Acknowledgement
This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIT) (RS-2023-00261247, RS-2023-00223069) and the Ewha Womans University Research Grant of 2022.
References
- Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 2019;157:107843
- Iannuzzi JP, King JA, Leong JH, et al. Global incidence of acute pancreatitis is increasing over time: a systematic review and meta-analysis. Gastroenterology 2022;162:122-134
- Park W, Chawla A, O'Reilly EM. Pancreatic cancer: a review. JAMA 2021;326:851-862
- Redondo MJ, Balasubramanyam A. Toward an improved classification of type 2 diabetes: lessons from research into the heterogeneity of a complex disease. J Clin Endocrinol Metab 2021;106:e4822-e4833
- Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA 2023;330:1795-1797
- Patel F, Gan A, Chang K, Vega KJ. Acute pancreatitis in a patient taking semaglutide. Cureus 2023;15:e43773
- Abdulreda MH, Caicedo A, Berggren PO. A natural body window to study human pancreatic islet cell function and survival. CellR4 Repair Replace Regen Reprogram 2013;1:111-122
- Dolensek J, Rupnik MS, Stozer A. Structural similarities and differences between the human and the mouse pancreas. Islets 2015;7:e1024405
- Furman BL. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc 2021;1:e78
- Yang H, Wright JR Jr. Human beta cells are exceedingly resistant to streptozotocin in vivo. Endocrinology 2002;143:2491-2495
- Nemeth BC, Wartmann T, Halangk W, Sahin-Toth M. Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loop. J Biol Chem 2013;288:24049-24062
- Cala G, Sina B, De Coppi P, Giobbe GG, Gerli MFM. Primary human organoids models: current progress and key milestones. Front Bioeng Biotechnol 2023;11:1058970
- Fasolino M, Schwartz GW, Patil AR, et al. Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes. Nat Metab 2022;4:284-299
- Millman JR, Xie C, Van Dervort A, Gurtler M, Pagliuca FW, Melton DA. Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat Commun 2016;7:11463
- Boj SF, Hwang CI, Baker LA, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 2015;160:324-338
- Huang L, Holtzinger A, Jagan I, et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat Med 2015;21:1364-1371
- Seino T, Kawasaki S, Shimokawa M, et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 2018;22:454-467.e6
- Loomans CJM, Williams Giuliani N, Balak J, et al. Expansion of adult human pancreatic tissue yields organoids harboring progenitor cells with endocrine differentiation potential. Stem Cell Reports 2018;10:712-724
- Bonfanti P, Nobecourt E, Oshima M, et al. Ex vivo expansion and differentiation of human and mouse fetal pancreatic progenitors are modulated by epidermal growth factor. Stem Cells Dev 2015;24:1766-1778
- Adolph TE, Mayr L, Grabherr F, Schwarzler J, Tilg H. Pancreas-microbiota cross talk in health and disease. Annu Rev Nutr 2019;39:249-266
- Puri S, Folias AE, Hebrok M. Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease. Cell Stem Cell 2015;16:18-31
- Roder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016;48:e219
- Brissova M, Fowler MJ, Nicholson WE, et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 2005;53:1087-1097
- Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut 2005;54(Suppl 6):vi1-vi28
- Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep 2007;9:116-122
- Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, Maitra A. Pancreatic cancer: advances and challenges. Cell 2023;186:1729-1754
- Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48
- Pantaleo A, Forte G, Fasano C, et al. Understanding the genetic landscape of pancreatic ductal adenocarcinoma to support personalized medicine: a systematic review. Cancers (Basel) 2023;16:56
- Ying H, Dey P, Yao W, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2016;30:355-385
