Background: Acute pancreatitis (AP) is a severe inflammation of the pancreas, marked by elevated enzyme levels, cellular inflammation, and necrosis. Recent studies emphasize the critical role of inflammation in AP progression. Tirzepatide, a multi-target agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, has demonstrated notable anti-inflammatory and metabolic benefits.
Methods: This study explores the therapeutic potential of Tirzepatide in pancreatitis induced by L-arginine in rats, focusing on enzymatic markers, cytokine profiles, oxidative stress, and histological outcomes. Over 27 days, rats were distributed into Control, Tirzepatide, L-Arginine, and L-Arginine + Tirzepatide groups, with the latter receiving L-Arginine to induce pancreatitis followed by Tirzepatide administration.
Results: L-Arginine significantly elevated serum amylase, lipase, and inflammatory mediators (IL-6, IL-4, and IL-10), alongside oxidative stress markers and histopathological deterioration. Conversely, the L-Arginine + Tirzepatide group exhibited reduced lipase and IL-6 levels, suppressed reactive oxygen species (ROS) generation, and enhanced anti-inflammatory cytokines IL-4 and IL-10. Histopathological analysis revealed reduced necrosis and tissue damage in the L-Arginine + Tirzepatide group compared to the L-Arginine group, indicating Tirzepatide's possible protective effects. Immunofluorescence studies further demonstrated increased p-Akt expression, supporting the role of Tirzepatide in cellular repair and recovery.
Conclusion: These findings highlight Tirzepatide's ability to mitigate pancreatic damage through antioxidant and anti-inflammatory mechanisms, underscoring its potential as a pharmacological agent for acute pancreatitis.
| [1] |
Teshima CW, Bridges RJ, Fedorak RN. Canadian digestive health foundation public impact series 5: pancreatitis in Canada. Incidence, prevalence, and direct and indirect economic impact. Can J Gastroenterol. 2012;26(8):544-545.
|
| [2] |
Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143(5):1179-1187.
|
| [3] |
Hyun JJ, Lee HS. Experimental models of pancreatitis. Clin Endosc. 2014;47(3):212-216.
|
| [4] |
Ko J, Cho J, Petrov MS. Low serum amylase, lipase, and trypsin as biomarkers of metabolic disorders: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2020;159:107974.
|
| [5] |
Yu JH, Kim H. Oxidative stress and inflammatory signaling in cerulein pancreatitis. World J Gastroenterol. 2014;20(46):17324-17329.
|
| [6] |
Rao SA, Kunte AR. Interleukin-6: an early predictive marker for severity of acute pancreatitis. Indian J Crit Care Med. 2017;21(7):424-428.
|
| [7] |
Inagaki T, Hoshino M, Hayakawa T, et al. Interleukin-6 is a useful marker for early prediction of the severity of acute pancreatitis. Pancreas. 1997;14(1):1-8.
|
| [8] |
Al-Qahtani AA, Alhamlan FS, Al-Qahtani AA. Pro-inflammatory and anti-inflammatory interleukins in infectious diseases: a comprehensive review. Trop Med Infect Dis. 2024;9(1):13.
|
| [9] |
Gea-Sorlí S, Closa D. Role of macrophages in the progression of acute pancreatitis. World J Gastrointest Pharmacol Ther. 2010;1(5):107-111.
|
| [10] |
Villalpando-Rodriguez GE, Gibson SB. Reactive oxygen species (ROS) regulates different types of cell death by acting as a rheostat. Oxidative Med Cell Longev. 2021;2021:9912436.
|
| [11] |
Yu JH, Lim JW, Kim H, Kim KH. NADPH oxidase mediates interleukin-6 expression in cerulein-stimulated pancreatic acinar cells. Int J Biochem Cell Biol. 2005;37(7):1458-1469.
|
| [12] |
Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress−activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes. 2003;52(1):1-8.
|
| [13] |
Tani S, Itoh H, Okabayashi Y, et al. New model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats. Dig Dis Sci. 1990;35(3):367-374.
|
| [14] |
Hegyi P, Rakonczay Z, Sári R, et al. L-arginine-induced experimental pancreatitis. World J Gastroenterol. 2004;10(14):2003-2009.
|
| [15] |
Yang X, Yao L, Fu X, et al. Experimental acute pancreatitis models: history, current status, and role in translational research. Front Physiol. 2020;11:614591.
|
| [16] |
Miao R, Fang X, Wei J, Wu H, Wang X, Tian J. Akt: a potential drug target for metabolic syndrome. Front Physiol. 2022;13:822333.
