Mức độ ghrelin và LEAP2 trong huyết thanh ở bệnh nhân tiểu đường loại 2: mối liên hệ với glucose và lipid tuần hoàn
Tóm tắt
Ghrelin điều chỉnh trọng lượng cơ thể, lượng thức ăn và glucose trong máu. Nó cũng điều tiết sự tiết insulin từ các tế bào tiểu đảo tụy. LEAP2 là một ligand nội sinh mới được phát hiện của thụ thể hormone kích thích sự phát triển (GHSR). Nó không chỉ đối kháng với sự kích thích của GHSR bởi ghrelin mà còn ức chế sự hoạt động cấu trúc của GHSR với vai trò là một đối kháng ngược. Bệnh nhân tiểu đường loại 2 (T2D) có rối loạn nội tiết và mất cân bằng chuyển hóa. Mức độ ghrelin và LEAP2 trong huyết tương có thể thay đổi ở bệnh nhân béo phì và T2D. Tuy nhiên, chưa có báo cáo nào về mức độ LEAP2 lưu hành hoặc tỷ lệ ghrelin/LEAP2 ở bệnh nhân T2D. Trong nghiên cứu này, mức độ ghrelin và LEAP2 trong huyết thanh của những người lớn khỏe mạnh và bệnh nhân T2D được đánh giá để làm rõ mối liên hệ giữa hai hormone với các thông số nhân trắc lâm sàng và chuyển hóa khác nhau.
Tổng cộng có 16 nữ và 40 nam, tuổi từ 23–68, người bình thường (
Mức độ ghrelin trong huyết thanh thấp hơn nhưng mức độ LEAP2 trong huyết thanh cao hơn ở bệnh nhân T2D. Mức độ ghrelin có mối tương quan tích cực với mức insulin huyết thanh lúc đói và HOMA-IR ở người trưởng thành khỏe mạnh. Mức LEAP2 có mối tương quan tích cực với tuổi tác và hemoglobin A1c (HbA1c) trong tất cả các mẫu đã thử nghiệm. Tỷ lệ ghrelin/LEAP2 có mối tương quan nghịch với tuổi tác, glucose trong máu lúc đói và HbA1c.
Nghiên cứu này đã chứng minh sự giảm mức ghrelin trong huyết thanh và sự tăng mức LEAP2 trong huyết thanh ở bệnh nhân T2D. Mức LEAP2 có mối tương quan tích cực với HbA1c, cho thấy rằng LEAP2 có liên quan đến sự phát triển của T2D. Tỷ lệ ghrelin/LEAP2 có mối liên hệ gần gũi với kiểm soát glycemic ở bệnh nhân T2D với mối tương quan nghịch với glucose và HbA1c.
Từ khóa
Tài liệu tham khảo
Kojima MHosoda HDate YNakazato MMatsuo HKangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature1999402656–660. (https://doi.org/10.1038/45230)10.1038/45230
Müller TDNogueiras RAndermann MLAndrews ZBAnker SDArgente JBatterham RLBenoit SCBowers CYBroglio FGhrelin. Molecular Metabolism20154437–460. (https://doi.org/10.1016/j.molmet.2015.03.005)10.1016/j.molmet.2015.03.005
Sun YWang PZheng HSmith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. PNAS20041014679–4684. (https://doi.org/10.1073/pnas.0305930101)10.1073/pnas.0305930101
Mani BKUchida ALee YOsborne-Lawrence SCharron MJUnger RHBerglund EDZigman JM. Hypoglycemic effect of combined ghrelin and glucagon receptor blockade. Diabetes2017661847–1857. (https://doi.org/10.2337/db16-1303)10.2337/db16-1303
Liu JPrudom CENass RPezzoli SSOliveri MCJohnson MLVeldhuis PGordon DAHoward ADWitcher DRNovel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. Journal of Clinical Endocrinology and Metabolism2008931980–1987. (https://doi.org/10.1210/jc.2007-2235)10.1210/jc.2007-2235
Zhang YFang FGoldstein JLBrown MSZhao TJ. Reduced autophagy in livers of fasted, fat-depleted, ghrelin-deficient mice: reversal by growth hormone. PNAS20151121226–1231. (https://doi.org/10.1073/pnas.1423643112)10.1073/pnas.1423643112
Zhao TJLiang GLi RLXie XSleeman MWMurphy AJValenzuela DMYancopoulos GDGoldstein JLBrown MS. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. PNAS20101077467–7472. (https://doi.org/10.1073/pnas.1002271107)10.1073/pnas.1002271107
Li RLSherbet DPElsbernd BLGoldstein JLBrown MSZhao TJ. Profound hypoglycemia in starved, ghrelin-deficient mice is caused by decreased gluconeogenesis and reversed by lactate or fatty acids. Journal of Biological Chemistry201228717942–17950. (https://doi.org/10.1074/jbc.M112.358051)10.1074/jbc.M112.358051
