Effects of Traditional Chinese Medicinal Plants on Antiinsulin Resistance Bioactivity of DXMS-Induced Insulin Resistant HepG2 Cells

Medicinal plants have a long history of use in China to treat diabetic symptoms.Ancient Chinese medical manuscripts and ethnobotanical surveys document plant remedies that continue to be actively used in China for the treatment of diabetic symptoms.Based on a systematic ancient Chinese medical manuscripts review in combination with ethnobotanical survey,16 medicinal plants for the traditional treatment of diabetic symptoms were identified for the evaluation of anti-insulin resistance bioactivity.The biological activity of 16 medicinal plants was tested on dexamethasone(DXMS)-induced insulin resistant HepG2 cells.The result shows that 11 of the 16 medicinal plants enhanced glucose uptake of DXMS-induced insulin resistant HepG2 cells,thereby demonstrating their ability to increase insulin sensitivity,other five medicinal plants including Astragalus membranaceus were found ineffective.The study shows that ancient Chinese medical manuscripts and ethnobotanical surveys on plants for the prevention and treatment of diabetic symptoms provide a promising knowledge base for drug discovery to mitigate the global diabetes epidemic.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhance Insulin Sensitivity in Insulin Resistant Human Adipocytes

Insulin resistance is an essential characteristic of type 2 diabetes mellitus(T2DM),which can be induced by glucotoxicity and adipose chronic inflammation.Mesenchymal stem cells(MSCs)and their exosomes were reported to ameliorate T2DM and its complications by their immunoregulatory and healing abilities.Exosomes derived from MSCs contain abundant molecules to mediate crosstalk between cells and mimic biological function of MSCs.But the role of exosomes derived from human umbilical cord mesenchymal stem cells(hUC-MSCs)in insulin resistance of human adipocytes is unclear.In this study,exosomes were harvested from the conditioned medium of hUC-MSCs and added to insulin-resistant adipocytes.Insulin-stimulated glucose uptake was measured by glucose oxidase/peroxidase assay.The signal pathway involved in exosome-treated adipocytes was detected by RT-PCR and Western blotting.The biological characteristics and function were compared between hUC-MSCs and human adipose-derived mesenchymal stem cells(hAMSCs).The results showed that hAMSCs had better adipogenic ability than hUC-MSCs.After induction of mature adipocytes by adipogenesis of hAMSC,the model of insulin-resistant adipocytes was successfully established by TNF-αand high glucose intervention.After exosome treatment,the insulin-stimulated glucose uptake was significantly increased.In addition,the effect of exosomes could be stabilized for at least 48 h.Furthermore,the level of leptin was significantly decreased,and the mRNA expression of sirtuin-1 and insulin receptor substrate-1 was significantly upregulated after exosome treatment.In conclusion,exosomes significantly improve insulin sensitivity in insulin-resistant human adipocytes,and the mechanism involves the regulation of adipokines.

Postprandial dyslipidemia in insulin resistant states in adolescent populations

Obesity and the metabolic syndrome are becoming increasingly prevalent not only in adults,but also in adolescents.The metabolic syndrome,a complex cluster of metabolic abnormalities,increases one’s risk of developing type 2 diabetes and cardiovascular disease(CVD).Dyslipidemia,a key component of the metabolic syndrome,is highly associated with insulin resistance and contributes to increased CVD risk.Dyslipidemia has traditionally been assessed using a fasting lipid profile [i.e.fasting triglycerides,total cholesterol,low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C)].However,the postprandial state predominates over the course of a day and non-fasting triglycerides independently predict CVD risk.In insulin resistant states,the intestine overproduces triglyceride-rich lipoprotein(TRL) particles,termed chylomicrons(CMs),following ingestion of a fat-containing meal,as well as in the fasting state.Along with elevated hepatic TRLs(i.e.very-low density lipoproteins),CMs contribute to remnant lipoprotein accumulation,small dense LDL particles,and reduced HDL-C,which collectively increase CVD risk.Given the early genesis of atherosclerosis and physiological metabolic changes during adolescence,studying postprandial dyslipidemia in the adolescent population is an important area of study.Postprandial dyslipidemia in the pediatric population poses a significant public health concern,warranting a better understanding of its pathogenesis and association with insulin resistance and CVD.This review discusses the metabolic syndrome,focusing on the link between insulin resistance,postprandial dyslipidemia,and CVD risk.Furthermore,the clinical significance and functional assessment of postprandial dyslipidemia,specifically in the adolescent population,is discussed in more detail.

Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells

Objective:Research has shown that celastrol can effectively treat a variety of diseases,yet when passing a certain dosage threshold,celastrol becomes toxic,causing complications such as liver and kidney damage and erythrocytopenia,among others.With this dichotomy in mind,it is extremely important to find ways to preserve celastrol’s efficacy while reducing or preventing its toxicity.Methods:In this study,insulin-resistant Hep G2(IR-Hep G2)cells were prepared using palmitic acid and used for in vitro experiments.IR-Hep G2 cells were treated with celastrol alone or in combination with Nacetylcysteine(NAC)or ferrostatin-1(Fer-1)for 12,24 or 48 h,at a range of doses.Cell counting kit-8assay,Western blotting,quantitative reverse transcription-polymerase chain reaction,glucose consumption assessment,and flow cytometry were performed to measure celastrol’s cytotoxicity and whether the cell death was linked to ferroptosis.Results:Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-Hep G2 cells.Celastrol downregulated glutathione peroxidase 4(GPX4)m RNA.Molecular docking models predicted that solute carrier family 7 member 11(SLC7A11)and GPX4 were covalently bound by celastrol.Importantly,we found for the first time that the application of ferroptosis inhibitors(especially NAC)was able to reduce celastrol’s toxicity while preserving its ability to improve insulin sensitivity in IR-Hep G2 cells.Conclusion:One potential mechanism of celastrol’s cytotoxicity is the induction of ferroptosis,which can be alleviated by treatment with ferroptosis inhibitors.These findings provide a new strategy to block celastrol’s toxicity while preserving its therapeutic effects.

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.

Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

With the prevalence of obesity and obesity-related metabolic syndrome,such as insulin resistance in recent years,it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic syndrome.Palmitoleic acid is a monounsaturated fatty acid that is available from dietary sources,mainly derived from marine products.P almitoleic acid plays a positive role in maintaining glucose homeostasis and reducing inflammation.However,it is still unknow the mechanism of palmitoleic acid in ameliorating insulin resistance.Here,we investigated the effects of palmitoleic acid on chow diet(CD)-fed and high-fat diet(HFD)-fed mice,which were fed CD or HFD for 12 weeks before administration.We administrated mice with BSA(control),oleic acid,or palmitoleic acid for 6 weeks on top of CD or HFD feeding.We found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing HOMA-IR.Further study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes population.In colon,palmitoleic acid increased intestinal tight junction integrity and reduced inflammation.Moreover,palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose tissue.Diacylglycerol(DAG)in tissue(for example,liver)is found to positively correlated with HOMA-IR.HFD enhanced the levels of DAGs in liver but not in adipose tissue in this study.Palmitoleic acid did not reverse the high DAG levels induced by HFD in liver.Therefore,in HFD-fed mice,palmitoleic acid reduced insulin resistance by an independent-manner of DAGs.It might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition,improving of intestinal barrier function,and downregulating the inflammation in colon,liver,and adipose tissue.

Growth hormone improves insulin resistance in visceral adipose tissue after duodenal-jejunal bypass by regulating adiponectin secretion

BACKGROUND The mechanism of improvement of type 2 diabetes after duodenal-jejunal bypass(DJB)surgery is not clear.AIM To study the morphological and functional changes in adipose tissue after DJB and explore the potential mechanisms contributing to postoperative insulin sensitivity improvement of adipose tissue in a diabetic male rat model.METHODS DJB and sham surgery was performed in a-high-fat-diet/streptozotocin-induced diabetic rat model.All adipose tissue was weighed and observed under microscope.Use inguinal fat to represent subcutaneous adipose tissue(SAT)and mesangial fat to represent visceral adipose tissue.RNA-sequencing was utilized to evaluate gene expression alterations adipocytes.The hematoxylin and eosin staining,reverse transcription-quantitative polymerase chain reaction,western blot,and enzyme-linked immunosorbent assay were used to study the changes.Insulin resistance was evaluated by immunofluorescence.RESULTS After DJB,whole body blood glucose metabolism and insulin sensitivity in adipose tissue improved.Fat cell volume in both visceral adipose tissue(VAT)and SAT increased.Compared to SAT,VAT showed more significantly functional alterations after DJB and KEGG analysis indicated growth hormone(GH)pathway and downstream adiponectin secretion were involved in metabolic regulation.The circulating GH and adiponectin levels and GH receptor and adiponectin levels in VAT increased.Cytological experiment showed that GH stimulated adiponectin secretion and improve insulin sensitivity.CONCLUSION GH improves insulin resistance in VAT in male diabetic rats after receiving DJB,possibly by increasing adiponectin secretion.

