Type 2 diabetes mellitus (T2D) is nowadays a worldwide epidemic and has become a major challenge for health systems around the world. It is a multifactorial disorder, characterized by a chronic state of hyperglycemia caused by defects in the production as well as in the peripheral action of insulin. This minireview highlights the experimental and clinical evidence that supports the novel idea that intercellular junctions (IJs)-mediated cell–cell contacts play a role in the pathogenesis of T2D. It focuses on IJs repercussion for endocrine pancreas, intestinal barrier, and kidney dysfunctions that contribute to the onset and evolution of this metabolic disorder.
DelmarMLairdDWNausCCNielsenMSVerselisVKWhiteTW. Connexins and disease.Cold Spring Harb Perspect Biol2018;10:a029348
2.
FarquharMGPaladeGE. Junctional complexes in various epithelia.J Cell Biol1963;17:375–412
3.
GarciaMANelsonWJChavezN. Cell-cell junctions organize structural and signaling networks.Cold Spring Harb Perspect Biol2018;10:a029181
4.
Van ItallieCMAndersonJM. Architecture of tight junctions and principles of molecular composition.Semin Cell Dev Biol2014;36:157–65
5.
YulisMKustersDHMNusratA. Cadherins: cellular adhesive molecules serving as signalling mediators.J Physiol2018;596:3883–98
6.
ChelakkotCGhimJRyuSH. Mechanisms regulating intestinal barrier integrity and its pathological implications.Exp Mol Med2018;50:1–9
7.
ZihniCMillsCMatterKBaldaMS. Tight junctions: from simple barriers to multifunctional molecular gates.Nat Rev Mol Cell Biol2016;17:564–80
8.
BaldaMSMatterK. Tight junctions and the regulation of gene expression.Biochim Biophys Acta2009;1788:761–7
9.
Conacci-SorrellMZhurinskyJBen-Ze’evA. The cadherin-catenin adhesion system in signaling and cancer.J Clin Invest2002;109:987–91
10.
KourtidisALuRPenceLJAnastasiadisPZ. A central role for cadherin signaling in cancer.Exp Cell Res2017;358:78–85
11.
JepsonMASchlechtHBCollares-BuzatoCB. Localization of dysfunctional tight junctions in Salmonella enterica serovar typhimurium-infected epithelial layers.Infect Immun2000;68:7202–8
12.
PeixotoEBCollares-BuzatoCB. Protamine-induced epithelial barrier disruption involves rearrangement of cytoskeleton and decreased tight junction-associated protein expression in cultured MDCK strains.Cell Struct Funct2005;29:165–78
13.
PeixotoEBCollares-BuzatoCB. Modulation of the epithelial barrier by dexamethasone and prolactin in cultured Madin-Darby canine kidney (MDCK) cells.Cell Biol Int2006;30:101–13
14.
TotlandMZRasmussenNLKnudsenLMLeitheE. Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications.Cell Mol Life Sci2020;77:573–91
15.
ReicheJHuberO. Post-translational modifications of tight junction transmembrane proteins and their direct effect on barrier function.Biochim Biophys Acta Biomembr2020;1862:183330
16.
ShigetomiKIkenouchiJ. Regulation of the epithelial barrier by post-translational modifications of tight junction membrane proteins.J Biochem2018;163:265–72
17.
WHO. Global report on diabetes. Geneva: WHO, 2016, p.83.
18.
EizirikDLPasqualiLCnopM. Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: different pathways to failure.Nat Rev Endocrinol2020;16:349–62
19.
Collares-BuzatoCB. High-fat diets and β-cell dysfunction: molecular aspects. In: MauricioD (ed.) Molecular nutrition and diabetes. 1st ed. San Diego, CA: Elsevier, 2016, pp.115–130
20.
LingCRonnT. Epigenetics in human obesity and type 2 diabetes.Cell Metab2019;29:1028–44
21.
d OliveiraRBCarvalhoCPPoloCCDorighelloGdGBoscheroACd OliveiraHCCollares-BuzatoCB. Impaired compensatory beta-cell function and growth in response to high-fat diet in LDL receptor knockout mice.Int J Exp Pathol2014;95:296–308
22.
