Combined Metformin and Baricitinib Therapy Attenuates Inflammation in STZ-Induced Diabetic Rats via AMPK/JAK-STAT Pathway Crosstalk

Abstract

Background: Chronic inflammation is a critical factor contributing to diabetes complications. Baricitinib inhibits JAK-STAT signalling, which can contribute to an anti-inflammatory effect. Similarly, metformin demonstrates anti-inflammatory properties by activating the AMPK-SIRT pathway and suppressing the NF-ᴋB signalling pathway. Here, we explored the effects of the coadministration of metformin and baricitinib in diabetic rats.

Methods: Streptozotocin (40 mg/kg body weight) was administered to rats to develop diabetes after 2 weeks of 10% fructose solution consumption. The rats were treated with baricitinib (0.5, 2.5 and 5 mg/kg) and 150 mg/kg metformin for 1 month. A dose of 0.5 mg/kg baricitinib was chosen for combination therapy with metformin.

Key findings: Baricitinib induced significant weight loss at all three doses (p ≤ 0.05) and significantly increased lipid profile parameters in comparison to the diabetic control group (p ≤ 0.05). Pancreatic NF-ᴋB levels and HOMA-IR were meaningfully reduced in all treatment groups (p ≤ 0.01). Metformin and combination therapy significantly reduced serum TNF-α levels (p ≤ 0.05). Furthermore, baricitinib at different doses and combination therapy significantly elevated serum IL-10 levels (p ≤ 0.05). Additionally, combination therapy significantly upregulated the liver expression of NF-ᴋB, SOCS1, SOCS3, AMPK and SIRT-1 (p ≤ 0.01).

Conclusion: Our results suggest that the coadministration of metformin with baricitinib reduces insulin resistance, improves histopathological alterations in the liver and pancreatic islet cells and counteracts the adverse effects of baricitinib on the lipid profile in diabetic rats. These findings hold particular significance for patients undergoing baricitinib treatment.

Keywords: AMPK; JAK–STAT; NF‐kB; SIRT1; baricitinib; metformin.

FIGURE 1

Body weight changes were monitored in the normal control (NC), diabetic control (DC) and treatment groups. Rats were given fructose for 2 weeks and then received a single injection of streptozotocin (STZ) to induce type 2 diabetes. The diabetic rats were subsequently treated for 1 month with 150 mg/kg of metformin, Baricitinib (0.5, 2.5 and 5 mg/kg), or a combination of metformin and 0.5 mg/kg of Baricitinib. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. Data are expressed as mean ± SEM.

FIGURE 2

Serum levels of TNF‐α (A), IL‐10 (B), SIRT1 (D) and pancreatic NF‐κB (C) were analysed in the normal control (NC), diabetic control (DC) and treatment groups. Rats were given fructose for 2 weeks and then received a single injection of streptozotocin (STZ) to induce type 2 diabetes. The diabetic rats were subsequently treated for 1 month with 150 mg/kg of metformin, baricitinib (0.5, 2.5 and 5 mg/kg), or a combination of metformin and 0.5 mg/kg of baricitinib. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001 in comparison to the diabetic control group. Data are expressed as mean ± SEM.

FIGURE 3

Photomicrographs of rat liver tissue (400× magnification) stained with haematoxylin and eosin (H&E) from control and treatment groups. Normal control (NC) rats are compared with SZT‐induced diabetic rats, which were divided into the following categories: Diabetic control (DC), 150 mg/kg Metformin (MET), combination (Metformin +0.5 mg/kg baricitinib), 0.5 BAR (0.5 mg/kg baricitinib), 2.5 BAR (2.5 mg/kg baricitinib) and 5 BAR (5 mg/kg baricitinib).

FIGURE 4

Photomicrographs of rat pancreatic tissue (400× magnification) stained with haematoxylin and eosin (H&E) from control and treatment groups. Normal control (NC) rats are compared with SZT‐induced diabetic rats, which were divided into the following categories: Diabetic control (DC), 150 mg/kg Metformin (MET), combination (Metformin +0.5 mg/kg baricitinib), 0.5 BAR (0.5 mg/kg baricitinib), 2.5 BAR (2.5 mg/kg baricitinib) and 5 BAR (5 mg/kg baricitinib).

FIGURE 5

AMPK (A), SIRT1 (B), NF‐κB (C), SOCS1 (D) and SOCS3 (E), liver gene expression after receiving different treatments. Data are presented as mean ± SEM. Following is an indication of statistical significance: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 and ****p ≤ 0.0001.

FIGURE 6

This schematic illustrates the potential interaction between metformin and baricitinib in mitigating metaflammation associated with diabetes. By combining these drugs, insulin sensitivity is enhanced, the production of anti‐inflammatory cytokines is promoted, and pro‐inflammatory cytokines are suppressed.