Effects of vitamin family members on insulin resistance and diabetes complications

The following letter to the editor highlights the article“Effects of vitamin D supplementation on glucose and lipid metabolism in patients with type 2 diabetes mellitus and risk factors for insulin resistance”in World J Diabetes 2023 Oct 15;14(10):1514-1523.It is necessary to explore the role of vitamin family members in insulin resistance and diabetes complications.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance

BACKGROUND Lingguizhugan(LGZG)decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet(HFD)-induced insulin resistance(IR)in animal studies.AIM To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism.METHODS To establish an IR rat model,a 12-wk HFD was administered,followed by a 4-wk treatment with LGZG.The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests.Using a targeted metabolomics platform to analyze changes in serum metabolites,quantitative real-time PCR(qRT-PCR)was used to assess the gene expression of the ribosomal protein S6 kinase beta 1(S6K1).RESULTS In IR rats,LGZG decreased body weight and indices of hepatic steatosis.It effectively controlled blood glucose and food intake while protecting islet cells.Metabolite analysis revealed significant differences between the HFD and HFDLGZG groups.LGZG intervention reduced branched-chain amino acid levels.Levels of IR-related metabolites such as tryptophan,alanine,taurine,and asparagine decreased significantly.IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression,as shown by qRT-PCR.CONCLUSIONS Our study strongly suggests that LGZG decoction reduces HFD-induced IR.LGZG may activate S6K1 via metabolic pathways.These findings lay the groundwork for the potential of LGZG as an IR treatment.

KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer’s disease

BACKGROUND Epidemiological studies have revealed a correlation between Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2D).Insulin resistance in the brain is a common feature in patients with T2D and AD.KAT7 is a histone acetyltransferase that participates in the modulation of various genes.AIM To determine the effects of KAT7 on insulin patients with AD.METHODS APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes,respectively.An in vitro model of AD was established by Aβstimulation.Insulin resistance was induced by chronic stimulation with high insulin levels.The expression of microtubule-associated protein 2(MAP2)was assessed using immunofluorescence.The protein levels of MAP2,Aβ,dual-specificity tyrosine phosphorylation-regulated kinase-1A(DYRK1A),IRS-1,p-AKT,total AKT,p-GSK3β,total GSK3β,DYRK1A,and KAT7 were measured via western blotting.Accumulation of reactive oxygen species(ROS),malondialdehyde(MDA),and SOD activity was measured to determine cellular oxidative stress.Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation,respectively.Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR.A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A.RESULTS KAT7 expression was suppressed in the AD mice.Overexpression of KAT7 decreased Aβaccumulation and MAP2 expression in AD brains.KAT7 overexpression decreased ROS and MDA levels,elevated SOD activity in brain tissues and neurons,and simultaneously suppressed neuronal apoptosis.KAT7 upregulated levels of p-AKT and p-GSK3βto alleviate insulin resistance,along with elevated expression of DYRK1A.KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A.HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion.CONCLUSION We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation.Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

Ghrelin regulates insulin resistance by targeting insulin-like growth factor-1 receptor via miR-455-5p in hepatic cells

Objective: To explore the mechanism by which ghrelin regulates insulin sensitivity through modulation of miR-455-5p in hepatic cells. Methods: HepG2 cells were treated with or without DAG (1 μM). Glucose consumption, intracellular glycogen content, phosphorylation of PI3K and Akt stimulated by insulin, expression of miR-455-5p, as well as IGF-1R protein level were analyzed. In addition, bioinformatic analysis, dual luciferase reporter assay, miR- 455-5p mimic or inhibitor treatment was conducted to investigate the molecular mechanisms. Results: High glucose treatment upregulated miR-455-5p expression but reduced glucose consumption and glycogen content. DAG reversed the effect of high glucose on glucose metabolism, increased protein level of IGF-1R and phosphorylation of PI3K/Akt stimulated by insulin, as well as downregulated miR-455-5p expression. Bioinformatic analysis indicated IGF-1R was the target of miR-455-5p. Dual luciferase reporter assay, as well as transfection with miR-455-5p mimic/inhibitor confirmed that DAG activated IGF-1R/PI3K/Akt signaling via inhibiting miR-455-5p. Conclusion: DAG improves insulin resistance via miR-455-5p- mediated activation of IGF-1R/PI3K/Akt system, suggesting that suppression of miR-455-5p or activation of DAG may be potential targets for T2DM therapy.