MaschioDAOliveiraRBSantosMRCarvalhoCPBarbosa-SampaioHCCollares-BuzatoCB. Activation of the Wnt/beta-catenin pathway in pancreatic beta cells during the compensatory islet hyperplasia in prediabetic mice.Biochem Biophys Res Commun2016;478:1534–40
23.
StancakovaALaaksoM. Genetics of type 2 diabetes.Endocr Dev2016;31:203–20
24.
AliO. Genetics of type 2 diabetes.World J Diabetes2013;4:114–23
25.
CaniPDAmarJIglesiasMAPoggiMKnaufCBastelicaDNeyrinckAMFavaFTuohyKMChaboCWagetADelmeeECousinBSulpiceTChamontinBFerrieresJTantiJFGibsonGRCasteillaLDelzenneNMAlessiMCBurcelinR. Metabolic endotoxemia initiates obesity and insulin resistance.Diabetes2007;56:1761–72
26.
CaniPDBibiloniRKnaufCWagetANeyrinckAMDelzenneNMBurcelinR. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.Diabetes2008;57:1470–81
27.
CunninghamALStephensJWHarrisDA. Gut microbiota influence in type 2 diabetes mellitus (T2DM).Gut Pathog2021;13:50
28.
GreggEWSattarNAliMK. The changing face of diabetes complications.Lancet Diabetes Endocrinol2016;4:537–47
29.
Serre-BeinierVBoscoDZulianelloLCharollaisACailleDCharpantierEGauthierBRDiaferiaGRGiepmansBNLupiRMarchettiPDengSBuhlerLBerneyTCirulliVMedaP. Cx36 makes channels coupling human pancreatic beta-cells, and correlates with insulin expression.Hum Mol Genet2009;18:428–39
30.
RutterGAHodsonDJ. Beta cell connectivity in pancreatic islets: a type 2 diabetes target?Cell Mol Life Sci2015;72:453–67
31.
CalabreseAZhangMSerre-BeinierVCatonDMasCSatinLSMedaP. Connexin 36 controls synchronization of Ca2+ oscillations and insulin secretion in MIN6 cells.Diabetes2003;52:417–24
32.
RavierMAGuldenagelMCharollaisAGjinovciACailleDSöhlGWollheimCBWilleckeKHenquinJCMedaP. Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release.Diabetes2005;54:1798–807
33.
HeadWSOrsethMLNunemakerCSSatinLSPistonDWBenningerRK. Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse.Diabetes2012;61:1700–7
34.
CottleLGanWJGilroyISamraJSGillAJLoudovarisTThomasHEHawthorneWJKebedeMAThornP. Structural and functional polarisation of human pancreatic beta cells in islets from organ donors with and without type 2 diabetes.Diabetologia2021;64:618–29
35.
DissanayakeWCSorrensonBShepherdPR. The role of adherens junction proteins in the regulation of insulin secretion.Biosci Rep2018;38:BSR20170989
36.
GanWJZavortinkMLudickCTemplinRWebbRWebbRMaWPoronnikPPartonRGGaisanoHYShewanAMThornP. Cell polarity defines three distinct domains in pancreatic beta-cells.J Cell Sci2017;130:143–51
37.
HughesJWChoJHConwayHEDiGruccioMRNgXWRosemanHFAbreuDUranoFPistonDW. Primary cilia control glucose homeostasis via islet paracrine interactions.Proc Natl Acad Sci U S A2020;117:8912–23
38.
ArousCHalbanPA. The skeleton in the closet: actin cytoskeletal remodeling in beta-cell function.Am J Physiol Endocrinol Metab2015; 309:E611–20
39.
SorrensonBCognardELeeKLDissanayakeWCFuYHanWHughesWEShepherdPR. A critical role for beta-catenin in modulating levels of insulin secretion from beta-cells by regulating actin cytoskeleton and insulin vesicle localization.J Biol Chem2016;291:25888–900
40.
EberhardDLammertE. The pancreatic beta-cell in the islet and organ community.Curr Opin Genet Dev2009;19:469–75
41.
Wakae-TakadaNXuanSWatanabeKMedaPLeibelRL. Molecular basis for the regulation of islet beta cell mass in mice: the role of E-cadherin.Diabetologia2013;56:856–66
42.
