Skip to content
2000
Volume 21, Issue 9
  • ISSN: 1573-3998
  • E-ISSN: 1875-6417

Abstract

In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects.

Loading

Article metrics loading...

/content/journals/cdr/10.2174/0115733998311738240813110032
2024-08-26
2025-04-12
Loading full text...

Full text loading...

References

  1. OjoO.A. IbrahimH.S. RotimiD.E. OgunlakinA.D. OjoA.B. Diabetes mellitus: From molecular mechanism to pathophysiology and pharmacology.Med. Novel Technol. Dev.20231910024710.1016/j.medntd.2023.100247
    [Google Scholar]
  2. SunH. SaeediP. KarurangaS. PinkepankM. OgurtsovaK. DuncanB.B. SteinC. BasitA. ChanJ.C.N. MbanyaJ.C. PavkovM.E. RamachandaranA. WildS.H. JamesS. HermanW.H. ZhangP. BommerC. KuoS. BoykoE.J. MaglianoD.J. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.Diabetes Res. Clin. Pract.202218310911910.1016/j.diabres.2021.10911934879977
    [Google Scholar]
  3. ZhaoX. AnX. YangC. SunW. JiH. LianF. The crucial role and mechanism of insulin resistance in metabolic disease.Front. Endocrinol. (Lausanne)202314114923910.3389/fendo.2023.114923937056675
    [Google Scholar]
  4. DeFronzoR.A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009.Diabetologia20105371270128710.1007/s00125‑010‑1684‑120361178
    [Google Scholar]
  5. TomicD. ShawJ.E. MaglianoD.J. The burden and risks of emerging complications of diabetes mellitus.Nat. Rev. Endocrinol.202218952553910.1038/s41574‑022‑00690‑735668219
    [Google Scholar]
  6. NortonL. ShannonC. GastaldelliA. DeFronzoR.A. Insulin: The master regulator of glucose metabolism.Metabolism202212915514210.1016/j.metabol.2022.15514235066003
    [Google Scholar]
  7. ThomasD.D. CorkeyB.E. IstfanN.W. ApovianC.M. Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction.J. Endocr. Soc.2019391727174710.1210/js.2019‑0006531528832
    [Google Scholar]
  8. XingJ. ChenC. Hyperinsulinemia: beneficial or harmful or both on glucose homeostasis.Am. J. Physiol. Endocrinol. Metab.20223231E2E710.1152/ajpendo.00441.202135635329
    [Google Scholar]
  9. CnopM. WelshN. JonasJ.C. JörnsA. LenzenS. EizirikD.L. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities.Diabetes200554Suppl. 2S97S10710.2337/diabetes.54.suppl_2.S9716306347
    [Google Scholar]
  10. KulkarniR.N. HolzenbergerM. ShihD.Q. OzcanU. StoffelM. MagnusonM.A. KahnC.R. β-cell–specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass.Nat. Genet.200231111111510.1038/ng87211923875
    [Google Scholar]
  11. SaishoY. β-cell dysfunction: Its critical role in prevention and management of type 2 diabetes.World J. Diabetes20156110912410.4239/wjd.v6.i1.10925685282
    [Google Scholar]
  12. KulkarniA. MuralidharanC. MayS.C. TerseyS.A. MirmiraR.G. Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis.Endocrinology20221641bqac18410.1210/endocr/bqac18436317483
    [Google Scholar]
  13. MarselliL. PironA. SuleimanM. ColliM.L. YiX. KhamisA. CarratG.R. RutterG.A. BuglianiM. GiustiL. RonciM. IbbersonM. TuratsinzeJ.V. BoggiU. De SimoneP. De TataV. LopesM. NasteskaD. De LucaC. TesiM. BosiE. SinghP. CampaniD. SchulteA.M. SolimenaM. HechtP. RadyB. BakajI. PocaiA. NorquayL. ThorensB. CanouilM. FroguelP. EizirikD.L. CnopM. MarchettiP. Persistent or Transient Human β Cell Dysfunction Induced by Metabolic Stress: Specific Signatures and Shared Gene Expression with Type 2 Diabetes.Cell Rep.202033910846610.1016/j.celrep.2020.10846633264613
    [Google Scholar]
  14. NtsapiC. LumkwanaD. SwartC. du ToitA. LoosB. New Insights Into Autophagy Dysfunction Related to Amyloid Beta Toxicity and Neuropathology in Alzheimer’s Disease.Int. Rev. Cell Mol. Biol.201833632136110.1016/bs.ircmb.2017.07.00229413893
    [Google Scholar]
  15. OhY.S. BaeG.D. BaekD.J. ParkE.Y. JunH.S. Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes.Front. Endocrinol. (Lausanne)2018938410.3389/fendo.2018.0038430061862
    [Google Scholar]
  16. CaoR. TianH. ZhangY. LiuG. XuH. RaoG. TianY. FuX. Signaling pathways and intervention for therapy of type 2 diabetes mellitus.MedComm202343e28310.1002/mco2.28337303813
    [Google Scholar]
  17. GoldsteinB.J. Insulin resistance as the core defect in type 2 diabetes mellitus.Am. J. Cardiol.200290531010.1016/S0002‑9149(02)02553‑512231073
    [Google Scholar]
  18. PetersenM.C. ShulmanG.I. Mechanisms of Insulin Action and Insulin Resistance.Physiol. Rev.20189842133222310.1152/physrev.00063.201730067154
    [Google Scholar]
  19. CoppackS.W. Pro-inflammatory cytokines and adipose tissue.Proc. Nutr. Soc.200160334935610.1079/PNS200111011681809
    [Google Scholar]
  20. ZatteraleF. LongoM. NaderiJ. RacitiG.A. DesiderioA. MieleC. BeguinotF. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes.Front. Physiol.202010160710.3389/fphys.2019.0160732063863