Mapping the global research landscape on nonalcoholic fatty liver disease and insulin resistance:A visualization and bibliometric study

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a liver condition that is prevalent worldwide and associated with significant health risks and economic burdens.As it has been linked to insulin resistance(IR),this study aimed to perform a bibliometric analysis and visually represent the scientific literature on IR and NAFLD.AIM To map the research landscape to underscore critical areas of focus,influential studies,and future directions of NAFLD and IR.METHODS This study conducted a bibliometric analysis of the literature on IR and NAFLD indexed in the SciVerse Scopus database from 1999 to 2022.The search strategy used terms from the literature and medical subject headings,focusing on terms related to IR and NAFLD.VOSviewer software was used to visualize research trends,collaborations,and key thematic areas.The analysis examined publication type,annual research output,contributing countries and institutions,funding agencies,journal impact factors,citation patterns,and highly cited references.RESULTS This analysis identified 23124 documents on NAFLD,revealing a significant increase in the number of publications between 1999 and 2022.The search retrieved 715 papers on IR and NAFLD,including 573(80.14%)articles and 88(12.31%)reviews.The most productive countries were China(n=134;18.74%),the United States(n=122;17.06%),Italy(n=97;13.57%),and Japan(n=41;5.73%).The leading institutions included the Universitàdegli Studi di Torino,Italy(n=29;4.06%),and the Consiglio Nazionale delle Ricerche,Italy(n=19;2.66%).The top funding agencies were the National Institute of Diabetes and Digestive and Kidney Diseases in the United States(n=48;6.71%),and the National Natural Science Foundation of China(n=37;5.17%).The most active journals in this field were Hepatology(27 publications),the Journal of Hepatology(17 publications),and the Journal of Clinical Endocrinology and Metabolism(13 publications).The main research hotspots were“therapeutic approaches for IR and NAFLD”and“inflammatory and high-fat diet impacts on NAFLD”.CONCLUSION This is the first bibliometric analysis to examine the relationship between IR and NAFLD.In response to the escalating global health challenge of NAFLD,this research highlights an urgent need for a better understanding of this condition and for the development of intervention strategies.Policymakers need to prioritize and address the increasing prevalence of NAFLD.

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.

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.

Therapeutic effects of hydrogen saturated saline on rat diabetic model and insulin resistant model via reduction of oxidative stress

Background Molecular hydrogen, as a novel antioxidant, has been proven effective in treating many diseases. This study aimed to evaluate the therapeutic effects of hydrogen saturated saline in treatment of a rat model of diabetes mellitus and a rat model of insulin resistant. Methods A rat diabetes mellitus model was established by feeding a high fat/high carbohydrate diet followed by injection of a small dose of streptozotocin, and an insulin resistant model was induced with a high glucose and high fat diet. Hydrogen saturated saline was administered to rats with both models conditions on a daily basis for eight weeks. A pioglitazone-treated group and normal saline-treated group served as positive and negative controls. The general condition, body weight, blood glucose, blood lipids, and serum insulin levels of rats were examined at the 8th week after treatment. The oxidative stress indices, including serum superoxide dismutase （SOD）, glutathione （GSH） and malondialdehyde （MDA） were also evaluated after eight weeks of treatment using the commercial kits.Results Hydrogen saturated saline showed great efficiency in improving the insulin sensitivity and lowering blood glucose and lipids. Meanwhile, the therapeutic effects of hydrogen saturated saline were superior to those of pioglitazone. Hydrogen saturated saline markedly attenuated the MDA level and elevated the levels of antioxidants SOD and GSH. Conclusion Hydrogen saturated saline may improve the insulin resistance and alleviate the symptoms of diabetes mellitus by reducing the oxidative stress and enhancing the anti-oxidant system.

