity was unimodal.No resistant strains were found in the isolates,which means that the pathogens were still sensitive to fluopyram.The minimal inhibition concentration(MIC)of fluopyram against D.bryoniae was 3μg mL^(–1).Four low-resistant mutants and two medium-resistant mutants were obtained using fungicide taming and the resistance of mutants could be inherited stably.The growth rate of mutants decreased significantly compared with that of wild-type strains while the biomass of most mutants was similar to that of wild-type strains.The sensitivity of most resistant mutants to various stresses was increased compared with that of wild-type strains.The virulence of mutants receded except for low-resistant mutant XN51FR-1,which had the same lesion area as XN51 on the watermelon leaves.The results indicated that the fitness of resistant mutants was decreased compared with that of wild-type strains.The cross-resistance assay indicated that fluopyram-resistant mutants were positive cross-resistant to all six SDHI fungicides in this test but were still sensitive to fluazinam and tebuconazole.So the resistance risk of D.bryoniae to fluopyram was moderate.In addition,we found that the SdhB gene of low-resistant mutant XN30FR-1 had three new point mutations at positions K258N,A259P,and H277N.Medium-resistant mutant XN52FR-1 showed a mutation at position H277N and other mutants did not have any point mutation.