    [Google Scholar]
  21. Silva RosaS.C. NayakN. CaymoA.M. GordonJ.W. Mechanisms of muscle insulin resistance and the cross‐talk with liver and adipose tissue.Physiol. Rep.2020819e1460710.14814/phy2.1460733038072
    [Google Scholar]
  22. VogelzangsN. van der KallenC.J.H. van GreevenbroekM.M.J. van der KolkB.W. JockenJ.W.E. GoossensG.H. SchaperN.C. HenryR.M.A. EussenS.J.P.M. ValsesiaA. HankemeierT. AstrupA. SarisW.H.M. StehouwerC.D.A. BlaakE.E. ArtsI.C.W. Metabolic profiling of tissue-specific insulin resistance in human obesity: results from the Diogenes study and the Maastricht Study.Int. J. Obes.20204461376138610.1038/s41366‑020‑0565‑z32203114
    [Google Scholar]
  23. NandipatiK.C. SubramanianS. AgrawalD.K. Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance.Mol. Cell. Biochem.20174261-2274510.1007/s11010‑016‑2878‑827868170
    [Google Scholar]
  24. ShiJ. FanJ. SuQ. YangZ. Cytokines and Abnormal Glucose and Lipid Metabolism.Front. Endocrinol. (Lausanne)20191070310.3389/fendo.2019.0070331736870
    [Google Scholar]
  25. SamuelV.T. ShulmanG.I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.J. Clin. Invest.20161261122210.1172/JCI7781226727229
    [Google Scholar]
  26. LuH. BogdanovicE. YuZ. ChoC. LiuL. HoK. GuoJ. YeungL.S.N. LehmannR. HundalH.S. GiaccaA. FantusI.G. Combined Hyperglycemia- and Hyperinsulinemia-Induced Insulin Resistance in Adipocytes Is Associated With Dual Signaling Defects Mediated by PKC-ζ.Endocrinology201815941658167710.1210/en.2017‑0031229370351
    [Google Scholar]
  27. SaadM.J.A. Obesity, Diabetes, and Endothelium: Molecular Interactions.Endothelium and Cardiovascular Diseases. Da LuzP.L. LibbyP. ChagasA.C.P. LaurindoF.R.M. Academic Press201863965210.1016/B978‑0‑12‑812348‑5.00044‑1
    [Google Scholar]
  28. HuangX. LiuG. GuoJ. SuZ. The PI3K/AKT pathway in obesity and type 2 diabetes.Int. J. Biol. Sci.201814111483149610.7150/ijbs.2717330263000
    [Google Scholar]
  29. MaffeiA. LemboG. CarnevaleD. PI3Kinases in diabetes mellitus and its related complications.Int. J. Mol. Sci.20181912409810.3390/ijms1912409830567315
    [Google Scholar]
  30. CoppsK.D. WhiteM.F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.Diabetologia201255102565258210.1007/s00125‑012‑2644‑822869320
    [Google Scholar]
  31. LeonB.M. MaddoxT.M. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research.World J. Diabetes20156131246125810.4239/wjd.v6.i13.124626468341
    [Google Scholar]
  32. PoznyakA. GrechkoA.V. PoggioP. MyasoedovaV.A. AlfieriV. OrekhovA.N. The diabetes mellitus–atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation.Int. J. Mol. Sci.2020215183510.3390/ijms2105183532155866
    [Google Scholar]
  33. Jebari-BenslaimanS. Galicia-GarcíaU. Larrea-SebalA. OlaetxeaJ.R. AllozaI. VandenbroeckK. Benito-VicenteA. MartínC. Pathophysiology ofllerosis.Int. J. Mol. Sci.2022236334610.3390/ijms2306334635328769
    [Google Scholar]
  34. StandlE. Hyperinsulinemia and atherosclerosis.Clin. Invest. Med.19951842612668549011
    [Google Scholar]
  35. YuanT. YangT. ChenH. FuD. HuY. WangJ. YuanQ. YuH. XuW. XieX. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis.Redox Biol.20192024726010.1016/j.redox.2018.09.02530384259
    [Google Scholar]
  36. LuY. CuiX. ZhangL. WangX. XuY. QinZ. LiuG. WangQ. TianK. LimK.S. CharlesC.J. ZhangJ. TangJ. The Functional Role of Lipoproteins in Atherosclerosis: Novel Directions for Diagnosis and Targeting Therapy.Aging Dis.202213249152010.14336/AD.2021.092935371605
    [Google Scholar]
  37. SansburyB.E. HillB.G. Regulation of obesity and insulin resistance by nitric oxide.Free Radic. Biol. Med.20147338339910.1016/j.freeradbiomed.2014.05.01624878261
    [Google Scholar]
  38. BahadoranZ. MirmiranP. KashfiK. GhasemiA. Vascular nitric oxide resistance in type 2 diabetes.Cell Death Dis.202314741010.1038/s41419‑023‑05935‑537433795
    [Google Scholar]
  39. MuniyappaR. SowersJ.R. Role of insulin resistance in endothelial dysfunction.Rev. Endocr. Metab. Disord.201314151210.1007/s11154‑012‑9229‑123306778
    [Google Scholar]
  40. BahadoranZ. MirmiranP. GhasemiA. Role of Nitric Oxide in Insulin Secretion and Glucose Metabolism.Trends Endocrinol. Metab.202031211813010.1016/j.tem.2019.10.00131690508
    [Google Scholar]
  41. SchultzeS.M. HemmingsB.A. NiessenM. TschoppO. PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis.Expert Rev. Mol. Med.201214e110.1017/S146239941100210922233681
    [Google Scholar]
  42. CusiK. MaezonoK. OsmanA. PendergrassM. PattiM.E. PratipanawatrT. DeFronzoR.A. KahnC.R. MandarinoL.J. Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle.J. Clin. Invest.2000105331132010.1172/JCI753510675357
    [Google Scholar]