Date YNakazato MHashiguchi SDezaki KMondal MSHosoda HKojima MKangawa KArima TMatsuo HGhrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes200251124–129. (https://doi.org/10.2337/diabetes.51.1.124)10.2337/diabetes.51.1.124
Adeghate EPonery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. Journal of Neuroendocrinology200214555–560. (https://doi.org/10.1046/j.1365-2826.2002.00811.x)10.1046/j.1365-2826.2002.00811.x
Gauna CDelhanty PJvan Aken MOJanssen JAThemmen APHofland LJCuller MBroglio FGhigo Evan der Lely AJ. Unacylated ghrelin is active on the INS-1E rat insulinoma cell line independently of the growth hormone secretagogue receptor type 1a and the corticotropin releasing factor 2 receptor. Molecular and Cellular Endocrinology2006251103–111. (https://doi.org/10.1016/j.mce.2006.03.040)10.1016/j.mce.2006.03.040
Lindqvist AShcherbina LPrasad RBMiskelly MGAbels MMartínez-Lopéz JAFred RGNergård BJHedenbro JGroop LGhrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels. Molecular and Cellular Endocrinology2020511110835. (https://doi.org/10.1016/j.mce.2020.110835)10.1016/j.mce.2020.110835
Granata RBaragli ASettanni FScarlatti FGhigo E. Unraveling the role of the ghrelin gene peptides in the endocrine pancreas. Journal of Molecular Endocrinology201045107–118. (https://doi.org/10.1677/JME-10-0019)10.1677/JME-10-0019
Reimer MKPacini GAhrén B. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology2003144916–921. (https://doi.org/10.1210/en.2002-220819)10.1210/en.2002-220819
Sun YAsnicar MSaha PKChan LSmith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metabolism20063379–386. (https://doi.org/10.1016/j.cmet.2006.04.004)10.1016/j.cmet.2006.04.004
Ge XYang HBednarek MAGalon-Tilleman HChen PChen MLichtman JSWang YDalmas OYin YLEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metabolism201827461–469.e6. (https://doi.org/10.1016/j.cmet.2017.10.016)10.1016/j.cmet.2017.10.016
Lu XHuang LHuang ZFeng DClark RJChen C. LEAP-2: an emerging endogenous ghrelin receptor antagonist in the pathophysiology of obesity. Frontiers in Endocrinology202112717544. (https://doi.org/10.3389/fendo.2021.717544)10.3389/fendo.2021.717544
Krause ASillard RKleemeier BKlüver EMaronde EConejo-García JRForssmann WGSchulz-Knappe PNehls MCWattler FIsolation and biochemical characterization of LEAP-2, a novel blood peptide expressed in the liver. Protein Science200312143–152. (https://doi.org/10.1110/ps.0213603)10.1110/ps.0213603
Xiao XBi MJiao QChen XDu XJiang H. A new understanding of GHSR1a – independent of ghrelin activation. Ageing Research Reviews202064101187. (https://doi.org/10.1016/j.arr.2020.101187)10.1016/j.arr.2020.101187
Mani BKPuzziferri NHe ZRodriguez JAOsborne-Lawrence SMetzger NPChhina NGaylinn BThorner MOThomas ELLEAP2 changes with body mass and food intake in humans and mice. Journal of Clinical Investigation20191293909–3923. (https://doi.org/10.1172/JCI125332)10.1172/JCI125332
M'Kadmi CCabral ABarrile FGiribaldi JCantel SDamian MMary SDenoyelle SDutertre SPéraldi-Roux SN-terminal liver-expressed antimicrobial Peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. Journal of Medicinal Chemistry201962965–973. (https://doi.org/10.1021/acs.jmedchem.8b01644)10.1021/acs.jmedchem.8b01644
Hagemann CAZhang CHansen HHJorsal TRigbolt KTGMadsen MRBergmann NCHeimbürger SMNFalkenhahn MTheis SIdentification and metabolic profiling of a novel human gut-derived LEAP2 fragment. Journal of Clinical Endocrinology and Metabolism2021106e966–e981. (https://doi.org/10.1210/clinem/dgaa803)10.1210/clinem/dgaa803
Shiiya TNakazato MMizuta MDate YMondal MSTanaka MNozoe SHosoda HKangawa KMatsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. Journal of Clinical Endocrinology and Metabolism200287240–244. (https://doi.org/10.1210/jcem.87.1.8129)10.1210/jcem.87.1.8129