CerneaSDobreanuM. Diabetes and beta cell function: from mechanisms to evaluation and clinical implications.Biochem Med (Zagreb)2013;23:266–80
43.
OhYS. Mechanistic insights into pancreatic beta-cell mass regulation by glucose and free fatty acids.Anat Cell Biol2015;48:16–24
44.
PrentkiMNolanCJ. Islet beta cell failure in type 2 diabetes.J Clin Invest2006;116:1802–12
45.
GonzalezAMerinoBMarroquiLNecoPAlonso-MagdalenaPCaballero-GarridoEVieiraESorianoSGomisRNadalAQuesadaI. Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese female mice is associated with several functional adaptations in individual beta-cells.Endocrinology2013;154:3515–24
46.
KannoAAsaharaSIMasudaKMatsudaTKimura-KoyanagiMSeinoSOgawaWKidoY. Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets.Biochem Biophys Res Commun2015;458:681–6
47.
MontaneJCadavezLNovialsA. Stress and the inflammatory process: a major cause of pancreatic cell death in type 2 diabetes.Diabetes Metab Syndr Obes2014;7:25–34
48.
CarvalhoCPOliveiraRBBritanASantos-SilvaJCBoscheroACMedaPCollares-BuzatoCB. Impaired beta-cell-beta-cell coupling mediated by Cx36 gap junctions in prediabetic mice.Am J Physiol Endocrinol Metab2012;303:E144–51
49.
FalcaoVTMaschioDAde FontesCCOliveiraRBSantos-SilvaJCAlmeidaACVanzelaECCartaxoMTCarvalhoCPCollares-BuzatoCB. Reduced insulin secretion function is associated with pancreatic islet redistribution of cell adhesion molecules (CAMS) in diabetic mice after prolonged high-fat diet.Histochem Cell Biol2016;146:13–31
50.
CorezoladoAmaralMEKravetsVDwuletJMFarnsworthNLPiscopioRSchleicherWEMirandaJGBenningerRKP. Caloric restriction recovers impaired beta-cell-beta-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice.Am J Physiol Endocrinol Metab2020;319:E709–20
51.
BenningerRKZhangMHeadWSSatinLSPistonDW. Gap junction coupling and calcium waves in the pancreatic islet.Biophys J2008;95: 5048–61
52.
HodsonDJMitchellRKBellomoEASunGVinetLMedaPLiDLiWHBuglianiMMarchettiPBoscoDPiemontiLJohnsonPHughesSJRutterGA. Lipotoxicity disrupts incretin-regulated human beta cell connectivity.J Clin Invest2013;123:4182–94
AllagnatFMartinDCondorelliDFWaeberGHaefligerJA. Glucose represses connexin36 in insulin-secreting cells.J Cell Sci2005;118:5335–44
55.
FarnsworthNLWalterRLHemmatiAWestacottMJBenningerRK. Low level pro-inflammatory cytokines decrease connexin36 gap junction coupling in mouse and human islets through nitric oxide-mediated protein kinase Cdelta.J Biol Chem2016;291:3184–96
56.
MedaP. Gap junction proteins are key drivers of endocrine function.Biochim Biophys Acta Biomembr2018;1860:124–40
BosseYDespresJPChagnonYCRiceTRaoDCBouchardCPerusseLVohlMC. Quantitative trait locus on 15q for a metabolic syndrome variable derived from factor analysis.Obesity (Silver Spring)2007;15:544–50
59.
CoxNJFriggeMNicolaeDLConcannonPHanisCLBellGIKongA. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans.Nat Genet1999;21:213–5
60.
CigliolaVPopulaireCPierriCLDeutschSHaefligerJAFadistaJLyssenkoVGroopLRueediRThorelFHerreraPLMedaP. A variant of GJD2, encoding for connexin 36, alters the function of insulin producing beta-cells.PLoS ONE2016;11:e0150880
61.
FarnsworthNLWalterRPiscopioRASchleicherWEBenningerRKP. Exendin-4 overcomes cytokine-induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets.J Physiol2019;597:431–47
62.
LamprianouSGysemansCBou SaabJPontesHMathieuCMedaP. Glibenclamide prevents diabetes in NOD mice.PLoS ONE2016;11:e0168839
63.
