Assessing the therapeutic potential of Tirzepatide in modulating inflammatory responses and mitigating acute pancreatitis

Abstract

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.

Keywords: L‐arginine; Tirzepatide; acute pancreatitis; disease treatment; inflammation; p‐Akt.

FIGURE 1

Experimental design timeline for L‐arginine‐induced pancreatitis and Tirzepatide treatment in rats. Male rats were subjected to L‐Arginine‐induced pancreatitis starting on day 0, receiving two intraperitoneal injections of 2.5 g/kg administered 1 h apart. Tirzepatide treatment commenced on day 4, with subcutaneous injections at a dose of 1.55 mg/kg every 3 days until day 27. Blood and tissue samples were collected for ELISA and histopathology analysis, and the animals were euthanized for final assessments.

FIGURE 2

Temporal dynamics of lipase and amylase levels in the different groups. (A) Serum lipase. (B) Serum amylase. Data are expressed as mean ± SD. *p< 0.05 compared to the control group. ^$ p < 0.05 compared to the Tirzepatide group. ^@ p < 0.05 compared to the L‐Arginine group.

FIGURE 3

Variations in inflammatory markers over time. (A) Pro‐inflammatory IL6. (B) Anti‐inflammatory IL4. Data are expressed as mean ±SD. *p< 0.05 compared to the control group. ^$ p < 0.05 compared to the Tirzepatide group. ^@ p < 0.05 compared to the L‐Arginine group.

FIGURE 4

IL‐10 protein expression in the pancreatic tissue sections. (A) Rats were treated with L‐arginine for 4, 8, and 27 days. (B) IL‐10 fluorescence intensities. (C) Rats were treated with L‐arginine in the presence or absence of Tirzepatide. (D) IL‐10 fluorescence intensities. Data are presented as mean ± SD. *p < 0.05 compared to the control group, ^$ p < 0.05 compared to the L‐Arginine group on day 8. ^# p < 0.05 compared to the L‐Arginine group on day 27 (magnification for both A & C: 400×). IP denotes pancreatic islets.

FIGURE 5

Changes in reactive oxygen species (ROS) across treatment groups. Data are expressed as mean ± SD. *p < 0.05 compared to the control group. ^$ p < 0.05 compared to the Tirzepatide group. ^@ p < 0.05 compared to the L‐Arginine group.

FIGURE 6

Photomicrographs of histopathological sections stained with Hematoxylin and Eosin (H&E). (A) H&E‐stained pancreatic tissue sections from control and L‐Arginine groups at various time points. (B) H&E‐stained pancreatic tissue sections from control and L‐Arginine groups, with or without Tirzepatide treatment. (C) Histological scores of pancreatic acinar necrosis are shown. Data are presented as mean ± SD. *p < 0.05, significantly different compared to the control group; ^# p < 0.05, significantly different compared to the L‐Arginine group on day 8; ^$ p < 0.05, significantly different compared to the L‐Arginine group on day 27. Magnification for both A & B: 400×.

FIGURE 7

Expression of p‐Akt protein in the tissues of the pancreas. (A) The rats were treated with L‐arginine for 4, 8, and 27 days. (B) p‐Akt fluorescence intensities. (C) The rats were treated with L‐arginine in the presence or absence of Tirzepatide. (D) p‐Akt fluorescence intensities. Data are presented as mean ± SD. *p < 0.05 compared to the control group; ^$ p < 0.05 compared to the L‐Arginine group on day 8; ^# p < 0.05 compared to the L‐Arginine group on day 27 (magnification for both A & C: 400×). IP denotes pancreatic islets.