Research advances in understanding crosstalk between organs and pancreatic β-cell dysfunction.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 100883645 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1463-1326 (Electronic) Linking ISSN: 14628902 NLM ISO Abbreviation: Diabetes Obes Metab Subsets: MEDLINE

Original Publication: Oxford : Wiley-Blackwell, c1999-

Insulin-Secreting Cells*/physiology ; Insulin-Secreting Cells*/metabolism ; Diabetes Mellitus, Type 2*/physiopathology ; Diabetes Mellitus, Type 2*/metabolism ; Adipose Tissue*/metabolism ; Adipose Tissue*/physiopathology ; Obesity*/physiopathology ; Obesity*/metabolism ; Obesity*/complications ; Liver*/metabolism; Humans ; Metabolic Syndrome/physiopathology ; Metabolic Syndrome/metabolism ; Brain/physiopathology ; Brain/metabolism ; Animals ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/physiopathology

Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.
(© 2024 John Wiley & Sons Ltd.)

Eizirik DL, Pasquali L, Cnop M. Pancreatic β‐cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020;16(7):349‐362.
DiMeglio LA, Evans‐Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449‐2462.
DeFronzo RA, Ferrannini E, Groop L, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019.
Joseph JJ. Advancing equity in diabetes prevention, treatment, and outcomes: delivering on our values. Endocrinol Metab Clin North Am. 2023;52(4):559‐572.
Hogrebe NJ, Ishahak M, Millman JR. Developments in stem cell‐derived islet replacement therapy for treating type 1 diabetes. Cell Stem Cell. 2023;30(5):530‐548.
Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54(10):2506‐2514.
Gignac T, Trépanier G, Pradeau M, et al. Metabolic‐associated fatty liver disease is characterized by a post‐oral glucose load hyperinsulinemia in individuals with mild metabolic alterations. Am J Physiol Endocrinol Metab. 2024;326(5):E616‐E625.
Drawshy Z, Neiman D, Fridlich O, et al. DNA methylation‐based assessment of cell composition in human pancreas and islets. Diabetes. 2024;73(4):554‐564.
Proshchina AE, Krivova YS, Barabanov VM, Saveliev SV. Pancreatic endocrine cell arrangement during human ontogeny. Acta Histochem. 2019;121(5):638‐645.
Kim SK, Melton DA. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci. 1998;95(22):13036‐13041.
Shih HP, Wang A, Sander M. Pancreas organogenesis: from lineage determination to morphogenesis. Annu Rev Cell Dev Biol. 2013;29:81‐105.
Bramswig NC, Kaestner KH. Organogenesis and functional genomics of the endocrine pancreas. Cell Mol Life Sci. 2012;69:2109‐2123.
Son J, Accili D. Reversing pancreatic β‐cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med. 2023;55(8):1652‐1658.
Spears E, Serafimidis I, Powers AC, Gavalas A. Debates in pancreatic beta cell biology: proliferation versus progenitor differentiation and Transdifferentiation in restoring β cell mass. Front Endocrinol (Lausanne). 2021;12:722250.
Wang W, Zhang C. Targeting β‐cell dedifferentiation and transdifferentiation: opportunities and challenges. Endocr Connect. 2021;10(8):R213‐R228.
Rutter GA, Pullen TJ, Hodson DJ, Martinez‐Sanchez A. Pancreatic β‐cell identity, glucose sensing and the control of insulin secretion. Biochem J. 2015;466(2):203‐218.
Bernardo AS, Hay CW, Docherty K. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol. 2008;294(1–2):1‐9.
Lenzen S. Oxidative stress: the vulnerable beta‐cell. Biochem Soc Trans. 2008;36(Pt 3):343‐347.
Patel S, Yan Z, Remedi MS. Intermittent fasting protects β‐cell identity and function in a type‐2 diabetes model. Metabolism. 2024;153:155813.
Numazawa S, Sakaguchi H, Aoki R, Taira T, Yoshida T. Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic beta‐cells. Am J Physiol Cell Physiol. 2008;295(2):C468‐C474.
Zraika S, Aston‐Mourney K, Laybutt DR, et al. The influence of genetic background on the induction of oxidative stress and impaired insulin secretion in mouse islets. Diabetologia. 2006;49(6):1254‐1263.
Freeman H, Shimomura K, Horner E, Cox RD, Ashcroft FM. Nicotinamide nucleotide transhydrogenase: a key role in insulin secretion. Cell Metab. 2006;3(1):35‐45.
Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic β‐cell death. Trends Endocrinol Metab. 2011;22(7):266‐274.
Kang T, Boland BB, Jensen P, et al. Characterization of signaling pathways associated with pancreatic β‐cell adaptive flexibility in compensation of obesity‐linked diabetes in db/db mice. Mol Cell Proteomics. 2020;19(6):971‐993.
Scheuner D, Vander Mierde D, Song B, et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med. 2005;11(7):757‐764.
Xiong Z, Li J, Huang R, et al. The gut microbe‐derived metabolite trimethylamine‐N‐oxide induces aortic valve fibrosis via PERK/ATF‐4 and IRE‐1α/XBP‐1s signaling in vitro and in vivo. Atherosclerosis. 2023;391:117431.
Kopp MC, Larburu N, Durairaj V, Adams CJ, Ali MMU. UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nat Struct Mol Biol. 2019;26(11):1053‐1062.
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000;5(5):897‐904.
Jin J, Ma Y, Tong X, et al. Metformin inhibits testosterone‐induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK. Hum Reprod. 2020;35(5):1145‐1158.
Dror E, Dalmas E, Meier DT, et al. Postprandial macrophage‐derived IL‐1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol. 2017;18(3):283‐292.
Burke SJ, Batdorf HM, Burk DH, et al. Pancreatic deletion of the interleukin‐1 receptor disrupts whole body glucose homeostasis and promotes islet β‐cell de‐differentiation. Mol Metab. 2018;14:95‐107.