  43. BönnerG. Hyperinsulinemia, insulin resistance, and hypertension.J. Cardiovasc. Pharmacol.199424Suppl. 2S39S4910.1097/00005344‑199412001‑000077898093
    [Google Scholar]
  44. BrandsM.W. ManhianiM.M. Sodium-retaining effect of insulin in diabetes.Am. J. Physiol. Regul. Integr. Comp. Physiol.201230311R1101R110910.1152/ajpregu.00390.201223034715
    [Google Scholar]
  45. WangH. WangA.X. AylorK. BarrettE.J. Nitric oxide directly promotes vascular endothelial insulin transport.Diabetes201362124030404210.2337/db13‑062723863813
    [Google Scholar]
  46. Daza-ArnedoR. Rico-FontalvoJ. Aroca-MartínezG. Rodríguez-YanezT. Martínez-ÁvilaM.C. Almanza-HurtadoA. Cardona-BlancoM. Henao-VelásquezC. Fernández-FrancoJ. Unigarro-PalaciosM. Osorio-RestrepoC. Uparella-GulfoI. Insulin and the kidneys: a contemporary view on the molecular basis.Front. Neurol.20233113335210.3389/fneph.2023.113335237675359
    [Google Scholar]
  47. da SilvaA.A. do CarmoJ.M. LiX. WangZ. MoutonA.J. HallJ.E. Role of hyperinsulinemia and insulin resistance in hypertension: Metabolic syndrome revisited.Can. J. Cardiol.202036567168210.1016/j.cjca.2020.02.06632389340
    [Google Scholar]
  48. MonuS. Renal hyperinsulinemia causes thickening of glomerular basement membrane independent of hypertension and hyperglycemia.FASEB J.202034S11110.1096/fasebj.2020.34.s1.02118
    [Google Scholar]
  49. De CosmoS. MenzaghiC. PrudenteS. TrischittaV. Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence.Nephrol. Dial. Transplant.2013281293610.1093/ndt/gfs29023048172
    [Google Scholar]
  50. SinhaS. HaqueM. Insulin Resistance Is Cheerfully Hitched with Hypertension.Life (Basel)202212456410.3390/life1204056435455055
    [Google Scholar]
  51. JiaG. SowersJ.R. Hypertension in diabetes: An update of basic mechanisms and clinical disease.Hypertension20217851197120510.1161/HYPERTENSIONAHA.121.17981
    [Google Scholar]
  52. HosszúfalusiN. PánczélP. JánoskutiL. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men.Circulation199910024e11810.1161/01.CIR.100.24.e11810595966
    [Google Scholar]
  53. Rask-MadsenC. KingG.L. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes.Nat. Clin. Pract. Endocrinol. Metab.200731465610.1038/ncpendmet036617179929
    [Google Scholar]
  54. DesprésJ.P. LamarcheB. MauriègeP. CantinB. DagenaisG.R. MoorjaniS. LupienP.J. Hyperinsulinemia as an independent risk factor for ischemic heart disease.N. Engl. J. Med.19963341595295810.1056/NEJM1996041133415048596596
    [Google Scholar]
  55. CuiJ. LiuY. LiY. XuF. LiuY. Type 2 Diabetes and Myocardial Infarction: Recent Clinical Evidence and Perspective.Front. Cardiovasc. Med.2021864418910.3389/fcvm.2021.64418933718461
    [Google Scholar]
  56. WarraichH.J. RanaJ.S. Dyslipidemia in diabetes mellitus and cardiovascular disease.Cardiovasc. Endocrinol.201761273210.1097/XCE.000000000000012031646116
    [Google Scholar]
  57. GinsbergH.N. PackardC.J. ChapmanM.J. BorénJ. Aguilar-SalinasC.A. AvernaM. FerenceB.A. GaudetD. HegeleR.A. KerstenS. LewisG.F. LichtensteinA.H. MoulinP. NordestgaardB.G. RemaleyA.T. StaelsB. StroesE.S.G. TaskinenM.R. TokgözoğluL.S. Tybjaerg-HansenA. StockJ.K. CatapanoA.L. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society.Eur. Heart J.202142474791480610.1093/eurheartj/ehab55134472586
    [Google Scholar]
  58. ShimanoH. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes.Prog. Lipid Res.200140643945210.1016/S0163‑7827(01)00010‑811591434
    [Google Scholar]
  59. MourikisP. ZakoS. DannenbergL. NiaA.M. HeinenY. BuschL. RichterH. HohlfeldT. ZeusT. KelmM. PolzinA. Lipid lowering therapy in cardiovascular disease: From myth to molecular reality.Pharmacol. Ther.202021310759210.1016/j.pharmthera.2020.10759232492513
    [Google Scholar]
  60. LongoM. ZatteraleF. NaderiJ. ParrilloL. FormisanoP. RacitiG.A. BeguinotF. MieleC. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications.Int. J. Mol. Sci.2019209235810.3390/ijms2009235831085992
    [Google Scholar]
  61. WeyerC. FunahashiT. TanakaS. HottaK. MatsuzawaY. PratleyR.E. TataranniP.A. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.J. Clin. Endocrinol. Metab.20018651930193510.1210/jcem.86.5.746311344187
    [Google Scholar]
  62. KershawE.E. FlierJ.S. Adipose tissue as an endocrine organ.J. Clin. Endocrinol. Metab.20048962548255610.1210/jc.2004‑039515181022
    [Google Scholar]
  63. AhmedB. SultanaR. GreeneM.W. Adipose tissue and insulin resistance in obese.Biomed. Pharmacoth202113711131510.1016/j.biopha.2021.111315
    [Google Scholar]
  64. DharmalingamM. YamasandhiP.G. Nonalcoholic fatty liver disease and Type 2 diabetes mellitus.Indian J. Endocrinol. Metab.201822342142810.4103/ijem.IJEM_585_1730090738
    [Google Scholar]
  65. UtzschneiderK.M. KahnS.E. Review: The role of insulin resistance in nonalcoholic fatty liver disease.J. Clin. Endocrinol. Metab.200691124753476110.1210/jc.2006‑058716968800