Santos-SilvaJCCarvalhoCPde OliveiraRBBoscheroACCollares-BuzatoCB. Cell-to-cell contact dependence and junctional protein content are correlated with in vivo maturation of pancreatic beta cells.Can J Physiol Pharmacol2012;90:837–50
64.
YamagataKNammoTMoriwakiMIharaAIizukaKYangQSatohTLiMUenakaROkitaKIwahashiHZhuQCaoYImagawaATochinoYHanafusaTMiyagawaJMatsuzawaY. Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes.Diabetes2002;51:114–23
65.
ParnaudGLavallardVBedatBMatthey-DoretDMorelPBerneyTBoscoD. Cadherin engagement improves insulin secretion of single human beta-cells.Diabetes2015;64:887–96
66.
AamodtKIPowersAC. Signals in the pancreatic islet microenvironment influence beta-cell proliferation.Diabetes Obes Metab2017;19:124–36
67.
KulkarniRNMizrachiEBOcanaAGStewartAF. Human beta-cell proliferation and intracellular signaling: driving in the dark without a road map.Diabetes2012;61:2205–13
68.
YesilPLammertE. Islet dynamics: a glimpse at beta cell proliferation.Histol Histopathol2008;23:883–95
69.
GraingerSWillertK. Mechanisms of Wnt signaling and control.Wiley Interdiscip Rev Syst Biol Med. Epub ahead of print 30 March 2018. DOI: 10.1002/wsbm.1422.
70.
MaschioDAMatheusVACollares-BuzatoCB. Islet cells are the source of Wnts that can induce beta-cell proliferationin vitro. J Cell Physiol2019;234:19852–65
71.
ShuLZienKGutjahrGOberholzerJPattouFKerr-ConteJMaedlerK. TCF7L2 promotes beta cell regeneration in human and mouse pancreas.Diabetologia2012;55:3296–307
72.
ZhouAXMondalTTabishAMAbadpourSEricsonESmithDMKnollRScholzHKanduriCTyrbergBAlthageM. The long noncoding RNA TUNAR modulates Wnt signaling and regulates human beta-cell proliferation.Am J Physiol Endocrinol Metab2021;320:E846–57
73.
GrantSFThorleifssonGReynisdottirIBenediktssonRManolescuASainzJHelgasonAStefanssonHEmilssonVHelgadottirAStyrkarsdottirUMagnussonKPWaltersGBPalsdottirEJonsdottirTGudmundsdottirTGylfasonASaemundsdottirJWilenskyRLReillyMPRaderDJBaggerYChristiansenCGudnasonVSigurdssonGThorsteinsdottirUGulcherJRKongAStefanssonK. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.Nat Genet2006;38:320–3
74.
LuoYWangHHanXRenQWangFZhangXSunXZhouXJiL. Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in East Asian population.Diabetes Res Clin Pract2009;85:139–46
75.
LyssenkoVLupiRMarchettiPDel GuerraSOrho-MelanderMAlmgrenPSjögrenMLingCErikssonKFLethagenALMancarellaRBerglundGTuomiTNilssonPDel PratoSGroopL. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.J Clin Invest2007;117:2155–63
76.
WeltersHJKulkarniRN. Wnt signaling: relevance to beta-cell biology and diabetes.Trends Endocrinol Metab2008;19:349–55
77.
LarsenNVogensenFKvan den BergFWNielsenDSAndreasenASPedersenBKAl-SoudWASorensenSJHansenLHJakobsenM. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults.PLoS ONE2010;5:e9085
78.
CoxAJZhangPBowdenDWDevereauxBDavorenPMCrippsAWWestNP. Increased intestinal permeability as a risk factor for type 2 diabetes.Diabetes Metab2017;43:163–6
79.
PasiniECorsettiGAssanelliDTestaCRomanoCDioguardiFSAquilaniR. Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes.Minerva Med2019;110:3–11
80.
YuanJHXieQSChenGCHuangCLYuTChenQKLiJY. Impaired intestinal barrier function in type 2 diabetic patients measured by serum LPS, Zonulin, and IFABP.J Diabetes Complications2021;35:107766
81.
ZhangDZhangLZhengYYueFRussellRDZengY. Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients.Diabetes Res Clin Pract2014;106:312–8
82.
de KortSKeszthelyiDMascleeAA. Leaky gut and diabetes mellitus: what is the link.Obes Rev2011;12:449–58
83.