Effect of Huanglian Jiedu Decoction (黄连解毒汤) on Glucose Transporter 4 Expression in Adipose and Skeletal Muscle Tissues of Insulin Resistant Rats

Objective： To investigate the effects of Huanglian Jiedu Decoction （黄连解毒汤, HLJDD） on glucose transporter 4 （GLUT4） protein expressions in insulin-resistant murine target tissues. Methods： The experimental male Wistar rats were established into insulin resistant models by injecting streptozotocin （STZ 30 mg/kg） via caudal vein and feeding them with high fat high caloric diet, and randomly divided into the model group, the aspirin group and the HLJDD group. Besides, a normal group was set up for control. Changes of body weight （BW）, levels of serum fasting blood glucose （FBG）, serum fasting insulin （FINS） and oral glucose tolerance test （OGTT） were routinely determined. The expression of GLUT4 protein in adipose and skeletal muscle tissues before and after insulin stimulation was determined with Western blot. Results： In the HLJDD group after treatment, BW and FBG got decreased, OGTT improved, and the expression and translocation of GLUT4 protein elevated obviously, either before or after insulin stimulation, as compared with those in the model group, showing significant differences respectively. Conclusion： The mechanism of improving insulin resistance by HLJDD is probably associated with its effect in elevating GLUT4 protein expression and translocation in adipose and skeletal muscle tissues of insulin resistant rats.

Hemin, a heme oxygenase-1 inducer, improves aortic endothelial dysfunction in insulin resistant rats

Background Under an insulin resistance （IR） state, overproduction of reactive oxygen species （ROS） may be playing a major role in the pathogenesis of endothelial dysfunction, hypertension and atherosclerosis. Recently, increasing attention has been drawn to the beneficial effects of heme oxygenase-1 （HO-1） in the cardiovascular system. This study aimed to investigate the effects of HO-1 on vascular function of thoracic aorta in IR rats and demonstrate the probable mechanisms of HO-1 against endothelial dysfunction in IR states. Methods Sprague-Dawley （SD） rats fed with high-fat diet for 6 weeks and the IR models were validated with hyperinsulinemic-euglycemic clamp test. Then the IR rat models （n=-44） were further randomized into 3 subgroups, namely, the IR control group （n=26, in which 12 were sacrificed immediately and evaluated for all study measures）, a hemin treated IR group （n=-10） and a zinc protoporphyrin-Ⅸ （ZnPP-Ⅸ） treated IR group （n=-8） that were fed with a high-fat diet. Rats with standardized chow diet were used as the normal control group （n=-12）. The rats in IR control group, hemin treated IR group and ZnPP-Ⅸ treated IR group were subsequently treated every other day with an intraperitoneal injection of normal saline, hemin （inducer of HO-1, 30 μmol/kg） or ZnPP-Ⅸ （inhibitor of HO-1, 10 μmol/kg） for 4 weeks. Rats in the normal control group remained on a standardized chow diet and were treated with intraperitoneal injections of normal saline every other day for 4 weeks. Systolic arterial blood pressure （SABP） was measured by tail-cuffed microphotoelectric plethysmography. The blood carbon monoxide （CO） was measured by blood gas analysis. The levels of nitdc oxide （NO）, inducible nitric oxide synthase （iNOS）, endothelial nitric oxide synthase （eNOS）, blood glucose （BG）, insulin, total cholesterol （TC） and triglyceride （TG） in serum, and the levels of total antioxidant capacity （TAOC）, malondialdehyde （MDA） and superoxide dismutase （SOD） in the aorta were measured. The expression of HO-1 mRNA and HO-1 protein in aortal tissue were detected by semi-quantitative RT-PCR and Western blot. The vasoreacUve tensometry was performed with thoracic aortic rings （TARs）. Results Compared with the normal control group, the levels of SABP, BG, insulin, TC, TG, NO, iNOS and MDA were higher, while the levels of CO, TAOC, SOD and eNOS were lower in IR control rats. After treatment of IR rats for 4 weeks a more intensive expression of HO-1 mRNA and HO-1 protein were observed in hemin treated IR group compared with the normal control group. And compared with 4-week IR control rats, the levels of CO, TAOC, SOD and eNOS were increased, while the levels of SABP and iNOS activity were lower in the hemin treated IR group. Administration of hemin in IR rats appeared to improve the disordered vasorelaxation of TARs to acetylcholine （ACh）. Alternatively, the reverse results of SABP, CO, TAOC, SOD, iNOS and vasorelaxation responses to ACh were observed in IR rats with administration of ZnPP-Ⅸ. Conclusions The endothelial dysfunction in the aorta is present in the IR state. The protective effects of HO-1 against aortic endothelial dysfunction may be due to its antioxidation and regulative effect of vasoactive substances. It is proposed that hemin, inducer of HO-1, could be a potential therapeutic option for vascular dysfunction in IR states.