|
| [17] |
Matsuda S, Kobayashi M, Kitagishi Y. Roles for PI3K/AKT/PTEN pathway in cell signaling of nonalcoholic fatty liver disease. ISRN Endocrinol. 2013;2013:1-7.
|
| [18] |
Weichhart T, Saemann MD. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis. 2008;67(Suppl 3):iii70-iii74.
|
| [19] |
Saltiel AR. Insulin signaling in health and disease. J Clin Invest. 2021;131(1):e142241.
|
| [20] |
Altomare DA, Lyons GE, Mitsuuchi Y, Cheng JQ, Testa JR. Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin. Oncogene. 1998;16(18):2407-2411.
|
| [21] |
Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C. Akt signaling pathway in macrophage activation and M1/M2 polarization. J Immunol. 2017;198(3):1006-1014.
|
| [22] |
Zhao H, Wang L, Wei R, et al. Activation of glucagon-like peptide-1 receptor inhibits tumourigenicity and metastasis of human pancreatic cancer cells via PI3K/Akt pathway. Diabetes Obes Metab. 2014;16(9):850-860.
|
| [23] |
Chavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: a mini-review. Molecules. 2022;27(13):4315.
|
| [24] |
Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like Peptide-1-based therapies. Gastroenterology. 2011;141(1):150-156.
|
| [25] |
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of Liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and Normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development program. Diabetes Care. 2017;40(7):839-848.
|
| [26] |
Zeng Q, Xu J, Mu X, Shi Y, Fan H, Li S. Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023;14:1214334.
|
| [27] |
Majid IA, AlKashgari RH, AlYahya AA, Alikutty FK, Rahman SM. Developing and establishing research guidelines in a private higher education institution of Saudi Arabia. An experience. Saudi Med J. 2019;40(5):507-511.
|
| [28] |
Jacob S, Nair AB, Morsy MA. Dose conversion between animals and humans: a practical solution. Indian J Pharm Educ Res. 2022;56(3):600-607.
|
| [29] |
Abdelzaher WY, Ahmed SM, Welson NN, Marraiki N, Batiha GES, Kamel MY. RETRACTED: Vinpocetine ameliorates L-arginine induced acute pancreatitis via Sirt1/Nrf2/TNF pathway and inhibition of oxidative stress, inflammation, and apoptosis. Biomed Pharmacother. 2021;133:110976.
|
| [30] |
Rolls G. An introduction to specimen processing. Accessed March 2025. https://www.leicabiosystems.com/pathology-resources/knowledge-pathway/an-introduction-to-specimen-processing/
|
| [31] |
Binker MG, Binker-Cosen AA, Richards D, Gaisano HY, de Cosen RH, Cosen-Binker LI. Chronic stress sensitizes rats to pancreatitis induced by cerulein: role of TNF-α. World J Gastroenterol. 2010;16(44):5565-5581.
|
| [32] |
Abdel-Bakky MS, Hammad MA, Walker LA, Ashfaq MK. Silencing of tissue factor by antisense deoxyoligonucleotide prevents monocrotaline/LPS renal injury in mice. Arch Toxicol. 2011;85(10):1245-1256.
|
| [33] |
Lerch MM, Adler G. Experimental animal models of acute pancreatitis. Int J Pancreatol. 1994;15(3):159-170.
|
| [34] |
Gaman L, Dragos D, Vlad A, et al. Phytoceuticals in acute pancreatitis: targeting the balance between apoptosis and necrosis. Evid Based Complement Alternat Med. 2018;2018(1):5264592.
|
| [35] |
Szatmary P, Grammatikopoulos T, Cai W, et al. Acute pancreatitis: diagnosis and treatment. Drugs. 2022;82(12):1251-1276.
|
| [36] |
Banks PA, Freeman ML, Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-2400.
|
| [37] |
Kamrul-Hasan ABM, Mondal S, Dutta D, Nagendra L, Kabir MR, Pappachan JM. Pancreatic safety of Tirzepatide and its effects on islet cell function: a systematic review and meta-analysis. Obes Sci Pract. 2024;10(6):e70032.
|
| [38] |
Nassar M, Nassar O, Abosheaishaa H, Misra A. Decreased risk of recurrent acute pancreatitis with semaglutide and tirzepatide in people with type 2 diabetes or obesity with a history of acute pancreatitis: a propensity matched global federated TriNetX database-based retrospective cohort study. Diabetes Metab Syndr. 2024;18(9):103116.
|
| [39] |
Shi C, Andersson R, Zhao X, Wang X. Potential role of reactive oxygen species in pancreatitis-associated multiple organ dysfunction. Pancreatology. 2005;5(4–5):492-500.