EverardACaniPD. Diabetes, obesity and gut microbiota.Best Pract Res Clin Gastroenterol2013;27:73–83
84.
NeuJReverteCMMackeyADLiboniKTuhacek-TenaceLMHatchMLiNCaicedoRASchatzDAAtkinsonM. Changes in intestinal morphology and permeability in the biobreeding rat before the onset of type 1 diabetes.J Pediatr Gastroenterol Nutr2005;40:589–95
85.
SabatinoARegolistiGCosolaCGesualdoLFiaccadoriE. Intestinal microbiota in type 2 diabetes and chronic kidney disease.Curr Diab Rep2017;17:16
86.
BuckleyATurnerJR. Cell biology of tight junction barrier regulation and mucosal disease.Cold Spring Harb Perspect Biol2018;10:a029314
87.
BalakumarMPrabhuDSathishkumarCPrabuPRokanaNKumarRRaghavanSSoundarajanAGroverSBatishVKMohanVBalasubramanyamM. Improvement in glucose tolerance and insulin sensitivity by probiotic strains of Indian gut origin in high-fat diet-fed C57BL/6J mice.Eur J Nutr2018;57:279–95
88.
SuzukiTHaraH. Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats.Nutr Metab (Lond)2010;7:19
89.
AkibaY. Which comes first: increased intestinal paracellular permeability or subepithelial inflammation?Dig Dis Sci2021;66:3222–3
90.
FasanoA. Gut permeability, obesity, and metabolic disorders: who is the chicken and who is the egg.Am J Clin Nutr2017;105:3–4
91.
MatheusVAMonteiroLOliveiraRBMaschioDACollares-BuzatoCB. Butyrate reduces high-fat diet-induced metabolic alterations, hepatic steatosis and pancreatic beta cell and intestinal barrier dysfunctions in prediabetic mice.Exp Biol Med (Maywood)2017;242:1214–26
92.
NascimentoJCMatheusVAOliveiraRBTadaSFSCollares-BuzatoCB. High-fat diet induces disruption of the tight junction-mediated paracellular barrier in the proximal small intestine before the onset of type 2 diabetes and endotoxemia.Dig Dis Sci2021;66:3359–74
93.
de OliveiraRBMatheusVACanutoLPDe Sant ana’ACollares-BuzatoCB. Time-dependent alteration to the tight junction structure of distal intestinal epithelia in type 2 prediabetic mice.Life Sci2019;238:116971
94.
ButtAMKhanIBHussainMIdressMLuJTongY. Role of post translational modifications and novel crosstalk between phosphorylation and O-beta-GlcNAc modifications in human claudin-1, -3 and -4.Mol Biol Rep2012;39:1359–69
95.
StamatovicSMJohnsonAMSladojevicNKeepRFAndjelkovicAV. Endocytosis of tight junction proteins and the regulation of degradation and recycling.Ann N Y Acad Sci2017;1397:54–65
96.
UtechMMennigenRBruewerM. Endocytosis and recycling of tight junction proteins in inflammation.J Biomed Biotechnol2010;2010:484987
97.
OliveiraRBCanutoLPCollares-BuzatoCB. Intestinal luminal content from high-fat-fed prediabetic mice changes epithelial barrier functionin vitro. Life Sci2019;216:10–21
98.
GenserLAguannoDSoulaHADongLTrystramLAssmannKSalemJEVaillantJCOppertJMLaugeretteFMichalskiMCWindPRoussetMBrot-LarocheELeturqueAClementKThenetSPoitouC. Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes.J Pathol2018;246:217–30
99.
ThaissCALevyMGroshevaIZhengDSofferEBlacherEBravermanSTengelerACBarakOElazarMBen-ZeevRLehavi-RegevDKatzMNPevsner-FischerMGertlerAHalpernZHarmelinAAamarSSerradasPGrosfeldAShapiroHGeigerBElinavE. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.Science2018;359:1376–83
100.
GhezzalSPostalBGQuevrainEBrotLSeksikPLeturqueAThenetSCarrièreV. Palmitic acid damages gut epithelium integrity and initiates inflammatory cytokine production.Biochim Biophys Acta Mol Cell Biol Lipids2020;1865:158530
101.