- Leung PS. Common pancreatic disease. Adv Exp Med Biol 2010;690:29-51
- Weiss FU, Laemmerhirt F, Lerch MM. Etiology and risk factors of acute and chronic pancreatitis. Visc Med 2019;35:73-81
- Mitra V, Munnelly S, Grammatikopoulos T, et al. The top 10 research priorities for pancreatitis: findings from a James Lind Alliance priority setting partnership. Lancet Gastroenterol Hepatol 2023;8:780-782
- Bellin MD, Whitcomb DC, Abberbock J, et al. Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the United States. Am J Gastroenterol 2017;112:1457-1465
- Kleeff J, Whitcomb DC, Shimosegawa T, et al. Chronic pancreatitis. Nat Rev Dis Primers 2017;3:17060
- Ma DM, Dong XW, Han X, et al. Pancreatitis and pancreatic cancer risk. Technol Cancer Res Treat 2023;22:15330338231164875
- Beltrand J, Busiah K, Vaivre-Douret L, et al. Neonatal diabetes mellitus. Front Pediatr 2020;8:540718
- Urakami T. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. Diabetes Metab Syndr Obes 2019;12:1047-1056
- Tshivhase A, Matsha T, Raghubeer S. Diagnosis and treatment of MODY: an updated mini review. Appl Sci 2021;11:9436
- Nkonge KM, Nkonge DK, Nkonge TN. The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY). Clin Diabetes Endocrinol 2020;6:20
- Ebrahim N, Shakirova K, Dashinimaev E. PDX1 is the cornerstone of pancreatic β-cell functions and identity. Front Mol Biosci 2022;9:1091757
- Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes 2010;59:2326-2331
- Beinsteiner B, Billas IML, Moras D. Structural insights into the HNF4 biology. Front Endocrinol (Lausanne) 2023;14:1197063
- Delvecchio M, Pastore C, Giordano P. Treatment options for MODY patients: a systematic review of literature. Diabetes Ther 2020;11:1667-1685
- Hulin J, Skopkova M, Valkovicova T, et al. Clinical implications of the glucokinase impaired function - GCK MODY today. Physiol Res 2020;69:995-1011
- Zhao Q, Ding L, Yang Y, et al. Clinical characteristics of patients with HNF1-alpha MODY: a literature review and retrospective chart review. Front Endocrinol (Lausanne) 2022;13:900489
- Shepherd M, Ellis I, Ahmad AM, et al. Predictive genetic testing in maturity-onset diabetes of the young (MODY). Diabet Med 2001;18:417-421
- Francis Y, Tiercelin C, Alexandre-Heyman L, Larger E, Dubois-Laforgue D. HNF1B-MODY masquerading as type 1 diabetes: a pitfall in the etiological diagnosis of diabetes. J Endocr Soc 2022;6:bvac087
- Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, et al. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci USA 2005;102:4807-4812
- Johansson BB, Fjeld K, El Jellas K, et al. The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. Pancreatology. 2018;18:12-19
- Nelson HA, Johnson LM. Hereditary pancreatitis in a young adult: acute to chronic. Clin Biochem 2021;98:78-80
- Rebours V, Boutron-Ruault MC, Schnee M, et al. The natural history of hereditary pancreatitis: a national series. Gut 2009;58:97-103
- Rebours V, Boutron-Ruault MC, Schnee M, et al. Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol 2008;103:111-119
- Piseddu I, Vielhauer J, Mayerle J. Genetic testing in acute and chronic pancreatitis. Curr Treat Options Gastro 2022;20:429-444
- Rinderknecht H. Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig Dis Sci 1986;31:314-321
- Hegyi E, Sahin-Toth M. Genetic risk in chronic pancreatitis: the trypsin-dependent pathway. Dig Dis Sci 2017;62:1692-1701
- Girodon E, Rebours V, Chen JM, et al. Clinical interpretation of PRSS1 variants in patients with pancreatitis. Clin Res Hepatol Gastroenterol 2021;45:101497
- Nemeth BC, Sahin-Toth M. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2014;306:G466-G473
- Rowen L, Koop BF, Hood L. The complete 685-kilobase DNA sequence of the human beta T cell receptor locus. Science 1996;272:1755-1762
- Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14:141-145