Böni‐Schnetzler M, Boller S, Debray S, et al. Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin‐1 receptor I. Endocrinology. 2009;150(12):5218‐5229.
Maedler K, Sergeev P, Ris F, et al. Glucose‐induced beta cell production of IL‐1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110(6):851‐860.
Roca‐Rivada A, Marín‐Cañas S, Colli ML, et al. Inhibition of the type 1 diabetes candidate gene PTPN2 aggravates TNF‐α‐induced human beta cell dysfunction and death. Diabetologia. 2023;66(8):1544‐1556.
Ying W, Fu W, Lee YS, Olefsky JM. The role of macrophages in obesity‐associated islet inflammation and β‐cell abnormalities. Nat Rev Endocrinol. 2020;16(2):81‐90.
Templin AT, Samarasekera T, Meier DT, et al. Apoptosis repressor with caspase recruitment domain ameliorates amyloid‐induced β‐cell apoptosis and JNK pathway activation. Diabetes. 2017;66(10):2636‐2645.
Kahn SE, D'Alessio DA, Schwartz MW, et al. Evidence of cosecretion of islet amyloid polypeptide and insulin by beta‐cells. Diabetes. 1990;39(5):634‐638.
Fernández MS. Human IAPP amyloidogenic properties and pancreatic β‐cell death. Cell Calcium. 2014;56(5):416‐427.
Butler AE, Janson J, Soeller WC, Butler PC. Increased beta‐cell apoptosis prevents adaptive increase in beta‐cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes. 2003;52(9):2304‐2314.
Casas S, Gomis R, Gribble FM, Altirriba J, Knuutila S, Novials A. Impairment of the ubiquitin‐proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta‐cell apoptosis. Diabetes. 2007;56(9):2284‐2294.
Westwell‐Roper C, Dai DL, Soukhatcheva G, et al. IL‐1 blockade attenuates islet amyloid polypeptide‐induced proinflammatory cytokine release and pancreatic islet graft dysfunction. J Immunol. 2011;187(5):2755‐2765.
Westwell‐Roper CY, Chehroudi CA, Denroche HC, Courtade JA, Ehses JA, Verchere CB. IL‐1 mediates amyloid‐associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice. Diabetologia. 2015;58(3):575‐585.
Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL‐1β in type 2 diabetes. Nat Immunol. 2010;11(10):897‐904.
Ebato C, Uchida T, Arakawa M, et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high‐fat diet. Cell Metab. 2008;8(4):325‐332.
Jung HS, Chung KW, Kim JW, et al. Loss of autophagy diminishes pancreatic β cell mass and function with resultant hyperglycemia. Cell Metab. 2008;8(4):318‐324.
Park K, Lim H, Kim J, et al. Lysosomal Ca2+‐mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β‐cells to metabolic stress. Nat Commun. 2022;13(1):1300.
Israeli T, Riahi Y, Garzon P, et al. Nutrient sensor mTORC1 regulates insulin secretion by modulating β‐cell autophagy. Diabetes. 2022;71(3):453‐469.
Goginashvili A, Zhang Z, Erbs E, et al. Insulin secretory granules control autophagy in pancreatic β cells. Science. 2015;347(6224):878‐882.
Blandino‐Rosano M, Barbaresso R, Jimenez‐Palomares M, et al. Loss of mTORC1 signalling impairs β‐cell homeostasis and insulin processing. Nat Commun. 2017;8(1):16014.
Bartolomé A, Kimura‐Koyanagi M, Asahara S‐I, et al. Pancreatic β‐cell failure mediated by mTORC1 hyperactivity and autophagic impairment. Diabetes. 2014;63(9):2996‐3008.
Zuber C, Fan J‐Y, Guhl B, Roth J. Misfolded proinsulin accumulates in expanded pre‐Golgi intermediates and endoplasmic reticulum subdomains in pancreatic beta cells of Akita mice. FASEB J. 2004;18(7):917‐919.
Riahi Y, Wikstrom JD, Bachar‐Wikstrom E, et al. Autophagy is a major regulator of beta cell insulin homeostasis. Diabetologia. 2016;59:1480‐1491.
Hoshino A, Ariyoshi M, Okawa Y, et al. Inhibition of p53 preserves parkin‐mediated mitophagy and pancreatic β‐cell function in diabetes. Proc Natl Acad Sci. 2014;111(8):3116‐3121.
Maamoun H, Abdelsalam SS, Zeidan A, Korashy HM, Agouni A. Endoplasmic reticulum stress: a critical molecular driver of endothelial dysfunction and cardiovascular disturbances associated with diabetes. Int J Mol Sci. 2019;20(7):1658.
Cui X, Feng J, Wei T, et al. Pancreatic alpha cell glucagon‐liver FGF21 axis regulates beta cell regeneration in a mouse model of type 2 diabetes. Diabetologia. 2023;66(3):535‐550.
Holst JJ, Holland W, Gromada J, et al. Insulin and glucagon: partners for life. Endocrinology. 2017;158(4):696‐701.
Jia Y, Liu Y, Feng L, Sun S, Sun G. Role of glucagon and its receptor in the pathogenesis of diabetes. Front Endocrinol (Lausanne). 2022;13:928016.
D'Alessio D. The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes Metab. 2011;13(Suppl 1):126‐132.
Longuet C, Robledo AM, Dean ED, et al. Liver‐specific disruption of the murine glucagon receptor produces α‐cell hyperplasia: evidence for a circulating α‐cell growth factor. Diabetes. 2013;62(4):1196‐1205.
Chung C‐H, Hao E, Piran R, Keinan E, Levine F. Pancreatic β‐cell neogenesis by direct conversion from mature α‐cells. Stem Cells. 2010;28(9):1630‐1638.
Sørensen H, Winzell MS, Brand CL, et al. Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta‐cell function. Diabetes. 2006;55(12):3463‐3469.