Tschöp MWeyer CTataranni PADevanarayan VRavussin EHeiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes200150707–709. (https://doi.org/10.2337/diabetes.50.4.707)10.2337/diabetes.50.4.707
Reinehr Tde Sousa GRoth CL. Obestatin and ghrelin levels in obese children and adolescents before and after reduction of overweight. Clinical Endocrinology200868304–310. (https://doi.org/10.1111/j.1365-2265.2007.03042.x)
Bellone SProdam FSavastio SDe Rienzo FDemarchi ITrovato LPetri ARapa AAimaretti GBona G. Acylated and unacylated ghrelin levels in normal weight and obese children: influence of puberty and relationship with insulin, leptin and adiponectin levels. Journal of Endocrinological Investigation201235191–197. (https://doi.org/10.3275/7761)
Soriano-Guillén LBarrios VMartos GChowen JACampos-Barros AArgente J. Effect of oral glucose administration on ghrelin levels in obese children. European Journal of Endocrinology2004151119–121. (https://doi.org/10.1530/eje.0.1510119)
Fittipaldi ASHernández JCastrogiovanni DLufrano DDe Francesco PNGarrido VVitaux PFasano MVFehrentz JAFernández APlasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance. European Journal of Endocrinology2020182165–175. (https://doi.org/10.1530/EJE-19-0684)10.1530/EJE-19-0684
Chou JJLee WJAlmalki OChen JCTsai PLYang SH. Dietary intake and weight changes 5 years after laparoscopic sleeve gastrectomy. Obesity Surgery2017273240–3246. (https://doi.org/10.1007/s11695-017-2765-8)10.1007/s11695-017-2765-8
Ağagündüz DGezmen-Karadağ M. Association of FTO common variant (rs9939609) with body fat in Turkish individuals. Lipids in Health and Disease201918 212. (https://doi.org/10.1186/s12944-019-1160-y)
Guerrero-Pérez FCasajoana AGómez-Vaquero CVirgili NLópez-Urdiales RHernández-Montoliu LPujol-Gebelli JOsorio JAlves CPerez-Maraver MChanges in bone mineral density in patients with type 2 diabetes after different bariatric surgery procedures and the role of gastrointestinal hormones. Obesity Surgery202030180–188. (https://doi.org/10.1007/s11695-019-04127-5)10.1007/s11695-019-04127-5
Razali NAbdul Aziz ALim CYMat Junit S. Investigation into the effects of antioxidant-rich extract of Tamarindus indica leaf on antioxidant enzyme activities, oxidative stress and gene expression profiles in HepG2 cells. PeerJ20153 e1292. (https://doi.org/10.7717/peerj.1292)
Yoshinaga HKosaka K. Heterogeneous relationship of early insulin response and fasting insulin level with development of non-insulin-dependent diabetes mellitus in non-diabetic Japanese subjects with or without obesity. Diabetes Research and Clinical Practice199944129–136. (https://doi.org/10.1016/S0168-8227(9900019-4)10.1016/S0168-8227(99)00019-4
Galicia-Garcia UBenito-Vicente AJebari SLarrea-Sebal ASiddiqi HUribe KBOstolaza HMartín C. Pathophysiology of type 2 diabetes mellitus. International Journal of Molecular Sciences202021 6275. (https://doi.org/10.3390/ijms21176275)
Nakahara THarada TYasuhara DShimada NAmitani HSakoguchi TKamiji MMAsakawa AInui A. Plasma obestatin concentrations are negatively correlated with body mass index, insulin resistance index, and plasma leptin concentrations in obesity and anorexia nervosa. Biological Psychiatry200864252–255. (https://doi.org/10.1016/j.biopsych.2007.08.005)10.1016/j.biopsych.2007.08.005
Ozgen ITAydin MGuven AAliyazicıoglu Y. Characteristics of polycystic ovarian syndrome and relationship with ghrelin in adolescents. Journal of Pediatric and Adolescent Gynecology201023285–289. (https://doi.org/10.1016/j.jpag.2010.02.011)10.1016/j.jpag.2010.02.011
Serra-Prat MAlfaro SRPalomera ECasamitjana RBuquet XFernández-Fernández CPuig-Domingo M & Mataró Ageing Study Group. Relationship between ghrelin and the metabolic syndrome in the elderly: a longitudinal population-based study. Clinical Endocrinology200970227–232. (https://doi.org/10.1111/j.1365-2265.2008.03307.x)10.1111/j.1365-2265.2008.03307.x