Van SpaendonkHCeuleersHWittersLPatteetEJoossensJAugustynsKLambeirAMDe MeesterIDe ManJGDe WinterBY. Regulation of intestinal permeability: the role of proteases.World J Gastroenterol2017;23:2106–23
102.
StenmanLKHolmaRKorpelaR. High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids.World J Gastroenterol2012;18:923–9
103.
ChenJYangYYangYDaiZKimIHWuGWuZ. Dietary supplementation with glycine enhances intestinal mucosal integrity and ameliorates inflammation in C57BL/6J mice with high-fat diet-induced obesity.J Nutr2021;151:1769–78
104.
LiPWuG. Composition of amino acids and related nitrogenous nutrients in feedstuffs for animal diets.Amino Acids2020;52:523–42
105.
HouYHeWHuSWuG. Composition of polyamines and amino acids in plant-source foods for human consumption.Amino Acids2019;51:1153–65
106.
JakobsdottirGXuJMolinGAhrneSNymanM. High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects.PLoS ONE2013;8:e80476
107.
Yan-DoRMacDonaldPE. Impaired “Glycine”-mia in type 2 diabetes and potential mechanisms contributing to glucose homeostasis.Endocrinology2017;158:1064–73
108.
DengJZengLLaiXLiJLiuLLinQChenY. Metformin protects against intestinal barrier dysfunction via AMPKalpha1-dependent inhibition of JNK signalling activation.J Cell Mol Med2018;22:546–57
109.
ForslundKHildebrandFNielsenTFalonyGLe ChatelierESunagawaSPriftiEVieira-SilvaSGudmundsdottirVPedersenHKArumugamMKristiansenKVoigtAYVestergaardHHercogRCosteaPIKultimaJRLiJJorgensenTLevenezFDoreJMetaHITcNielsenHBBrunakSRaesJHansenTWangJEhrlichSDBorkPPedersenO. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.Nature2015;528:262–6
110.
ZhouHYZhuHYaoXMQianJPYangJPanXDChenXD. Metformin regulates tight junction of intestinal epithelial cells via MLCK-MLC signaling pathway.Eur Rev Med Pharmacol Sci2017;21:5239–46
111.
GlynnELPinerLWHuffmanKMSlentzCAElliot-PenryLAbouAssiHWhitePJBainJRMuehlbauerMJIlkayevaORStevensRDPorter StarrKNBalesCWVolpiEBrosnanMJTrimmerJKRolphTPNewgardCBKrausWE. Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans.Diabetologia2015;58:2324–35
112.
GnudiLCowardRJMLongDA. Diabetic nephropathy: perspective on novel molecular mechanisms.Trends Endocrinol Metab2016;27:820–30
113.
LizicarovaDKrahulecBHirnerovaEGasparLCelecovaZ. Risk factors in diabetic nephropathy progression at present.Bratisl Lek Listy2014;115:517–21
114.
NakamichiRHayashiKItohH. Effects of high glucose and lipotoxicity on diabetic podocytes.Nutrients2021;13:241
115.
SrivastavaSPShiSKoyaDKanasakiK. Lipid mediators in diabetic nephropathy.Fibrogenesis Tissue Repair2014;7:12
116.
EftekhariAVahedSZKavetskyyTRameshradMJafariSChodariLHosseiniyanSMDerakhshankhahHAhmadianEArdalanM. Cell junction proteins: crossing the glomerular filtration barrier in diabetic nephropathy.Int J Biol Macromol2020;148:475–82
117.
SiddiqiFSAdvaniA. Endothelial-podocyte crosstalk: the missing link between endothelial dysfunction and albuminuria in diabetes.Diabetes2013;62:3647–55
118.
KawachiHFukusumiY. New insight into podocyte slit diaphragm, a therapeutic target of proteinuria.Clin Exp Nephrol2020;24:193–204
119.
LennonRRandlesMJHumphriesMJ. The importance of podocyte adhesion for a healthy glomerulus.Front Endocrinol (Lausanne)2014;5:160
120.
JiangYXieFLvXWangSLiaoXYuYDaiQZhangYMengJHuGPengZTaoL. Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice.FASEB J2021;35:e21198
121.