Gelling RW, Du XQ, Dichmann DS, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003;100(3):1438‐1443.
Ouhilal S, Vuguin P, Cui L, et al. Hypoglycemia, hyperglucagonemia, and fetoplacental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance. Am J Physiol Endocrinol Metab. 2012;302(5):E522‐E531.
Chen Z, Yang L, Liu Y, Huang P, Song H, Zheng P. The potential function and clinical application of FGF21 in metabolic diseases. Front Pharmacol. 2022;13:1089214.
Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18(3):333‐340.
Kharitonenkov A, Beals JM, Micanovic R, et al. Rational design of a fibroblast growth factor 21‐based clinical candidate, LY2405319. PLoS One. 2013;8(3):e58575.
Le CT, Nguyen G, Park SY, Choi DH, Cho E‐H. LY2405319, An analog of fibroblast growth factor 21 ameliorates α‐smooth muscle Actin production through inhibition of the succinate‐G‐protein couple receptor 91 (GPR91) pathway in mice. PLoS One. 2018;13(2):e0192146.
Weng Y, Chabot JR, Bernardo B, et al. Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF‐05231023 in diet‐induced obese and leptin‐deficient obese mice. PLoS One. 2015;10(3):e0119104.
Wente W, Efanov AM, Brenner M, et al. Fibroblast growth factor‐21 improves pancreatic beta‐cell function and survival by activation of extracellular signal‐regulated kinase 1/2 and Akt signaling pathways. Diabetes. 2006;55(9):2470‐2478.
Aguayo‐Mazzucato C, van Haaren M, Mruk M, et al. β cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 2017;25(4):898‐910.
Antal B, McMahon LP, Sultan SF, et al. Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK biobank and meta‐analyses. Elife. 2022;11:e73138.
Narasimhan A, Flores RR, Robbins PD, Niedernhofer LJ. Role of cellular senescence in type II diabetes. Endocrinology. 2021;162(10):bqab136.
López‐Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243‐278.
Coppé J‐P, Desprez P‐Y, Krtolica A, Campisi J. The senescence‐associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99‐118.
Iwasaki K, Lalani B, Kahng J, et al. Decreased IGF1R attenuates senescence and improves function in pancreatic β‐cells. Front Endocrinol (Lausanne). 2023;14:1203534.
Pal D, Dasgupta S, Kundu R, et al. Fetuin‐A acts as an endogenous ligand of TLR4 to promote lipid‐induced insulin resistance. Nat Med. 2012;18(8):1279‐1285.
Haukeland JW, Dahl TB, Yndestad A, et al. Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies. Eur J Endocrinol. 2012;166(3):503‐510.
Brown ML, Schneyer AL. Emerging roles for the TGFbeta family in pancreatic beta‐cell homeostasis. Trends Endocrinol Metab. 2010;21(7):441‐448.
Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616‐630.
Wu H, Mezghenna K, Marmol P, et al. Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands. Diabetologia. 2014;57(1):148‐156.
Gerst F, Kemter E, Lorza‐Gil E, et al. The hepatokine fetuin‐A disrupts functional maturation of pancreatic beta cells. Diabetologia. 2021;64(6):1358‐1374.
Shen X, Yang L, Yan S, et al. Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti‐lipotoxicity. Mol Cell Endocrinol. 2015;412:1‐11.
Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta‐cells are formed by self‐duplication rather than stem‐cell differentiation. Nature. 2004;429(6987):41‐46.
Rhodes CJ. Type 2 diabetes—a matter of beta—cell life and death? Science. 2005;307(5708):380‐384.
Ackermann AM, Gannon M. Molecular regulation of pancreatic beta‐cell mass development, maintenance, and expansion. J Mol Endocrinol. 2007;38(1–2):193‐206.
Inaishi J, Saisho Y. Beta‐cell mass in obesity and type 2 diabetes, and its relation to pancreas fat: a mini‐review. Nutrients. 2020;12(12):3846.
Shrivastava V, Lee M, Lee D, et al. Beta cell adaptation to pregnancy requires prolactin action on both beta and non‐beta cells. Sci Rep. 2021;11(1):10372.
Regazzi R, Dalle S, Abderrahmani A. Compensatory mechanisms of pancreatic beta cells: insights into the therapeutic perspectives for diabetes. J Diabetes Res. 2014;2014:217387.
Imai J, Oka Y, Katagiri H. Identification of a novel mechanism regulating β‐cell mass: neuronal relay from the liver to pancreatic β‐cells. Islets. 2009;1(1):75‐77.
Mahmoudi‐Aznaveh A, Tavoosidana G, Najmabadi H, Azizi Z, Ardestani A. The liver‐derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance. Front Endocrinol (Lausanne). 2023;14:1303930.
Xitong D, Xiaorong Z. Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases. Gene. 2016;575(2):377‐384.
Castaño C, Novials A, Párrizas M. Exosomes and diabetes. Diabetes Metab Res Rev. 2019;35(3):e3107.
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7(2):85‐96.
Tuttle RL, Gill NS, Pugh W, et al. Regulation of pancreatic β‐cell growth and survival by the serine/threonine protein kinase Akt1/PKBα. Nat Med. 2001;7(10):1133‐1137.
Assmann A, Ueki K, Winnay JN, Kadowaki T, Kulkarni RN. Glucose effects on beta‐cell growth and survival require activation of insulin receptors and insulin receptor substrate 2. Mol Cell Biol. 2009;29(11):3219‐3228.
Manell E, Puuvuori E, Svensson A, et al. Exploring the GLP‐1–GLP‐1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography. BMJ Open Diabetes Res Care. 2021;9(1):e002083.
Tomas A, Jones B, Leech C. New insights into Beta‐cell GLP‐1 receptor and cAMP signaling. J Mol Biol. 2020;432(5):1347‐1366.