    [Google Scholar]
  66. BourebabaN. MaryczK. Hepatic stellate cells role in the course of metabolic disorders development – A molecular overview.Pharmacol. Res.202117010573910.1016/j.phrs.2021.10573934171492
    [Google Scholar]
  67. TsamosG. VasdekiD. KoufakisT. MichouV. MakedouK. TzimagiorgisG. Therapeutic Potentials of Reducing Liver Fat in Non-Alcoholic Fatty Liver Disease: Close Association with Type 2 Diabetes.Metabolites202313451710.3390/metabo1304051737110175
    [Google Scholar]
  68. FinerN. Weight loss interventions and nonalcoholic fatty liver disease: Optimizing liver outcomes.Diabetes Obes. Metab.202224S2Suppl. 2445410.1111/dom.1456934622555
    [Google Scholar]
  69. MarshallJ.C. DunaifA. Should all women with PCOS be treated for insulin resistance?Fertil. Steril.2012971182210.1016/j.fertnstert.2011.11.03622192137
    [Google Scholar]
  70. BaburaoA. SouzaG. Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.N. Am. J. Med. Sci.201461050050410.4103/1947‑2714.14328025489561
    [Google Scholar]
  71. PateguanaN.B. JanesA. The contribution of hyperinsulinemia to the hyperandrogenism of polycystic ovary syndrome.Journal of Metabolic Health201941310.4102/jir.v4i1.50
    [Google Scholar]
  72. SongS.O. HeK. NarlaR.R. KangH.G. RyuH.U. BoykoE.J. Metabolic Consequences of Obstructive Sleep Apnea Especially Pertaining to Diabetes Mellitus and Insulin Sensitivity.Diabetes Metab. J.201943214415510.4093/dmj.2018.025630993938
    [Google Scholar]
  73. JärgenP. DietrichA. HerlingA.W. HammesH.P. WohlfartP. The role of insulin resistance in experimental diabetic retinopathy—Genetic and molecular aspects.PLoS One2017126e017865810.1371/journal.pone.017865828575111
    [Google Scholar]
  74. GiaccoF. BrownleeM. Oxidative stress and diabetic complications.Circ. Res.201010791058107010.1161/CIRCRESAHA.110.22354521030723
    [Google Scholar]
  75. GuiF. YouZ. FuS. WuH. ZhangY. Endothelial Dysfunction in Diabetic Retinopathy.Front. Endocrinol. (Lausanne)20201159110.3389/fendo.2020.0059133013692
    [Google Scholar]
  76. ForresterJ.V. KuffovaL. DelibegovicM. The Role of Inflammation in Diabetic Retinopathy.Front. Immunol.20201158368710.3389/fimmu.2020.58368733240272
    [Google Scholar]
  77. LiY. LiuY. LiuS. GaoM. WangW. ChenK. HuangL. LiuY. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies.Signal Transduct. Target. Ther.20238115210.1038/s41392‑023‑01400‑z37037849
    [Google Scholar]
  78. HernandezK. PollockL. Anand-ApteB. Role of Hyperinsulinemia and Hyperglycemia in Outer Blood Retinal Barrier (BRB) Breakdown.Invest. Ophthalmol. Vis. Sci.20226373620A0075
    [Google Scholar]
  79. SugandhF.N.U. ChandioM. RaveenaF.N.U. KumarL. KarishmaF.N.U. KhuwajaS. MemonU.A. BaiK. KashifM. VarrassiG. KhatriM. KumarS. Advances in the Management of Diabetes Mellitus: A Focus on Personalized Medicine.Cureus2023158e4369710.7759/cureus.4369737724233
    [Google Scholar]
  80. KuboM. KiyoharaY. KatoI. IwamotoH. NakayamaK. HirakataH. FujishimaM. Effect of hyperinsulinemia on renal function in a general Japanese population: The Hisayama study.Kidney Int.19995562450245610.1046/j.1523‑1755.1999.00458.x10354294
    [Google Scholar]
  81. PennoG. SoliniA. OrsiE. BonoraE. FondelliC. TrevisanR. VedovatoM. CavalotF. ZerbiniG. LamacchiaO. NicolucciA. PuglieseG. Insulin resistance, diabetic kidney disease, and all-cause mortality in individuals with type 2 diabetes: a prospective cohort study.BMC Med.20211916610.1186/s12916‑021‑01936‑333715620
    [Google Scholar]
  82. SarafidisP.A. GrekasD.M. Insulin resistance and oxidant stress: an interrelation with deleterious renal consequences?J. Cardiometab. Syndr.20072213914210.1111/j.1559‑4564.2007.06666.x17684472
    [Google Scholar]
  83. SarafidisP.A. RuilopeL.M. Insulin resistance, hyperinsulinemia, and renal injury: mechanisms and implications.Am. J. Nephrol.200626323224410.1159/00009363216733348
    [Google Scholar]
  84. UnderwoodP.C. AdlerG.K. The renin angiotensin aldosterone system and insulin resistance in humans.Curr. Hypertens. Rep.2013151597010.1007/s11906‑012‑0323‑223242734
    [Google Scholar]
  85. FoggensteinerL. MulroyS. FirthJ. Management of diabetic nephropathy.J. R. Soc. Med.200194521021710.1177/01410768010940050411385086
    [Google Scholar]
  86. GroteC.W. WrightD.E. A Role for Insulin in Diabetic Neuropathy.Front. Neurosci.20161058110.3389/fnins.2016.0058128066166
    [Google Scholar]
  87. FeldmanE.L. CallaghanB.C. Pop-BusuiR. ZochodneD.W. WrightD.E. BennettD.L. BrilV. RussellJ.W. ViswanathanV. Diabetic neuropathy.Nat. Rev. Dis. Primers2019514110.1038/s41572‑019‑0092‑131197183
    [Google Scholar]