|
| [40] |
Chen L, Chen X, Ruan B, Yang H, Yu Y. Tirzepatide protects against doxorubicin-induced cardiotoxicity by inhibiting oxidative stress and inflammation via PI3K/Akt signaling. Peptides. 2024;178:171245.
|
| [41] |
Yang Y, Wang Y, Zhou Y, Deng J, Wu L. Tirzepatide alleviates oxidative stress and inflammation in diabetic nephropathy via IL-17 signaling pathway. Mol Cell Biochem. 2025;480(2):1241-1245.
|
| [42] |
Ma J, Liu Y, Hu J, et al. Tirzepatide administration improves cognitive impairment in HFD mice by regulating the SIRT3-NLRP3 axis. Endocrine. 2025;87(2):486-497.
|
| [43] |
Jain S, Midha S, Mahapatra SJ, et al. Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis. Pancreatology. 2018;18(5):500-506.
|
| [44] |
Mititelu A, Grama A, Colceriu MC, Benţa G, Popoviciu MS, Pop TL. Role of interleukin 6 in acute pancreatitis: a possible marker for disease prognosis. Int J Mol Sci. 2024;25(15):8283.
|
| [45] |
Miossec P. Anti-inflammatory properties of interleukin-4. Rev Rhum Ed Fr. 1993;60(2):119-124.
|
| [46] |
Zhou X, Schmidtke P, Zepp F, Meyer CU. Boosting Interleukin-10 production: therapeutic effects and mechanisms. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5(4):465-475.
|
| [47] |
Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy—review of a new approach. Pharmacol Rev. 2003;55(2):241-269.
|
| [48] |
Chen CC, Wang SS, Lu RH, Chang FY, Lee SD. Serum interleukin 10 and interleukin 11 in patients with acute pancreatitis. Gut. 1999;45(6):895-899.
|
| [49] |
Henry BM, Benoit SW, Vikse J, et al. The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19). Clin Chem Lab Med. 2021;59(3):599-607.
|
| [50] |
Lee B, Zhao Q, Habtezion A. Immunology of pancreatitis and environmental factors. Curr Opin Gastroenterol. 2017;33(5):383-389.
|
| [51] |
Tsomidis I, Voumvouraki A, Kouroumalis E. The pathogenesis of pancreatitis and the role of autophagy. Gastroenterol Insights. 2024;15(2):303-341.
|
| [52] |
Hassan NF, Ragab D, Ibrahim SG, et al. The potential role of Tirzepatide as adjuvant therapy in countering colistin-induced nephro and neurotoxicity in rats via modulation of PI3K/p-Akt/GSK3-β/NF-kB p65 hub, shielding against oxidative and endoplasmic reticulum stress, and activation of p-CREB/BDNF/TrkB cascade. Int Immunopharmacol. 2024;135:112308.
|
| [53] |
Weaver C, Bishop AE, Polak JM. Pancreatic changes elicited by chronic Administration of Excess L-arginine. Exp Mol Pathol. 1994;60(2):71-87.
|
| [54] |
Thomas MK, Nikooienejad A, Bray R, et al. Dual GIP and GLP-1 receptor agonist Tirzepatide improves Beta-cell function and insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab. 2021;106(2):388-396.
|
| [55] |
Tanday N, English A, Lafferty RA, Flatt PR, Irwin N. Benefits of sustained upregulated unimolecular GLP-1 and CCK receptor signalling in obesity-diabetes. Front Endocrinol. 2021;12:674704.
|
| [56] |
Hamann I, Klotz LO. Arsenite-induced stress signaling: modulation of the phosphoinositide 3′-kinase/Akt/FoxO signaling cascade. Redox Biol. 2013;1(1):104-109.
|
| [57] |
Parsons CM, Muilenburg D, Bowles TL, Virudachalam S, Bold RJ. The role of Akt activation in the response to chemotherapy in pancreatic cancer. Anticancer Res. 2010;30(9):3279-3289.
|
| [58] |
Guo X, Lei M, Zhao J, et al. Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats. Front Pharmacol. 2023;14:1146960.
|
| [59] |
Fontanella RA, Ghosh P, Pesapane A, et al. Tirzepatide prevents neurodegeneration through multiple molecular pathways. J Transl Med. 2024;22(1):114.
|
| [60] |
Sarker RS, Steiger K. A critical role for Akt1 signaling in acute pancreatitis progression †. J Pathol. 2020;251(1):1-3.
|
| [61] |
Yang JL, Chen WY, Chen YP, Kuo CY, Chen SD. Activation of GLP-1 receptor enhances neuronal base excision repair via PI3K-AKT-induced expression of apurinic/apyrimidinic endonuclease 1. Theranostics. 2016;6(12):2015-2027.
|
RIGHTS & PERMISSIONS
2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences
PDF