Thompson A, Stephens JW, Bain SC, Kanamarlapudi V. Molecular characterisation of small molecule agonists effect on the human glucagon like peptide‐1 receptor internalisation. PLoS One. 2016;11(4):e0154229.
Holz GG. Epac: a new cAMP‐binding protein in support of glucagon‐like peptide‐1 receptor‐mediated signal transduction in the pancreatic beta‐cell. Diabetes. 2004;53(1):5‐13.
Kim S‐J, Nian C, Widenmaier S, McIntosh CHS. Glucose‐dependent insulinotropic polypeptide‐mediated up‐regulation of beta‐cell antiapoptotic Bcl‐2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP‐responsive CREB coactivator 2. Mol Cell Biol. 2008;28(5):1644‐1656.
Guo K‐M, Li W, Wang Z‐H, He L‐C, Feng Y, Liu H‐S. Low‐dose aspirin inhibits trophoblast cell apoptosis by activating the CREB/Bcl‐2 pathway in pre‐eclampsia. Cell Cycle. 2022;21(21):2223‐2238.
El K, Gray SM, Capozzi ME, et al. GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells. Sci Adv. 2021;7(11):eabf1948.
Ceperuelo‐Mallafré V, Duran X, Pachón G, et al. Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance. J Clin Endocrinol Metab. 2014;99(5):E908‐E919.
Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17(6):819‐837.
Seino Y, Fukushima M, Yabe D. GIP and GLP‐1, the two incretin hormones: similarities and differences. J Diabetes Investig. 2010;1:1‐2.
Kang G, Chepurny OG, Holz GG. cAMP‐regulated guanine nucleotide exchange factor II (Epac2) mediates Ca2+‐induced Ca2+ release in INS‐1 pancreatic beta‐cells. J Physiol. 2001;536(Pt 2):375‐385.
Kim S‐J, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CHS. Glucose‐dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta‐cell survival is dependent upon phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down‐regulation of Bax expression. J Biol Chem. 2005;280(23):22297‐22307.
Gregory RA, Tracy HJ. The constitution and properties of two GASTRINS extracted from hog antral mucosa. Gut. 1964;5(2):103‐114.
Gregory RA, Tracy HJ. Isolation of two "big gastrins" from Zollinger‐Ellison tumour tissue. Lancet. 1972;2(7781):797‐799.
Rehfeld JF, Hansen CP, Johnsen AH. Post‐poly(Glu) cleavage and degradation modified by O‐sulfated tyrosine: a novel post‐translational processing mechanism. EMBO J. 1995;14(2):389‐396.
Rehfeld JF. The new biology of gastrointestinal hormones. Physiol Rev. 1998;78(4):1087‐1108.
Brand SJ, Andersen BN, Rehfeld JF. Complete tyrosine‐O‐sulphation of gastrin in neonatal rat pancreas. Nature. 1984;309(5967):456‐458.
Fakhry J, Wang J, Martins P, et al. Distribution and characterisation of CCK containing enteroendocrine cells of the mouse small and large intestine. Cell Tissue Res. 2017;369(2):245‐253.
Zhang X, Grosfeld A, Williams E, et al. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism. FASEB J. 2019;33(6):7126‐7142.
Rehfeld JF, Friis‐Hansen L, Goetze JP, Hansen TVO. The biology of cholecystokinin and gastrin peptides. Curr Top Med Chem. 2007;7(12):1154‐1165.
Kopin AS, Lee YM, McBride EW, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A. 1992;89(8):3605‐3609.
Wank SA, Harkins R, Jensen RT, Shapira H, de Weerth A, Slattery T. Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. Proc Natl Acad Sci U S A. 1992;89(7):3125‐3129.
Téllez N, Montanya E. Gastrin induces ductal cell dedifferentiation and β‐cell neogenesis after 90% pancreatectomy. J Endocrinol. 2014;223(1):67‐78.
Suarez‐Pinzon WL, Power RF, Yan Y, Wasserfall C, Atkinson M, Rabinovitch A. Combination therapy with glucagon‐like peptide‐1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes. 2008;57(12):3281‐3288.
Matson CA, Reid DF, Ritter RC. Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion. Am J Physiol Regul Integr Comp Physiol. 2002;282(5):R1368‐R1373.
Irwin N, Montgomery IA, Moffett RC, Flatt PR. Chemical cholecystokinin receptor activation protects against obesity‐diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. Biochem Pharmacol. 2013;85(1):81‐91.
Lavine JA, Kibbe CR, Baan M, et al. Cholecystokinin expression in the β‐cell leads to increased β‐cell area in aged mice and protects from streptozotocin‐induced diabetes and apoptosis. Am J Physiol Endocrinol Metab. 2015;309(10):E819‐E828.
Kim HT, Desouza AH, Umhoefer H, et al. Cholecystokinin attenuates β‐cell apoptosis in both mouse and human islets. Transl Res. 2022;243:1‐13.
Diaz‐Garrido N, Cordero C, Olivo‐Martinez Y, Badia J, Baldomà L. Cell‐to‐cell communication by host‐released extracellular vesicles in the gut: implications in health and disease. Int J Mol Sci. 2021;22(4):2213.
Baghaei K, Tokhanbigli S, Asadzadeh H, Nmaki S, Reza Zali M, Hashemi SM. Exosomes as a novel cell‐free therapeutic approach in gastrointestinal diseases. J Cell Physiol. 2019;234(7):9910‐9926.
Yang S, Cao J, Wang Y, et al. Small intestinal endocrine cell derived exosomal ACE2 protects islet β‐cell function by inhibiting the activation of NLRP3 inflammasome and reducing β‐cell pyroptosis. Int J Nanomedicine. 2024;19:4957‐4976.
Yao Q, Yu Z, Meng Q, et al. The role of small intestinal bacterial overgrowth in obesity and its related diseases. Biochem Pharmacol. 2023;212:115546.