  88. YagihashiS. MizukamiH. SugimotoK. Mechanism of diabetic neuropathy: Where are we now and where to go?J. Diabetes Investig.201121183210.1111/j.2040‑1124.2010.00070.x24843457
    [Google Scholar]
  89. ChengY. ChenY. LiK. LiuS. PangC. GaoL. How inflammation dictates diabetic peripheral neuropathy: An enlightening review.CNS Neurosci Ther.2024304e1447710.1111/cns.14477
    [Google Scholar]
  90. AliO. Genetics of type 2 diabetes.World J. Diabetes20134411412310.4239/wjd.v4.i4.11423961321
    [Google Scholar]
  91. ColeJ.B. FlorezJ.C. Genetics of diabetes mellitus and diabetes complications.Nat. Rev. Nephrol.202016737739010.1038/s41581‑020‑0278‑532398868
    [Google Scholar]
  92. FlorezJ.C. HirschhornJ. AltshulerD. The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits.Annu. Rev. Genomics Hum. Genet.20034125729110.1146/annurev.genom.4.070802.11043614527304
    [Google Scholar]
  93. NakamuraF. TairaM. HashimotoN. MakinoH. SasakiN. Familial type C syndrome of insulin resistance and short stature with possible autosomal dominant transmission.Endocrinol. Jpn.198936334935810.1507/endocrj1954.36.3492684618
    [Google Scholar]
  94. LadhaF.A. StitzelM.L. HinsonJ.T. From GWAS association to function: candidate gene screening within insulin resistance-associated genomic loci using a preadipocyte differentiation model.Circ. Res.2020126334734910.1161/CIRCRESAHA.119.31640531999535
    [Google Scholar]
  95. McCarthyM.I. ZegginiE. Genome-wide association studies in type 2 diabetes.Curr. Diab. Rep.20099216417110.1007/s11892‑009‑0027‑419323962
    [Google Scholar]
  96. KidoY. Gene–environment interaction in type 2 diabetes.Diabetol. Int.20178171310.1007/s13340‑016‑0299‑230603301
    [Google Scholar]
  97. LindP.M. LindL. Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review.Diabetologia20186171495150210.1007/s00125‑018‑4621‑329744538
    [Google Scholar]
  98. LiJ.H. SzczerbinskiL. DawedA.Y. KaurV. ToddJ.N. PearsonE.R. FlorezJ.C. A Polygenic Score for Type 2 Diabetes Risk Is Associated With Both the Acute and Sustained Response to Sulfonylureas.Diabetes202170129330010.2337/db20‑053033106254
    [Google Scholar]
  99. GalchevaS. DemirbilekH. Al-KhawagaS. HussainK. The Genetic and Molecular Mechanisms of Congenital Hyperinsulinism.Front. Endocrinol. (Lausanne)20191011110.3389/fendo.2019.0011130873120
    [Google Scholar]
  100. MureaM. MaL. FreedmanB.I. Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications.Rev. Diabet. Stud.20129162210.1900/RDS.2012.9.622972441
    [Google Scholar]
  101. YaribeygiH. MalekiM. SathyapalanT. JamialahmadiT. SahebkarA. Pathophysiology of Physical Inactivity-Dependent Insulin Resistance: A Theoretical Mechanistic Review Emphasizing Clinical Evidence.J. Diabetes Res.2021202111210.1155/2021/779672734660812
    [Google Scholar]
  102. AnderssonD.P. KerrA.G. DahlmanI. RydénM. ArnerP. Relationship Between a Sedentary Lifestyle and Adipose Insulin Resistance.Diabetes202372331632510.2337/db22‑061236445942
    [Google Scholar]
  103. MartinsF.O. CondeS.V. Impact of Diet Composition on Insulin Resistance.Nutrients20221418371610.3390/nu1418371636145093
    [Google Scholar]
  104. FarrugiaF. AquilinaA. VassalloJ. PaceN.P. Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors.Int. J. Environ. Res. Public Health202118271610.3390/ijerph1802071633467592
    [Google Scholar]
  105. BoniniM.G. SargisR.M. Environmental toxicant exposures and type 2 diabetes mellitus: Two interrelated public health problems on the rise.Curr. Opin. Toxicol.20187525910.1016/j.cotox.2017.09.00329392186
    [Google Scholar]
  106. DendupT. FengX. ClinganS. Astell-BurtT. Environmental Risk Factors for Developing Type 2 Diabetes Mellitus: A Systematic Review.Int. J. Environ. Res. Public Health20181517810.3390/ijerph1501007829304014
    [Google Scholar]
  107. StahlhutR.W. MyersJ.P. TaylorJ.A. NadalA. DyerJ.A. vom SaalF.S. Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women.J. Endocr. Soc.20182101173118710.1210/js.2018‑0015130302422
    [Google Scholar]
  108. HagobianT.A. BirdA. StanelleS. WilliamsD. SchaffnerA. PhelanS. Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults.J. Endocr. Soc.20193364365410.1210/js.2018‑0032230842988
    [Google Scholar]
  109. GregoryJ.M. KraftG. Dalla ManC. SlaughterJ.C. ScottM.F. HastingsJ.R. EdgertonD.S. MooreM.C. CherringtonA.D. A high-fat and fructose diet in dogs mirrors insulin resistance and β-cell dysfunction characteristic of impaired glucose tolerance in humans.PLoS One20231812e029640010.1371/journal.pone.029640038134122
    [Google Scholar]
  110. CummingsP.J. NoakesT.D. NicholsD.M. BerchouK.D. KreherM.D. WashburnP.J. Lifestyle Therapy Targeting Hyperinsulinemia Normalizes Hyperglycemia and Surrogate Markers of Insulin Resistance in a Large, Free-Living Population.AJPM Focus20221210003410.1016/j.focus.2022.10003437791244