Insulin resistance and adipose tissue interactions as the cornerstone of metabolic(dysfunction)-associated fatty liver disease pathogenesis

The relationship between metabolic derangements and fatty liver development are undeniable,since more than 75% of patients with type 2 diabetes mellitus present with fatty liver.There is also significant epidemiological association between insulin resistance(IR)and metabolic(dysfunction)-associated fatty liver disease(MAFLD).For little more than 2 years,the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups.While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed,the bottom line relies on the role of IR as an initiator and perpetuator of this disease.There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations,where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory elementbinding protein-1c induced lipogenic enzyme stimulation;therefore,increased endogenous production of triglycerides.The same effect is achieved through impaired suppression of adipose tissue(AT)lipolysis in insulin-resistant states,increasing fatty acid influx into the liver.The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion,modifying fatty acid metabolism as well as IR in a variety of tissues,including skeletal muscle,AT,and the liver.The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Role of selenium in type 2 diabetes,insulin resistance and insulin secretion

Selenium is a trace mineral essential for life that acts physiologically through selenoproteins.Among other actions,the endogenous antioxidant selenoprotein glutathione peroxidase and the selenium transporter in blood,selenoprotein P,seem to play an important role in type 2 diabetes mellitus and insulin resistance by weakening the insulin signaling cascade through different mechanisms.Recent findings also suggest that selenoproteins also affect insulin biosynthesis and insulin secretion.This review discussed the role of selenium in type 2 diabetes and the complex interplay between selenoproteins and insulin pathways.

Association between cardiorespiratory fitness level and insulin resistance in adolescents with various obesity categories

BACKGROUND An association between cardiorespiratory fitness(CRF)and insulin resistance in obese adolescents,especially in those with various obesity categories,has not been systematically studied.There is a lack of knowledge about the effects of CRF on insulin resistance in severely obese adolescents,despite their continuous rise.AIM To investigate the association between CRF and insulin resistance in obese adolescents,with special emphasis on severely obese adolescents.METHODS We performed a prospective,cross-sectional study that included 200 pubertal adolescents,10 years to 18 years of age,who were referred to a tertiary care center due to obesity.According to body mass index(BMI),adolescents were classified as mildly obese(BMI 100% to 120% of the 95^(th)percentile for age and sex)or severely obese(BMI≥120% of the 95^(th)percentile for age and sex or≥35 kg/m^(2),whichever was lower).Participant body composition was assessed by bioelectrical impedance analysis.A homeostatic model assessment of insulin resistance(HOMA-IR)was calculated.Maximal oxygen uptake(VO_(2)max)was determined from submaximal treadmill exercise test.CRF was expressed as VO_(2)max scaled by total body weight(TBW)(mL/min/kg TBW)or by fat free mass(FFM)(mL/min/kg FFM),and then categorized as poor,intermediate,or good,according to VO_(2)max terciles.Data were analyzed by statistical software package SPSS(IBM SPSS Statistics for Windows,Version 24.0).P<0.05 was considered statistically significant.RESULTS A weak negative correlation between CRF and HOMA-IR was found[Spearman’s rank correlation coefficient(rs)=-0.28,P<0.01 for CRF_(TBW);(r_(s))=-0.21,P<0.01 for CRF_(FFM)].One-way analysis of variance(ANOVA)revealed a significant main effect of CRF on HOMA-IR[F(2200)=6.840,P=0.001 for CRF_(TBW);F_((2200))=3.883,P=0.022 for CRF_(FFM)].Subsequent analyses showed that obese adolescents with poor CRF had higher HOMA-IR than obese adolescents with good CRF(P=0.001 for CRF_(TBW);P=0.018 for CRF_(FFM)).Two-way ANOVA with Bonferroni correction confirmed significant effect of interaction of CRF level and obesity category on HOMA-IR[F_((2200))=3.292,P=0.039 for CRF_(TBW)].Severely obese adolescents had higher HOMA-IR than those who were mildly obese,with either good or poor CRF.However,HOMA-IR did not differ between severely obese adolescents with good and mildly obese adolescents with poor CRF.CONCLUSION CRF is an important determinant of insulin resistance in obese adolescents,regardless of obesity category.Therefore,CRF assessment should be a part of diagnostic procedure,and its improvement should be a therapeutic goal.