He J, Zhang P, Shen L, et al. Short‐chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci. 2020;21(17):6356.
Canfora EE, Jocken JW, Blaak EE. Short‐chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11(10):577‐591.
Hu S, Kuwabara R, de Haan BJ, Smink AM, de Vos P. Acetate and butyrate improve β‐cell metabolism and mitochondrial respiration under oxidative stress. Int J Mol Sci. 2020;21(4):1542.
Cui J, Ramesh G, Wu M, et al. Butyrate‐producing bacteria and insulin homeostasis: the microbiome and insulin longitudinal evaluation study (MILES). Diabetes. 2022;71(11):2438‐2446.
Pingitore A, Chambers ES, Hill T, et al. The diet‐derived short chain fatty acid propionate improves beta‐cell function in humans and stimulates insulin secretion from human islets in vitro. Diabetes Obes Metab. 2017;19(2):257‐265.
Sun M, Wu W, Liu Z, Cong Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J Gastroenterol. 2017;52(1):1‐8.
Zhang X, Guseinov A‐A, Jenkins L, et al. Structural basis for the ligand recognition and signaling of free fatty acid receptors. Sci Adv. 2024;10(2):eadj2384.
Husted AS, Trauelsen M, Rudenko O, Hjorth SA, Schwartz TW. GPCR‐mediated signaling of metabolites. Cell Metab. 2017;25(4):777‐796.
Tang C, Ahmed K, Gille A, et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med. 2015;21(2):173‐177.
Teyani R, Moniri NH. Gut feelings in the islets: the role of the gut microbiome and the FFA2 and FFA3 receptors for short chain fatty acids on β‐cell function and metabolic regulation. Br J Pharmacol. 2023;180(24):3113‐3129.
Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85‐97.
Vallianou NG, Stratigou T, Tsagarakis S. Microbiome and diabetes: where are we now? Diabetes Res Clin Pract. 2018;146:111‐118.
Scheithauer TPM, Herrema H, Yu H, et al. Gut‐derived bacterial flagellin induces beta‐cell inflammation and dysfunction. Gut Microbes. 2022;14(1):2111951.
Gewirtz AT, Simon PO, Schmitt CK, et al. Salmonella typhimurium translocates flagellin across intestinal epithelia, inducing a proinflammatory response. J Clin Invest. 2001;107(1):99‐109.
Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE. Diabetes and apoptosis: lipotoxicity. Apoptosis. 2009;14(12):1484‐1495.
Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121(6):2094‐2101.
Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36(7):461‐470.
Lo JC, Ljubicic S, Leibiger B, et al. Adipsin is an adipokine that improves β cell function in diabetes. Cell. 2014;158(1):41‐53.
Cook KS, Min HY, Johnson D, et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science. 1987;237(4813):402‐405.
Rosen BS, Cook KS, Yaglom J, et al. Adipsin and complement factor D activity: an immune‐related defect in obesity. Science. 1989;244(4911):1483‐1487.
Gómez‐Banoy N, Guseh JS, Li G, et al. Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans. Nat Med. 2019;25(11):1739‐1747.
Yamauchi T, Kamon J, Waki H, et al. The fat‐derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941‐946.
Ruiz M, Ståhlman M, Borén J, Pilon M. AdipoR1 and AdipoR2 maintain membrane fluidity in most human cell types and independently of adiponectin. J Lipid Res. 2019;60(5):995‐1004.
Kharroubi I, Rasschaert J, Eizirik DL, Cnop M. Expression of adiponectin receptors in pancreatic beta cells. Biochem Biophys Res Commun. 2003;312(4):1118‐1122.
Tao C, Sifuentes A, Holland WL. Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic β cells and adipocytes. Best Pract Res Clin Endocrinol Metab. 2014;28(1):43‐58.
Munhoz AC, Serna JDC, Vilas‐Boas EA, et al. Adiponectin reverses β‐cell damage and impaired insulin secretion induced by obesity. Aging Cell. 2023;22(6):e13827.
Moon HU, Ha KH, Han SJ, Kim HJ, Kim DJ. The association of adiponectin and visceral fat with insulin resistance and β‐cell dysfunction. J Korean Med Sci. 2019;34(1):e7.
Lin P, Chen L, Li D, et al. Adiponectin reduces glucotoxicity‐induced apoptosis of INS‐1 rat insulin‐secreting cells on a microfluidic chip. Tohoku J Exp Med. 2009;217(1):59‐65.
Wang Y, Li Y, Qiao J, Li N, Qiao S. AMPK α1 mediates the protective effect of adiponectin against insulin resistance in INS‐1 pancreatic β cells. Cell Biochem Funct. 2019;37(8):625‐632.
Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G, Wheeler MB. Adiponectin‐induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion. J Biol Chem. 2010;285(44):33623‐33631.
Bjørbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 1997;272(51):32686‐32695.
Kulkarni RN, Wang ZL, Wang RM, et al. Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. J Clin Invest. 1997;100(11):2729‐2736.
Covey SD, Wideman RD, McDonald C, et al. The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metab. 2006;4(4):291‐302.
Morioka T, Asilmaz E, Hu J, et al. Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice. J Clin Invest. 2007;117(10):2860‐2868.
Myers MG. Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res. 2004;59:287‐304.
Seufert J, Kieffer TJ, Leech CA, et al. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab. 1999;84(2):670‐676.
Frühbeck G. Intracellular signalling pathways activated by leptin. Biochem J. 2006;393(Pt 1):7‐20.
Maedler K, Schulthess FT, Bielman C, et al. Glucose and leptin induce apoptosis in human beta‐cells and impair glucose‐stimulated insulin secretion through activation of c‐Jun N‐terminal kinases. FASEB J. 2008;22(6):1905‐1913.
Okuya S, Tanabe K, Tanizawa Y, Oka Y. Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis. Endocrinology. 2001;142(11):4827‐4830.