    [Google Scholar]
  111. BesshoR. KashiwagiK. IkuraA. YamatakaK. InaishiJ. TakaishiH. KanaiT. A significant risk of metabolic dysfunction-associated fatty liver disease plus diabetes on subclinical atherosclerosis.PLoS One2022175e026926510.1371/journal.pone.026926535639744
    [Google Scholar]
  112. RegufeV.M.G. PintoC.M.C.B. PerezP.M.V.H.C. Metabolic syndrome in type 2 diabetic patients: a review of current evidence.Porto Biomed. J.202056e10110.1097/j.pbj.000000000000010133299950
    [Google Scholar]
  113. UnnikrishnanR. ShahV.N. MohanV. Challenges in diagnosis and management of diabetes in the young.Clin. Diabetes Endocrinol.2016211810.1186/s40842‑016‑0036‑628702252
    [Google Scholar]
  114. WangM.Y. YuX. LeeY. McCorkleS.K. ClarkG.O. StrowigS. UngerR.H. RaskinP. Iatrogenic hyperinsulinemia in type 1 diabetes: Its effect on atherogenic risk markers.J. Diabetes Complications2013271707410.1016/j.jdiacomp.2012.08.00823079124
    [Google Scholar]
  115. NathanD.M. Realising the long-term promise of insulin therapy: the DCCT/EDIC study.Diabetologia20216451049105810.1007/s00125‑021‑05397‑433550441
    [Google Scholar]
  116. PurnellJ.Q. HokansonJ.E. ClearyP.A. NathanD.M. LachinJ.M. ZinmanB. BrunzellJ.D. The effect of excess weight gain with intensive diabetes treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study.Circulation2013127218018710.1161/CIRCULATIONAHA.111.077487
    [Google Scholar]
  117. GoutaE.L. JerrayaH. DougazW. ChaouechM.A. BouaskerI. NouiraR. DziriC. Endogenous hyperinsulinism: Diagnostic and therapeutic difficulties.Pan Afr. Med. J.2019335710.11604/pamj.2019.33.57.1888531448019
    [Google Scholar]
  118. ShenY. SongX. RenY. Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series.BMC Endocr. Disord.201919114810.1186/s12902‑019‑0482‑031883520
    [Google Scholar]
  119. McAuleyK.A. WilliamsS.M. MannJ.I. GouldingA. ChisholmA. WilsonN. StoryG. McLayR.T. HarperM.J. JonesI.E. Intensive lifestyle changes are necessary to improve insulin sensitivity: a randomized controlled trial.Diabetes Care200225344545210.2337/diacare.25.3.44511874928
    [Google Scholar]
  120. ChiarelliF. Di MarzioD. Peroxisome proliferator-activated receptor-γ agonists and diabetes: current evidence and future perspectives.Vasc. Health Risk Manag.20084229730418561505
    [Google Scholar]
  121. RaguramanR. SrivastavaA. MunshiA. RameshR. Therapeutic approaches targeting molecular signaling pathways common to diabetes, lung diseases and cancer.Adv. Drug Deliv. Rev.202117811391810.1016/j.addr.2021.11391834375681
    [Google Scholar]
  122. FranceschiR. Precision Medicine in Diabetes, Current Research and Future Perspectives.J. Pers. Med.2022128123310.3390/jpm1208123336013182
    [Google Scholar]
  123. PerumalsamyS. HuriH.Z. AbdullahB.M. MazlanO. Wan AhmadW.A. VethakkanS.R.D.B. Genetic Markers of Insulin Resistance and Atherosclerosis in Type 2 Diabetes Mellitus Patients with Coronary Artery Disease.Metabolites202313342710.3390/metabo1303042736984867
    [Google Scholar]
  124. LarijaniB. GoodarziP. PayabM. Alavi-MoghadamS. RahimF. BanaN. AbediM. ArabiM. AdibiH. GilanyK. ArjmandB. Metabolomics and Cell Therapy in Diabetes Mellitus.Int. J. Mol. Cell. Med.20198Suppl. 1414810.22088/IJMCM.BUMS.8.2.4132351908
    [Google Scholar]
  125. GoddijnP.P.M. BiloH.J.G. FeskensE.J.M. GroenierK.H. van der ZeeK.I. de JongB.M. Longitudinal study on glycaemic control and quality of life in patients with Type 2 diabetes mellitus referred for intensified control.Diabet. Med.1999161233010.1046/j.1464‑5491.1999.00002.x10229289
    [Google Scholar]
  126. FerraraC. PatelP. BeckerS. StanleyC.A. KellyA. Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children.J. Pediatr.201616821221910.1016/j.jpeds.2015.09.04526490124
    [Google Scholar]
  127. KalraS. DasA.K. BajajS. PriyaG. GhoshS. MehrotraR.N. DasS. ShahP. DeshmukhV. SanyalD. ChandrasekaranS. KhandelwalD. JoshiA. NairT. ElianaF. PermanaH. FariduddinM.D. ShresthaP.K. ShresthaD. KahandawaS. SumanathilakaM. ShaheedA. RahimA.A.A. OrabiA. Al-aniA. HusseinW. KumarD. ShaikhK. Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel.Diabetes Ther.202011241142210.1007/s13300‑019‑00753‑531916214
    [Google Scholar]
  128. KolbH. KempfK. RöhlingM. MartinS. Insulin: too much of a good thing is bad.BMC Med.202018122410.1186/s12916‑020‑01688‑632819363
    [Google Scholar]
  129. FranksP.W. PovedaA. Lifestyle and precision diabetes medicine: will genomics help optimise the prediction, prevention and treatment of type 2 diabetes through lifestyle therapy?Diabetologia201760578479210.1007/s00125‑017‑4207‑528124081
    [Google Scholar]