- Gorry MC, Gabbaizedeh D, Furey W, et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997;113:1063-1068
- Teich N, Mossner J, Keim V. Mutations of the cationic trypsinogen in hereditary pancreatitis. Hum Mutat 1998;12:39-43
- Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2:252-261
- Whitcomb DC, Preston RA, Aston CE, et al. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 1996;110:1975-1980
- Solomon S, Gelrud A, Whitcomb DC. Low penetrance pancreatitis phenotype in a Venezuelan kindred with a PRSS1 R122H mutation. JOP 2013;14:187-189
- Szmola R, Sahin-Toth M. Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht's enzyme Y. Proc Natl Acad Sci USA 2007;104:11227-11232
- Wartmann T, Mayerle J, Kahne T, et al. Cathepsin L inactivates human trypsinogen, whereas cathepsin L-deletion reduces the severity of pancreatitis in mice. Gastroenterology 2010;138:726-737
- Szabo A, Sahin-Toth M. Determinants of chymotrypsin C cleavage specificity in the calcium-binding loop of human cationic trypsinogen. FEBS J 2012;279:4283-4292
- Szabo A, Sahin-Toth M. Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. J Biol Chem 2012;287:20701-20710
- Geisz A, Hegyi P, Sahin-Toth M. Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants. FEBS J 2013;280:2888-2899
- Joergensen MT, Geisz A, Brusgaard K, et al. Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis. Pancreas 2011;40:540-546
- Chen JM, Kukor Z, Le Marechal C, et al. Evolution of trypsinogen activation peptides. Mol Biol Evol 2003;20:1767-1777
- Nemoda Z, Sahin-Toth M. The tetra-aspartate motif in the activation peptide of human cationic trypsinogen is essential for autoactivation control but not for enteropeptidase recognition. J Biol Chem 2005;280:29645-29652
- LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol 2011;27:467-474
- Lasson A, Borgstrom A, Ohlsson K. Elevated pancreatic secretory trypsin inhibitor levels during severe inflammatory disease, renal insufficiency, and after various surgical procedures. Scand J Gastroenterol 1986;21:1275-1280
- Ogawa M. Pancreatic secretory trypsin inhibitor as an acute phase reactant. Clin Biochem 1988;21:19-25
- Pfutzer RH, Barmada MM, Brunskill AP, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000;119:615-623
- Aoun E, Muddana V, Papachristou GI, Whitcomb DC. SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event. Am J Gastroenterol 2010;105:446-451
- Kume K, Masamune A, Kikuta K, Shimosegawa T. [-215 G>A; IVS3+2T>C] mutation in the SPINK1 gene causes exon 3 skipping and loss of the trypsin binding site. Gut 2006;55:1214
- Kiraly O, Wartmann T, Sahin-Toth M. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut 2007;56:1433-1438
- Kiraly O, Boulling A, Witt H, et al. Signal peptide variants that impair secretion of pancreatic secretory trypsin inhibitor (SPINK1) cause autosomal dominant hereditary pancreatitis. Hum Mutat 2007;28:469-476
- Kereszturi E, Kiraly O, Sahin-Toth M. Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis. Gut 2009;58:545-549
- Boulling A, Le Marechal C, Trouve P, Raguenes O, Chen JM, Ferec C. Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene. Eur J Hum Genet 2007;15:936-942
- Threadgold J, Greenhalf W, Ellis I, et al. The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut 2002;50:675-681
- Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS One 2008;3:e2003
- Zhou J, Sahin-Toth M. Chymotrypsin C mutations in chronic pancreatitis. J Gastroenterol Hepatol 2011;26:1238-1246
- Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 2008;40:78-82
- Masson E, Chen JM, Scotet V, Le Marechal C, Ferec C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet 2008;123:83-91
- Beer S, Zhou J, Szabo A, et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut 2013;62:1616-1624
- Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 2013;45:1216-1220
