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.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Effects of axylitol-casein complex on insulin resistance and gut microbiota composition in high-fat-diet+streptozotocin-induced type 2 diabetes mellitus mice

This study investigated the effects of a xylitol-casein non-covalent complex(XC)on parameters related to type 2 diabetes mellitus(T2DM),in addition to related changes in gut microbiome composition and functions.High-fat-diet(HFD)+streptozotocin(STZ)-induced T2DM mice were treated with xylitol(XY),casein(CN),and XC,after which fecal samples were collected for gut microbiota composition and diversity analyses based on 16S rRNA high-throughput sequencing and multivariate statistics.XC decreased body weight and improved glucose tolerance,insulin sensitivity,pancreas impairment,blood lipid levels,and liver function in T2DM mice compared to XY-and CN-treated mice.Furthermore,XC modulated theα-diversity,β-diversity and gut microbiota composition.Based on Spearman’s correlation analysis,the relative abundances of Alistipes,Bacteroides,and Faecalibaculum were positively correlated and those of Akkermansia,Lactobacillus,Bifidobacterium,and Turicibacter were negatively correlated with the phenotypes related to the improvement of T2DM.In conclusion,we found that XC alleviated insulin resistance by restoring the gut microbiota of T2DM mice.Our results provide strong evidence for the beneficial effects of XC on T2DM and motivation for further investigation in animal models and,eventually,human trials.

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.

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.

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.

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.

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.

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.

Selenoprotein-p and insulin resistance in children and adolescents with obesity

BACKGROUND Insulin resistance and obesity present significant challenges in pediatric populations.Selenoprotein P1(SEPP1)serves as a biomarker for assessing selenium levels in the body.While its association with metabolic syndrome is established in adults,its relevance in children remains underexplored.AIM To ascertain SEPP1 blood levels in children and adolescents diagnosed with obesity and to assess its correlation with insulin resistance and adiposity indices.METHODS 170 children participated in this study,including 85 diagnosed with obesity and an equal number of healthy counterparts matched for age and sex.Each participant underwent a comprehensive medical evaluation,encompassing a detailed medical history,clinical examination,and anthropometric measurements like waist circumference and waist-to-height ratio.Furthermore,routine blood tests were conducted,including serum SEPP1,visceral adiposity index(VAI),and Homeostatic Model Assessment of Insulin Resistance(HOMA-IR)level.RESULTS Our findings revealed significantly lower serum SEPP1 levels in children with obesity compared to their healthy peers.Moreover,notable negative correlations were observed between serum SEPP1 levels and body mass index,VAI,and HOMA-IR.CONCLUSION The study suggests that SEPP1 could serve as a valuable predictor for insulin resistance among children and adolescents diagnosed with obesity.This highlights the potential utility of SEPP1 in pediatric metabolic health assessment and warrants further investigation.

Analysis of the Correlation Between Visceral Fat Area and Insulin Resistance in Patients with Type 2 Diabetes and Abdominal Obesity

Objective: To analyze the correlation between visceral fat area and insulin resistance index (HOMA-IR) in patients with type 2 diabetes mellitus (T2DM) and abdominal obesity and to provide a reference for screening and related research of such patients. Methods: Two hundred patients with T2DM admitted to Guandu People’s Hospital of Kunming were included. The study was carried out from October 2022 to December 2023. The patients were divided into three groups according to different abdominal visceral fat areas (VFA): Group A (n = 65) was less than 75cm2, Group B (n = 75) was 75-100 cm2, and Group C (n = 60) was greater than 100 cm2. The subjects in the three groups were all tested for glycated hemoglobin (HbA1c), fasting insulin (FINS), and fasting blood glucose (FPG). Height and weight were measured to calculate body mass index (BMI). The HOMA-IR and TYG (fasting triglyceride and glycemic index) were also calculated. Changes in the BMI, VFA, HOMA-IR, and TYG levels were observed in the three groups. Results: The VFA, BMI, HbA1c, FPG, FINS, HOMA-IR, and TYG of the patients all increased, with a more significant increase in the BMI, FINS, HOMA-IR, and TYG levels (P < 0.01). Multiple linear stepwise regression analyses used visceral fat area (VFA) as the dependent variable. The results showed that VFA was closely related to BMI, FINS, HOMA-IR, and TYG. Conclusion: Early reduction of VFA to reduce insulin resistance may be a better treatment and effective method for T2DM, providing powerful measures and new strategies for effective blood sugar control and early prevention in the treatment of metabolic diseases.

Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects

Periodontitis is a critical risk factor for the occurrence and development of diabetes.Porphyromonas gingivalis may participate in insulin resistance(IR)caused by periodontal inflammation,but the functional role and specific mechanisms of P.gingivalis in IR remain unclear.In the present study,clinical samples were analysed to determine the statistical correlation between P.gingivalis and IR occurrence.Through culturing of hepatocytes,myocytes,and adipocytes,and feeding mice P.gingivalis orally,the functional correlation between P.gingivalis and IR occurrence was further studied both in vitro and in vivo.Clinical data suggested that the amount of P.gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score.In vitro studies suggested that coculture with P.gingivalis decreased glucose uptake and insulin receptor(INSR)protein expression in hepatocytes,myocytes,and adipocytes.Mice fed P.gingivalis tended to undergo IR.P.gingivalis was detectable in the liver,skeletal muscle,and adipose tissue of experimental mice.The distribution sites of gingipain coincided with the downregulation of INSR.Gingipain proteolysed the functional insulin-binding region of INSR.Coculture with P.gingivalis significantly decreased the INSR–insulin binding ability.Knocking out gingipain from P.gingivalis alleviated the negative effects of P.gingivalis on IR in vivo.Taken together,these findings indicate that distantly migrated P.gingivalis may directly proteolytically degrade INSR through gingipain,thereby leading to IR.The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

Wedelolactone from Eclipta prostrata(L)L.suppresses inflammation and improves insulin resistance

Objective:To evaluate the effects of wedelolactone,a major flavonoid from Vietnamese Eclipta prostrata(L)L.,on inflammation and insulin resistance.Methods:Wedelolactone was extracted from the leaves of Vietnamese Eclipta prostrata(L.)L.with methanol by Soxhlet.The effects of wedelolactone on lipopolysaccharide(LPS)-induced cytokine production,reactive oxygen species(ROS)generation,and nicotinamide adenine dinucleotide phosphate(NADPH)oxidase activities in Raw 264.7 cells were measured by enzyme-linked immunosorbent assay(ELISA),specific immunofluorescent dyes and luminometric analysis,respectively.In addition,its effects on glucose uptake and the protein expression of insulin receptor substrate 1(IRS1)and glucose transporter 4(GLUT4)were examined in 3T3-L1 cells by immunofluorescent dyes and Western blot.Results:Wedelolactone at 30μg/mL significantly inhibited LPS-induced production of tumor necrosis factor-α,interleukin(IL)-6,and IL-8(P<0.01)with no noticeable effects on IL-10 level.It also reduced ROS generation and NADPH oxidase activities in LPS-stimulated Raw 264.7 cells(P<0.01).Furthermore,wedelolactone showed anti-insulin resistance activity,as evidenced by improved glucose uptake and the upregulated expression of IRS1 and GLUT4 in 3T3-L1 cells(P<0.01).Conclusions:Wedelolactone exhibits anti-inflammation and anti-insulin resistance effects,which may be used for the treatment of diabetes and inflammation-associated diseases.

Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.AIM To further investigate the mechanism of IGF2 specific to GISTs.METHODS IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)data.After IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry assays.We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated proteins.We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug resistance.GIST cells with high expression of IGF2 had increased proliferation and migration,invasiveness and EMT.Knockdown of IGF2 significantly inhibited those activities.In addition,OEIGF2 promoted GIST metastasis in vivo in nude mice.IGF2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.Moreover,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in GISTs.CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

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.

Ocular manifestations of central insulin resistance

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance my lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

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.

Huangqin decoction alleviates lipid metabolism disorders and insulin resistance in nonalcoholic fatty liver disease by triggering Sirt1/NF-κB pathway

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a clinicopathological entity characterized by intrahepatic ectopic steatosis.As a consequence of increased consumption of high-calorie diet and adoption of a sedentary lifestyle,the incidence of NAFLD has surpassed that of viral hepatitis,making it the most common cause of chronic liver disease globally.Huangqin decoction(HQD),a Chinese medicinal formulation that has been used clinically for thousands of years,has beneficial outcomes in patients with liver diseases,including NAFLD.However,the role and mechanism of action of HQD in lipid metabolism disorders and insulin resistance in NAFLD remain poorly understood.AIM To evaluate the ameliorative effects of HQD in NAFLD,with a focus on lipid metabolism and insulin resistance,and to elucidate the underlying mechanism of action.METHODS High-fat diet-induced NAFLD rats and palmitic acid(PA)-stimulated HepG2 cells were used to investigate the effects of HQD and identify its potential mechanism of action.Phytochemicals in HQD were analyzed by highperformance liquid chromatography(HPLC)to identify the key components.RESULTS Ten primary chemical components of HQD were identified by HPLC analysis.In vivo,HQD effectively prevented rats from gaining body and liver weight,improved the liver index,ameliorated hepatic histological aberrations,decreased transaminase and lipid profile disorders,and reduced the levels of pro-inflammatory factors and insulin resistance.In vitro studies revealed that HQD effectively alleviated PA-induced lipid accumulation,inflammation,and insulin resistance in HepG2 cells.In-depth investigation revealed that HQD triggers Sirt1/NF-κB pathwaymodulated lipogenesis and inflammation,contributing to its beneficial actions,which was further corroborated by the addition of the Sirt1 antagonist EX-527 that compromised the favorable effects of HQD.CONCLUSION In summary,our study confirmed that HQD mitigates lipid metabolism disorders and insulin resistance in NAFLD by triggering the Sirt1/NF-κB pathway.