Brown JEP, Dunmore SJ. Leptin decreases apoptosis and alters BCL‐2: Bax ratio in clonal rodent pancreatic beta‐cells. Diabetes Metab Res Rev. 2007;23(6):497‐502.
López‐Bermejo A, Chico‐Julià B, Fernàndez‐Balsells M, et al. Serum visfatin increases with progressive beta‐cell deterioration. Diabetes. 2006;55(10):2871‐2875.
Revollo JR, Körner A, Mills KF, et al. Nampt/PBEF/visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007;6(5):363‐375.
Brown JEP, Onyango DJ, Ramanjaneya M, et al. Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes‐related genes in mouse pancreatic beta‐cells. J Mol Endocrinol. 2010;44(3):171‐178.
Cheng Q, Dong W, Qian L, Wu J, Peng Y. Visfatin inhibits apoptosis of pancreatic β‐cell line, MIN6, via the mitogen‐activated protein kinase/phosphoinositide 3‐kinase pathway. J Mol Endocrinol. 2011;47(1):13‐21.
Tatemoto K, Hosoya M, Habata Y, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun. 1998;251(2):471‐476.
Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther. 2005;107(2):198‐211.
Daviaud D, Boucher J, Gesta S, et al. TNFalpha up‐regulates apelin expression in human and mouse adipose tissue. FASEB J. 2006;20(9):1528‐1530.
Boucher J, Masri B, Daviaud D, et al. Apelin, a newly identified adipokine up‐regulated by insulin and obesity. Endocrinology. 2005;146(4):1764‐1771.
Han S, Englander EW, Gomez GA, et al. Pancreatic islet APJ deletion reduces islet density and glucose tolerance in mice. Endocrinology. 2015;156(7):2451‐2460.
Guo L, Li Q, Wang W, et al. Apelin inhibits insulin secretion in pancreatic beta‐cells by activation of PI3‐kinase‐phosphodiesterase 3B. Endocr Res. 2009;34(4):142‐154.
Yang R‐Z, Huang Q, Xu A, et al. Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun. 2003;310(3):927‐935.
Brown JEP, Onyango DJ, Dunmore SJ. Resistin down‐regulates insulin receptor expression, and modulates cell viability in rodent pancreatic beta‐cells. FEBS Lett. 2007;581(17):3273‐3276.
Gao C‐l, Zhao D‐y, Qiu J, et al. Resistin induces rat insulinoma cell RINm5F apoptosis. Mol Biol Rep. 2009;36(7):1703‐1708.
Muse ED, Obici S, Bhanot S, et al. Role of resistin in diet‐induced hepatic insulin resistance. J Clin Invest. 2004;114(2):232‐239.
Nakata M, Okada T, Ozawa K, Yada T. Resistin induces insulin resistance in pancreatic islets to impair glucose‐induced insulin release. Biochem Biophys Res Commun. 2007;353(4):1046‐1051.
Park S, Hong SM, Sung SR, Jung HK. Long‐term effects of central leptin and resistin on body weight, insulin resistance, and beta‐cell function and mass by the modulation of hypothalamic leptin and insulin signaling. Endocrinology. 2008;149(2):445‐454.
Romere C, Duerrschmid C, Bournat J, et al. Asprosin, a fasting‐induced glucogenic protein hormone. Cell. 2016;165(3):566‐579.
O'Neill B, Simha V, Kotha V, Garg A. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am J Med Genet A. 2007;143A(13):1421‐1430.
Lee T, Yun S, Jeong JH, Jung TW. Asprosin impairs insulin secretion in response to glucose and viability through TLR4/JNK‐mediated inflammation. Mol Cell Endocrinol. 2019;486:96‐104.
Jung TW, Kim H‐C, Kim HU, et al. Asprosin attenuates insulin signaling pathway through PKCδ‐activated ER stress and inflammation in skeletal muscle. J Cell Physiol. 2019;234(11):20888‐20899.
Zummo FP, Krishnanda SI, Georgiou M, et al. Exendin‐4 stimulates autophagy in pancreatic β‐cells via the RAPGEF/EPAC‐Ca2+‐PPP3/calcineurin‐TFEB axis. Autophagy. 2022;18(4):799‐815.
Wang R, Hu W. Asprosin promotes β‐cell apoptosis by inhibiting the autophagy of β‐cell via AMPK‐mTOR pathway. J Cell Physiol. 2021;236(1):215‐221.
Zhang L‐S, Zhang Z‐S, Wu Y‐Z, et al. Activation of free fatty acid receptors, FFAR1 and FFAR4, ameliorates ulcerative colitis by promote fatty acid metabolism and mediate macrophage polarization. Int Immunopharmacol. 2024;130:111778.
Milligan G, Shimpukade B, Ulven T, Hudson BD. Complex pharmacology of free fatty acid receptors. Chem Rev. 2017;117(1):67‐110.
Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003;422(6928):173‐176.
Lewis B, Mancini M, Mattock M, Chait A, Fraser TR. Plasma triglyceride and fatty acid metabolism in diabetes mellitus. Eur J Clin Invest. 1972;2(6):445‐453.
Unger RH. Lipotoxicity in the pathogenesis of obesity‐dependent NIDDM. Genetic and clinical implications. Diabetes. 1995;44(8):863‐870.
Unger RH, Zhou YT, Orci L. Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci U S A. 1999;96(5):2327‐2332.
Brun T, Assimacopoulos‐Jeannet F, Corkey BE, Prentki M. Long‐chain fatty acids inhibit acetyl‐CoA carboxylase gene expression in the pancreatic beta‐cell line INS‐1. Diabetes. 1997;46(3):393‐400.
Acevedo N, Lozano A, Zakzuk J, et al. Cystatin from the helminth Ascaris lumbricoides upregulates mevalonate and cholesterol biosynthesis pathways and immunomodulatory genes in human monocyte‐derived dendritic cells. Front Immunol. 2024;15:1328401.
Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS. Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein‐1 in human and mouse organs and cultured cells. J Clin Invest. 1997;99(5):838‐845.
Yamashita T, Eto K, Okazaki Y, et al. Role of uncoupling protein‐2 up‐regulation and triglyceride accumulation in impaired glucose‐stimulated insulin secretion in a beta‐cell lipotoxicity model overexpressing sterol regulatory element‐binding protein‐1c. Endocrinology. 2004;145(8):3566‐3577.
Eitel K, Staiger H, Rieger J, et al. Protein kinase C delta activation and translocation to the nucleus are required for fatty acid‐induced apoptosis of insulin‐secreting cells. Diabetes. 2003;52(4):991‐997.
Shimabukuro M, Zhou YT, Levi M, Unger RH. Fatty acid‐induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A. 1998;95(5):2498‐2502.
Gerst F, Wagner R, Kaiser G, et al. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia. 2017;60(11):2240‐2251.
Stefan N, Sun Q, Fritsche A, et al. Impact of the adipokine adiponectin and the hepatokine fetuin‐A on the development of type 2 diabetes: prospective cohort‐ and cross‐sectional phenotyping studies. PLoS One. 2014;9(3):e92238.
Liu LF, Craig CM, Tolentino LL, et al. Adipose tissue macrophages impair preadipocyte differentiation in humans. PLoS One. 2017;12(2):e0170728.
Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin‐6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745‐E751.
Gerst F, Wagner R, Oquendo MB, et al. What role do fat cells play in pancreatic tissue? Mol Metab. 2019;25:1‐10.
Pal M, Febbraio MA, Lancaster GI. The roles of c‐Jun NH2‐terminal kinases (JNKs) in obesity and insulin resistance. J Physiol. 2016;594(2):267‐279.
Tenenbaum M, Plaisance V, Boutry R, et al. The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta‐cell proliferation during postnatal development. Cell Mol Life Sci. 2021;78(1):287‐298.
Ezanno H, Pawlowski V, Abdelli S, et al. JNK3 is required for the cytoprotective effect of exendin 4. J Diabetes Res. 2014;2014:814854.
Cardamone MD, Krones A, Tanasa B, et al. A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2. Mol Cell. 2012;46(1):91‐104.
Drareni K, Ballaire R, Barilla S, et al. GPS2 deficiency triggers maladaptive white adipose tissue expansion in obesity via HIF1A activation. Cell Rep. 2018;24(11):2957‐2971.e6.
Drareni K, Ballaire R, Alzaid F, et al. Adipocyte reprogramming by the transcriptional coregulator GPS2 impacts beta cell insulin secretion. Cell Rep. 2020;32(11):108141.
Huang‐Doran I, Zhang C‐Y, Vidal‐Puig A. Extracellular vesicles: novel mediators of cell communication in metabolic disease. Trends Endocrinol Metab. 2017;28(1):3‐18.
Gesmundo I, Pardini B, Gargantini E, et al. Adipocyte‐derived extracellular vesicles regulate survival and function of pancreatic β cells. JCI Insight. 2021;6(5):e141962.
Kulkarni RN, Mizrachi E‐B, Ocana AG, Stewart AF. Human β‐cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes. 2012;61(9):2205‐2213.
Javeed N, Her TK, Brown MR, et al. Pro‐inflammatory β cell small extracellular vesicles induce β cell failure through activation of the CXCL10/CXCR3 axis in diabetes. Cell Rep. 2021;36(8):109613.
Ying W, Riopel M, Bandyopadhyay G, et al. Adipose tissue macrophage‐derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171(2):372‐384.e12.
Meyerovich K, Ortis F, Allagnat F, Cardozo AK. Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. J Mol Endocrinol. 2016;57(1):R1‐R17.
Chan JY, Luzuriaga J, Maxwell EL, West PK, Bensellam M, Laybutt DR. The balance between adaptive and apoptotic unfolded protein responses regulates β‐cell death under ER stress conditions through XBP1, CHOP and JNK. Mol Cell Endocrinol. 2015;413:189‐201.
Deng Z‐b, Poliakov A, Hardy RW, et al. Adipose tissue exosome‐like vesicles mediate activation of macrophage‐induced insulin resistance. Diabetes. 2009;58(11):2498‐2505.
Hargreaves M, Spriet LL. Skeletal muscle energy metabolism during exercise. Nat Metab. 2020;2(9):817‐828.
Joost H‐G, Bell GI, Best JD, et al. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab. 2002;282(4):E974‐E976.
Marette A, Burdett E, Douen A, Vranic M, Klip A. Insulin induces the translocation of GLUT4 from a unique intracellular organelle to transverse tubules in rat skeletal muscle. Diabetes. 1992;41(12):1562‐1569.
Taylor EB, An D, Kramer HF, et al. Discovery of TBC1D1 as an insulin‐, AICAR‐, and contraction‐stimulated signaling nexus in mouse skeletal muscle. J Biol Chem. 2008;283(15):9787‐9796.
Kaddai V, Le Marchand‐Brustel Y, Cormont M. Rab proteins in endocytosis and Glut4 trafficking. Acta Physiol (Oxf). 2008;192(1):75‐88.
Ellingsgaard H, Hauselmann I, Schuler B, et al. Interleukin‐6 enhances insulin secretion by increasing glucagon‐like peptide‐1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481‐1489.
Rhode A, Pauza ME, Barral AM, et al. Islet‐specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development. J Immunol. 2005;175(6):3516‐3524.
Rutti S, Arous C, Schvartz D, et al. Fractalkine (CX3CL1), a new factor protecting β‐cells against TNFα. Mol Metab. 2014;3(7):731‐741.
Barlow J, Jensen VH, Jastroch M, Affourtit C. Palmitate‐induced impairment of glucose‐stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets. Biochem J. 2016;473(4):487‐496.
Henquin J‐C. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49(11):1751‐1760.