  130. GaredowA.W. JemanehT.M. HailemariamA.G. TesfayeG.T. Lifestyle modification and medication use among diabetes mellitus patients attending Jimma University Medical Center, Jimma zone, south west Ethiopia.Sci. Rep.2023131495610.1038/s41598‑023‑32145‑y36973400
    [Google Scholar]
  131. SliekerR.C. DonnellyL.A. AkalestouE. Lopez-NoriegaL. MelhemR. GüneşA. Abou AzarF. EfanovA. GeorgiadouE. Muniangi-MuhituH. SheikhM. GiordanoG.N. ÅkerlundM. AhlqvistE. AliA. BanasikK. BrunakS. BarovicM. BoulandG.A. BurdetF. CanouilM. DraganI. EldersP.J.M. FernandezC. FestaA. FitipaldiH. FroguelP. GudmundsdottirV. GudnasonV. GerlM.J. van der HeijdenA.A. JenningsL.L. HansenM.K. KimM. LeclercI. KloseC. KuznetsovD. Mansour AlyD. MehlF. MarekD. MelanderO. NiknejadA. OttossonF. PavoI. DuffinK. SyedS.K. ShawJ.L. CabreraO. PullenT.J. SimonsK. SolimenaM. SuvitaivalT. WretlindA. RossingP. LyssenkoV. Legido QuigleyC. GroopL. ThorensB. FranksP.W. LimG.E. EstallJ. IbbersonM. BeulensJ.W.J. ’t HartL.M. PearsonE.R. RutterG.A. Identification of biomarkers for glycaemic deterioration in type 2 diabetes.Nat. Commun.2023141253310.1038/s41467‑023‑38148‑737137910
    [Google Scholar]
  132. Orkunoglu-SuerF.E. Gordish-DressmanH. ClarksonP.M. ThompsonP.D. AngelopoulosT.J. GordonP.M. MoynaN.M. PescatelloL.S. VisichP.S. ZoellerR.F. HarmonB. SeipR.L. HoffmanE.P. DevaneyJ.M. INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men.BMC Med. Genet.20089111710.1186/1471‑2350‑9‑11719105843
    [Google Scholar]
  133. BedairR.N. MagourG.M. OodaS.A. AmarE.M. AwadA.M. Insulin receptor substrate-1 G972R single nucleotide polymorphism in Egyptian patients with chronic hepatitis C virus infection and type 2 diabetes mellitus.Egyptian Liver Journal2021111210.1186/s43066‑020‑00069‑1
    [Google Scholar]
  134. MohásM. KisfaliP. JáromiL. MaászA. FehérE. CsöngeiV. PolgárN. SáfrányE. CsehJ. SümegiK. HetyésyK. WittmannI. MeleghB. GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness?Cardiovasc. Diabetol.2010917910.1186/1475‑2840‑9‑7921114848
    [Google Scholar]
  135. WangF. HanL. HuD. Fasting insulin, insulin resistance and risk of hypertension in the general population: A meta-analysis.Clin. Chim. Acta2017464576310.1016/j.cca.2016.11.00927836689
    [Google Scholar]
  136. BrunzellJ.D. AyyobiA.F. Dyslipidemia in the metabolic syndrome and type 2 diabetes mellitus.Am. J. Med.20031158Suppl. 8A242810.1016/j.amjmed.2003.08.01114678862
    [Google Scholar]
  137. ByrneC.D. TargherG. NAFLD: A multisystem disease.J. Hepatol.2015621Suppl.S47S6410.1016/j.jhep.2014.12.01225920090
    [Google Scholar]
  138. RameshR. PanduranganV. MadhavanS. SrinivasanD. BhaskarE. MarappaL. NairA.M. RajendranV. VaradarajP. Comparison of Fasting Insulin Level, Homeostatic Model of Insulin Resistance, and Lipid Levels between Patients with Primary Hypertension and Normotensive Subjects.Rambam Maimonides Med. J.2022132e000910.5041/RMMJ.1046835482462
    [Google Scholar]
  139. BergmanR.N. IderY.Z. BowdenC.R. CobelliC. Quantitative estimation of insulin sensitivity.Am. J. Physiol. Endocrinol. Metab.19792366E667E67710.1152/ajpendo.1979.236.6.E667443421
    [Google Scholar]
  140. SievenpiperJ.L. JenkinsD.J. JosseR.G. VuksanV. Dilution of the 75-g oral glucose tolerance test increases postprandial glycemia: implications for diagnostic criteria.CMAJ: Canadian Med. Assoc. J20001627993996
    [Google Scholar]
  141. DeFronzoR.A. TobinJ.D. AndresR. Glucose clamp technique: a method for quantifying insulin secretion and resistance.Am. J. Physiol. Endocrinol. Metab.19792373E214E22310.1152/ajpendo.1979.237.3.E214382871
    [Google Scholar]
  142. AntoniolliL.P. NedelB.L. PazinatoT.C. de Andrade MesquitaL. GerchmanF. Accuracy of insulin resistance indices for metabolic syndrome: a cross-sectional study in adults.Diabetol. Metab. Syndr.20181016510.1186/s13098‑018‑0365‑y30151057
    [Google Scholar]
  143. LeightonE. SainsburyC.A.R. JonesG.C. A Practical Review of C-Peptide Testing in Diabetes.Diabetes Ther.20178347548710.1007/s13300‑017‑0265‑428484968
    [Google Scholar]
  144. RedondoM.J. HagopianW.A. OramR. SteckA.K. VehikK. WeedonM. BalasubramanyamA. DabeleaD. The clinical consequences of heterogeneity within and between different diabetes types.Diabetologia202063102040204810.1007/s00125‑020‑05211‑732894314
    [Google Scholar]
  145. Litwińczuk-HajdukJ. Bernat-KarpińskaM. KowrachM. Cielecka-KuszykJ. PiątkiewiczP. Autoimmunity markers in subjects with diabetes.Journal of Pre-Clinical and Clinical Research2016101283310.5604/18982395.1208185
    [Google Scholar]
  146. TeixeiraM.M. DinizM.F.H.S. ReisJ.S. FerrariT.C.A. de CastroM.G.B. TeixeiraB.P. ArantesI.C.S. BicalhoD.M. FóscoloR.B. Insulin resistance and associated factors in patients with Type 1 Diabetes.Diabetol. Metab. Syndr.20146113110.1186/1758‑5996‑6‑13125937839
