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Combined Metformin and Baricitinib Therapy Attenuates Inflammation in STZ-Induced Diabetic Rats via AMPK/JAK-STAT
Mostafa Allahyari1,2, AbdolJalal Marjani1,2, Marie Saghaeian Jazi1,2
1Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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.
Insights
Combining metformin and baricitinib in diabetic rats reduced insulin resistance and improved liver and pancreatic health. This combination therapy also counteracted baricitinib's negative effects on lipid profiles, offering potential benefits for patients.
Area of Science:
- Pharmacology and Toxicology
- Endocrinology and Metabolism
- Immunology
Background:
- Chronic inflammation is a key driver of diabetes complications.
- Baricitinib (JAK-STAT inhibitor) and metformin (AMPK-SIRT activator, NF-κB suppressor) possess anti-inflammatory properties.
- Investigated the combined effects of metformin and baricitinib in a diabetic rat model.
Purpose of the Study:
- To evaluate the efficacy of co-administering metformin and baricitinib in diabetic rats.
- To assess the impact on insulin resistance, inflammatory markers, and lipid profiles.
- To determine if combination therapy mitigates adverse effects of baricitinib.
Main Methods:
- Diabetes induced in rats using streptozotocin and fructose.
- Rats treated with varying doses of baricitinib and a fixed dose of metformin for one month.
- A specific dose of baricitinib (0.5 mg/kg) was selected for combination therapy.
Main Results:
- Baricitinib caused weight loss and altered lipid profiles; both drugs reduced NF-κB and HOMA-IR.
- Combination therapy significantly reduced TNF-α and increased IL-10 levels.
- Combination therapy upregulated liver expression of NF-κB, SOCS1, SOCS3, AMPK, and SIRT-1.
Conclusions:
- Metformin and baricitinib coadministration improved insulin resistance and liver/pancreatic histology in diabetic rats.
- The combination therapy counteracted baricitinib's adverse lipid profile effects.
- Findings are significant for patients receiving baricitinib treatment.
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