Umegaki HType 2 diabetes as a risk factor for cognitive impairment: current insights. Clinical Interventions in Aging201491011–1019. (https://doi.org/10.2147/CIA.S48926)
Biessels GJStrachan MWVisseren FLKappelle LJWhitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet: Diabetes and Endocrinology20142246–255. (https://doi.org/10.1016/S2213-8587(1370088-3)
Katsuki AUrakawa HGabazza ECMurashima SNakatani KTogashi KYano YAdachi YSumida Y. Circulating levels of active ghrelin is associated with abdominal adiposity, hyperinsulinemia and insulin resistance in patients with type 2 diabetes mellitus. European Journal of Endocrinology2004151573–577. (https://doi.org/10.1530/eje.0.1510573)
Couce MECottam DEsplen JTeijeiro RSchauer PBurguera B. Potential role of hypothalamic ghrelin in the pathogenesis of human obesity. Journal of Endocrinological Investigation200629599–605. (https://doi.org/10.1007/BF03344158)10.1007/BF03344158
Ueno HShiiya TMizuta MMondal SMNakazato M. Plasma ghrelin concentrations in different clinical stages of diabetic complications and glycemic control in Japanese diabetics. Endocrine Journal200754895–902. (https://doi.org/10.1507/endocrj.k07-007)10.1507/endocrj.K07-007
González-López MAOcejo-Viñals JGMata CVilanova IGuiral SPortilla VBlanco RHernández JL. Association of retinol binding protein4 (RBP4) and ghrelin plasma levels with insulin resistance and disease severity in non-diabetic patients with hidradenitis suppurativa. Experimental Dermatology202029828–832. (https://doi.org/10.1111/exd.14132)10.1111/exd.14132
Vestergaard ETGormsen LCJessen NLund SHansen TKMoller NJorgensen JO. Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling. Diabetes2008573205–3210. (https://doi.org/10.2337/db08-0025)10.2337/db08-0025
Vestergaard ETJessen NMøller NJørgensen JO. Acyl ghrelin induces insulin resistance independently of GH, cortisol, and free fatty acids. Scientific Reports2017742706. (https://doi.org/10.1038/srep42706)10.1038/srep42706
Dallak MAAcylated ghrelin induces but deacylated ghrelin prevents hepatic steatosis and insulin resistance in lean rats: effects on DAG/ PKC/JNK pathway. Biomedicine and Pharmacotherapy2018105299–311. (https://doi.org/10.1016/j.biopha.2018.05.098)10.1016/j.biopha.2018.05.098
Schalla MAStengel A. LEAP2: a novel regulator of food intake and body weight?Nature Reviews: Gastroenterology and Hepatology201916711–712. (https://doi.org/10.1038/s41575-019-0224-9)
Ma XXue XZhang JLiang SXu CWang YZhu J. Liver expressed antimicrobial peptide 2 is associated with steatosis in mice and humans. Experimental and Clinical Endocrinology and Diabetes2021129601–610. (https://doi.org/10.1055/a-1210-2357)10.1055/a-1210-2357
Barja-Fernández SLugilde JCastelao CVázquez-Cobela RSeoane LMDiéguez CLeis RTovar S. Circulating LEAP-2 is associated with puberty in girls. International Journal of Obesity202145502–514. (https://doi.org/10.1038/s41366-020-00703-3)10.1038/s41366-020-00703-3
Gupta DOgden SBShankar KVarshney SZigman JM. A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes. Molecular Metabolism202146101128. (https://doi.org/10.1016/j.molmet.2020.101128)10.1016/j.molmet.2020.101128
Price MLLey CDGorvin CM. The emerging role of heterodimerisation and interacting proteins in ghrelin receptor function. Journal of Endocrinology2021252R23–R39. (https://doi.org/10.1530/JOE-21-0206)
Gupta DDowsett GKCMani BKShankar KOsborne-Lawrence SMetzger NPLam BYHYeo GSHZigman JM. High coexpression of the ghrelin and LEAP2 receptor GHSR with pancreatic polypeptide in mouse and human islets. Endocrinology2021162 bqab148. (https://doi.org/10.1210/endocr/bqab148)