    [Google Scholar]
  147. BjornstadP. Snell-BergeonJ.K. NadeauK.J. MaahsD.M. Insulin sensitivity and complications in type 1 diabetes: New insights.World J. Diabetes20156181610.4239/wjd.v6.i1.825685274
    [Google Scholar]
  148. AtkinsonM.A. EisenbarthG.S. MichelsA.W. Type 1 diabetes.Lancet20143839911698210.1016/S0140‑6736(13)60591‑723890997
    [Google Scholar]
  149. FeeroG.W. GuttmacherA.E. Genomics, type 2 diabetes, and obesity.NEJM3632411210.1056/nejmra0906948
    [Google Scholar]
  150. ChenY. MaH. ZhuD. ZhaoG. WangL. FuX. ChenW. Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets.PPAR Res.2017201711310.1155/2017/836091928659972
    [Google Scholar]
  151. DruckerD.J. ShermanS.I. GorelickF.S. BergenstalR.M. SherwinR.S. BuseJ.B. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits.Diabetes Care201033242843310.2337/dc09‑149920103558
    [Google Scholar]
  152. HsiaD.S. GroveO. CefaluW.T. An Update on SGLT2 Inhibitors for the Treatment of Diabetes Mellitus.Curr. Opin. Endocrinol. Diabetes Obes.2017241737910.1097/MED.000000000000031127898586
    [Google Scholar]
  153. AtabekM.E. PirgonO. Use of metformin in obese adolescents with hyperinsulinemia: a 6-month, randomized, double-blind, placebo-controlled clinical trial.J. Pediatr. Endocrinol. Metab.200821433934810.1515/JPEM.2008.21.4.33918556965
    [Google Scholar]
  154. YeL. VaraminiB. LammingD.W. SabatiniD.M. BaurJ.A. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2.Front. Genet.2012317710.3389/fgene.2012.0017722973301
    [Google Scholar]
  155. MishraS. PericherlaS. ManthuruthilS. MishraS. HannoR. Effect of Physical activity on Insulin Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus.J. Clin. Diagn. Res.2013781764176610.7860/JCDR/2013/6518.330624086908
    [Google Scholar]
  156. WeickertM.O. What dietary modification best improves insulin sensitivity and why?Clin. Endocrinol. (Oxf.)201277450851210.1111/j.1365‑2265.2012.04450.x22640465
    [Google Scholar]
  157. KleinS. SheardN.F. Pi-SunyerX. DalyA. Wylie-RosettJ. KulkarniK. ClarkN.G. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies. A statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition.Am. J. Clin. Nutr.200480225726310.1093/ajcn/80.2.25715277143
    [Google Scholar]
  158. SvobodaS.A. ShieldsB.E. Cutaneous manifestations of nutritional excess: Pathophysiologic effects of hyperglycemia and hyperinsulinemia on the skin.Cutis20211072747810.12788/cutis.017333891835
    [Google Scholar]
  159. CroftsC. ZinnC. WheldonM. SchofieldG. Errata: Hyperinsulinemia: A unifying theory of chronic disease?Diabesity201622192910.15562/diabesity.2016.29
    [Google Scholar]
  160. Zhang, A.M.Y., Chu, K.H., Daly, B.F. et al. Effects of hyperinsulinemia on pancreatic cancer development and the immune micro-environment revealed through single-cell transcriptomics.Cancer Metab 10, 5202210.1186/s40170‑022‑00282‑z
    [Google Scholar]
  161. KurautiM.A. FerreiraS.M. SoaresG.M. VettorazziJ.F. CarneiroE.M. BoscheroA.C. Costa-JúniorJ.M. Hyperinsulinemia is associated with increasing insulin secretion but not with decreasing insulin clearance in an age‐related metabolic dysfunction mice model.J. Cell. Physiol.201923469802980910.1002/jcp.2766730370604
    [Google Scholar]
  162. ClementeE.G. KanungoS. SchmittC. MaajaliD. Hyperinsulinism.Endocrines20223111512610.3390/endocrines3010011
    [Google Scholar]
  163. KostopoulouE. DastamaniA. CaiuloS. AntellH. FlanaganS.E. ShahP. Hyperinsulinaemic hypoglycaemia: A new presentation of 16p11.2 deletion syndrome.Clin. Endocrinol.201990576676910.1111/cen.1395130776145
    [Google Scholar]
  164. ZhangA.M.Y. ChuK.H. DalyB.F. RuiterT. DouY. YangJ.C.C. de WinterT.J.J. ChhuorJ. WangS. FlibotteS. ZhaoY.B. HuX. LiH. RideoutE.J. SchaefferD.F. JohnsonJ.D. KoppJ.L. Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics.Cancer Metab.2022101510.1186/s40170‑022‑00282‑z35189981
    [Google Scholar]
  165. LakkaH.M. LakkaT.A. TuomilehtoJ. SiveniusJ. SalonenJ.T. Hyperinsulinemia and the risk of cardiovascular death and acute coronary and cerebrovascular events in men: the kuopio ischaemic heart disease risk factor study.Arch. Intern. Med.200016081160116810.1001/archinte.160.8.116010789610
    [Google Scholar]
  166. CenH.H. BotezelliJ.D. WangS. NoursadeghiN. JessenN. TimmonsJ.A. JohnsonJ.D. Transcriptomic analysis of human and mouse muscle during hyperinsulinemia demonstrates insulin receptor downregulation as a mechanism for insulin resistance.bioRxiv 556571202110.1101/556571
    [Google Scholar]
/content/journals/cdr/10.2174/0115733998311738240813110032
Loading
/content/journals/cdr/10.2174/0115733998311738240813110032
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test