Jalabert A, Vial G, Guay C, et al. Exosome‐like vesicles released from lipid‐induced insulin‐resistant muscles modulate gene expression and proliferation of beta recipient cells in mice. Diabetologia. 2016;59:1049‐1058.
Fred RG, Bang‐Berthelsen CH, Mandrup‐Poulsen T, Grunnet LG, Welsh N. High glucose suppresses human islet insulin biosynthesis by inducing miR‐133a leading to decreased polypyrimidine tract binding protein‐expression. PLoS One. 2010;5(5):e10843.
Vinod M, Patankar JV, Sachdev V, et al. MiR‐206 is expressed in pancreatic islets and regulates glucokinase activity. Am J Physiol Endocrinol Metab. 2016;311(1):E175‐E185.
Fukumoto S, Martin TJ. Bone as an endocrine organ. Trends Endocrinol Metab. 2009;20(5):230‐236.
Bisby MA. Axonal transport of labeled protein and regeneration rate in nerves of streptozocin‐diabetic rats. Exp Neurol. 1980;69(1):74‐84.
Oury F, Ferron M, Huizhen W, et al. Osteocalcin regulates murine and human fertility through a pancreas‐bone‐testis axis. J Clin Invest. 2013;123(6):2421‐2433.
Wei J, Hanna T, Suda N, Karsenty G, Ducy P. Osteocalcin promotes β‐cell proliferation during development and adulthood through Gprc6a. Diabetes. 2014;63(3):1021‐1031.
Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130(3):456‐469.
Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild‐type mice. Proc Natl Acad Sci U S A. 2008;105(13):5266‐5270.
Ferron M, Wei J, Yoshizawa T, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142(2):296‐308.
Nagao M, Esguerra JLS, Asai A, et al. Potential protection against type 2 diabetes in obesity through lower CD36 expression and improved exocytosis in β‐cells. Diabetes. 2020;69(6):1193‐1205.
Spaeth JM, Hunter CS, Bonatakis L, et al. The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia. 2015;58(8):1836‐1844.
Kaneko K, Ueki K, Takahashi N, et al. Class IA phosphatidylinositol 3‐kinase in pancreatic β cells controls insulin secretion by multiple mechanisms. Cell Metab. 2010;12(6):619‐632.
Zhang Y, Li L, Zhang Y, Yan S, Huang L. Improvement of lipotoxicity‐induced islet β cellular insulin secretion disorder by osteocalcin. J Diabetes Res. 2022;2022:3025538.
Kover K, Yan Y, Tong PY, et al. Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions. Biochem Biophys Res Commun. 2015;462(1):21‐26.
Liu J, Li D, Wu X, Dang L, Lu A, Zhang G. Bone‐derived exosomes. Curr Opin Pharmacol. 2017;34:64‐69.
Nakayama S, Uchida T, Choi J, et al. Impact of whole body irradiation and vascular endothelial growth factor‐A on increased beta cell mass after bone marrow transplantation in a mouse model of diabetes induced by streptozotocin. Diabetologia. 2009;52:115‐124.
Tsukita S, Yamada T, Takahashi K, et al. MicroRNAs 106b and 222 improve hyperglycemia in a mouse model of insulin‐deficient diabetes via pancreatic β‐cell proliferation. EBioMedicine. 2017;15:163‐172.
Lener T, Gimona M, Aigner L, et al. Applying extracellular vesicles based therapeutics in clinical trials–an ISEV position paper. J Extracell Vesicles. 2015;4(1):30087.
Shigemoto‐Kuroda T, Oh JY, Kim D‐k, et al. MSC‐derived extracellular vesicles attenuate immune responses in two autoimmune murine models: type 1 diabetes and uveoretinitis. Stem Cell Reports. 2017;8(5):1214‐1225.
Rodriguez‐Diaz R, Abdulreda MH, Formoso AL, et al. Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab. 2011;14(1):45‐54.
Molina J, Rodriguez‐Diaz R, Fachado A, Jacques‐Silva MC, Berggren P‐O, Caicedo A. Control of insulin secretion by cholinergic signaling in the human pancreatic islet. Diabetes. 2014;63(8):2714‐2726.
Liu B, Chen F. Neuropeptide Y promotes hepatic apolipoprotein A1 synthesis and secretion through neuropeptide Y Y5 receptor. Peptides. 2022;154:170824.
Cho YR, Kim CW. Neuropeptide Y promotes beta‐cell replication via extracellular signal‐regulated kinase activation. Biochem Biophys Res Commun. 2004;314(3):773‐780.
Tang S‐C, Shen C‐N, Lin P‐Y, et al. Pancreatic neuro‐insular network in young mice revealed by 3D panoramic histology. Diabetologia. 2018;61(1):158‐167.
Ahrén B, Veith RC, Paquette TL, Taborsky GJ. Sympathetic nerve stimulation versus pancreatic norepinephrine infusion in the dog: 2. Effects on basal release of somatostatin and pancreatic polypeptide. Endocrinology. 1987;121(1):332‐339.
Dolenšek J, Rupnik MS, Stožer A. Structural similarities and differences between the human and the mouse pancreas. Islets. 2015;7(1):e1024405.
Rosengren AH, Jokubka R, Tojjar D, et al. Overexpression of alpha2A‐adrenergic receptors contributes to type 2 diabetes. Science. 2010;327(5962):217‐220.
Papazoglou I, Lee J‐H, Cui Z, et al. A distinct hypothalamus‐to‐β cell circuit modulates insulin secretion. Cell Metab. 2022;34(2):285‐298.e7.

ZSQY7352021007 The "735" Project of the Seventh Affiliated Hospital, Sun Yat-sen University

Keywords: T2DM; crosstalk; organ; pancreatic β cells; tissue

Date Created: 20240723 Date Completed: 20240918 Latest Revision: 20240918

20240918

10.1111/dom.15787

39044309