KlimontovVVKorbutAITaskaevaISBgatovaNPDashkinMVOrlovNBKhotskinaASZavyalovELKleinT. Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice.World J Diabetes2020;11:596–610
122.
LanghamRGKellyDJCoxAJThomsonNMHolthöferHZaouiPPinelNCordonnierDJGilbertRE. Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition.Diabetologia2002;45:1572–6
123.
LiYXiaTLiRTseGLiuTLiG. Renal-protective effects of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in ob/ob mice.Med Sci Monit2019;25:1582–9
124.
Rincon-CholesHVasylyevaTLPergolaPEBhandariBBhandariKZhangJHWangWGorinYBarnesJLAbboudHE. ZO-1 expression and phosphorylation in diabetic nephropathy.Diabetes2006;55:894–900
125.
Rosas-MartinezLRodriguez-MunozRNamorado-TonixMDCMissirlisFDel Valle-MondragonLSanchez-MendozaAReyes-SanchezJLCervantes-PerezLG. Hyperglycemic levels in early stage of diabetic nephropathy affect differentially renal expression of claudins-2 and -5 by oxidative stress.Life Sci2021;268:119003
126.
SawaiKMukoyamaMMoriKYokoiHKoshikawaMYoshiokaTTakedaRSugawaraAKuwaharaTSaleemMAOgawaONakaoK. Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in patients with type 2 diabetes and overt nephropathy.Nephrol Dial Transplant2006;21:2472–7
127.
KorbutAIKlimontovVVVinogradovIVRomanovVV. Risk factors and urinary biomarkers of non-albuminuric and albuminuric chronic kidney disease in patients with type 2 diabetes.World J Diabetes2019;10:517–33
128.
KostovskaITosheska-TrajkovskaKTopuzovskaSCekovskaSSpasovskiGKostovskiOLabudovicD. Urinary nephrin is earlier, more sensitive and specific marker of diabetic nephropathy than microalbuminuria.J Med Biochem2020;39:83–90
129.
LiYZengQ. Effect of low protein diet combined with drug therapy on renal function and oxidation—anti-oxidation balance in patients with diabetic nephropathy.Journal of Hainan Medical University2018;24:77–80
130.
Molina-JijonERodri-guez-MunozRGonzalez-RamirezRNamorado-TonixCPedraza-ChaverriJReyesJL. Aldosterone signaling regulates the over-expression of claudin-4 and -8 at the distal nephron from type 1 diabetic rats.PLoS ONE2017;12:e0177362
131.
Molina-JijonERodri-guez-MunozRNamorado MdelCPedraza-ChaverriJReyesJL. Oxidative stress induces claudin-2 nitration in experimental type 1 diabetic nephropathy.Free Radic Biol Med2014;72:162–75
132.
SwardPRippeB. Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability.Acta Physiol (Oxf)2012;204:294–307
133.
XuZGRyuDRYooTHJungDSKimJJKimHJChoiHYKimJSAdlerSGNatarajanRHanDSKangSW. P-Cadherin is decreased in diabetic glomeruli and in glucose-stimulated podocytes in vivo and in vitro studies.Nephrol Dial Transplant2005;20:524–31
134.
Mongelli-SabinoBMCanutoLPCollares-BuzatoCB. Acute and chronic exposure to high levels of glucose modulates tight junction-associated epithelial barrier function in a renal tubular cell line.Life Sci2017;188:149–57
135.
CanutoLPCollares-BuzatoCB. Increased osmolality enhances the tight junction-mediated barrier function in a cultured renal epithelial cell line.Cell Biol Int2019;43:73–82
136.
RudrarajuMNarayananSPSomanathPR. Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy.Pharmacol Res2020;161:105115
137.
RichnerMFerreiraNDudeleAJensenTSVaegterCBGoncalvesNP. Functional and structural changes of the blood-nerve-barrier in diabetic neuropathy.Front Neurosci2018;12:1038
138.
TangSTTangHQSuHWangYZhouQZhangQWangYZhuHQ. Glucagon-like peptide-1 attenuates endothelial barrier injury in diabetes via cAMP/PKA mediated down-regulation of MLC phosphorylation.Biomed Pharmacother2019;113:108667