- Nemeth BC, Orekhova A, Zhang W, et al. Novel p.K374E variant of CPA1 causes misfolding-induced hereditary pancreatitis with autosomal dominant inheritance. Gut 2020;69:790-792
- Schneider A, Larusch J, Sun X, et al. Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology 2011;140:162-171
- Pezzulo AA, Tang XX, Hoegger MJ, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 2012;487:109-113
- McMaster P. Bile studies after liver transplantation. Ann R Coll Surg Engl 1979;61:435-440
- Derichs N, Jin BJ, Song Y, Finkbeiner WE, Verkman AS. Hyperviscous airway periciliary and mucous liquid layers in cystic fibrosis measured by confocal fluorescence photobleaching. FASEB J 2011;25:2325-2332
- Chen JH, Stoltz DA, Karp PH, et al. Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Cell 2010;143:911-923
- Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc 2008;108:832-839
- Hegyi P, Wilschanski M, Muallem S, et al. CFTR: a new horizon in the pathomechanism and treatment of pancreatitis. Rev Physiol Biochem Pharmacol 2016;170:37-66
- Noone PG, Zhou Z, Silverman LM, Jowell PS, Knowles MR, Cohn JA. Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001;121:1310-1319
- Berke G, Gede N, Szadai L, et al. Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: a meta-analysis. PLoS One 2022;17:e0276397
- Liang G, Zhang Y. Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res 2013;23:49-69
- Jin W, Jiang W. Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells. Cell Regen 2022;11:24
- Duque M, Amorim JP, Bessa J. Ptf1a function and transcriptional cis-regulation, a cornerstone in vertebrate pancreas development. FEBS J 2022;289:5121-5136
- Schaffer AE, Freude KK, Nelson SB, Sander M. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell 2010;18:1022-1029
- Hogrebe NJ, Maxwell KG, Augsornworawat P, Millman JR. Generation of insulin-producing pancreatic β cells from multiple human stem cell lines. Nat Protoc 2021;16:4109-4143
- Pagliuca FW, Millman JR, Gurtler M, et al. Generation of functional human pancreatic β cells in vitro. Cell 2014;159:428-439
- Liang S, Zhao J, Baker RK, Tran E, Zhan L, Kieffer TJ. Differentiation of stem cell-derived pancreatic progenitors into insulin-secreting islet clusters in a multiwell-based static 3D culture system. Cell Rep Methods 2023;3:100466
- Veres A, Faust AL, Bushnell HL, et al. Charting cellular identity during human in vitro β-cell differentiation. Nature 2019;569:368-373
- Huang L, Desai R, Conrad DN, et al. Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids. Cell Stem Cell 2021;28:1090-1104.e6
- Simsek S, Zhou T, Robinson CL, et al. Modeling cystic fibrosis using pluripotent stem cell-derived human pancreatic ductal epithelial cells. Stem Cells Transl Med 2016;5:572-579
- Breunig M, Merkle J, Wagner M, et al. Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells. Cell Stem Cell 2021;28:1105-1124.e19
- Ng NHJ, Jasmen JB, Lim CS, et al. HNF4A haploinsufficiency in MODY1 abrogates liver and pancreas differentiation from patient-derived induced pluripotent stem cells. iScience 2019;16:192-205
- Cujba AM, Alvarez-Fallas ME, Pedraza-Arevalo S, et al. An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function. Cell Rep 2022;38:110425
- Kim J, Hoffman JP, Alpaugh RK, et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep 2013;3:2088-2099
- Hohwieler M, Illing A, Hermann PC, et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut 2017;66:473-486
- Shapiro AMJ, Thompson D, Donner TW, et al. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep Med 2021;2:100466
- Ramzy A, Thompson DM, Ward-Hartstonge KA, et al. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 2021;28:2047-2061.e5
- Leite NC, Sintov E, Meissner TB, et al. Modeling type 1 diabetes in vitro using human pluripotent stem cells. Cell Rep 2020;32:107894