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Indapamide Increases IRS1 Expression and Modifies Adiponectin/NLRP3/PPARγ Crosstalk in Type 2 Diabetic Rats
Mahmoud M Samaha1, Manar G Helal1, Mohamed El-Sherbiny2,3
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Abstract:
The current study aimed to evaluate the anti-diabetic effects of canagliflozin (CANA) and indapamide (INDA) and their impacts as adiponectin modulators in experimentally induced type 2 diabetes mellitus (T2DM). T2DM was associated with a significant rise in blood glucose level and HbA1C%, andreduced adiponectin and insulin secretions. Moreover, the malondialdehyde (MDA) contents in both the epididymal adipocytes and soleus muscle significantly escalated, while the total antioxidant capacity (TAC) and epididymal adipocyte Nrf2 expression significantly declined. Moreover, serum TNF-α, epididymal adipocyte's NOD-like receptor protein 3, NLRP3, NF-κB and CD68 expressions markedly escalated, and serum IL-10 significantly declined. Furthermore, there was a significant escalation in PPARγ expression in epididymal adipocytes, with a significant reduction in soleus muscle's expression of IRS1. CANA and INDA treatments markedly reduced blood glucose levels, increased adiponectin and insulin secretion, enhanced anti-oxidant defenses, and reduced oxidative burden, with marked anti-inflammatory impact. Interestingly, the impact of indapamide on DM indices and oxidative and inflammatory changes was comparable to that of canagliflozin. Nevertheless, indapamide had a superior effect compared to canagliflozin on HbA1c%, expression of IRS1 and reduction of NF-κB and CD68 expressions. INDA could be effective in regulating T2DM, with underlined anti-diabetic, antioxidant, and anti-inflammatory properties. INDA increased IRS1 expression and modified adiponectin/NLRP3/PPARγ crosstalk. The impacts of INDA are comparable to those of the standard anti-diabetic drug CANA.
Insights
Indapamide demonstrates significant anti-diabetic, antioxidant, and anti-inflammatory effects comparable to canagliflozin in type 2 diabetes. This study highlights indapamide
Area of Science:
- Endocrinology
- Pharmacology
- Metabolic Diseases
Background:
- Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, impaired insulin secretion, and altered adipokine profiles.
- Oxidative stress and inflammation are key contributors to T2DM pathogenesis.
- Adiponectin plays a crucial role in metabolic regulation, and its modulation is a therapeutic target.
Purpose of the Study:
- To evaluate the anti-diabetic efficacy of canagliflozin (CANA) and indapamide (INDA) in a T2DM model.
- To investigate their roles as adiponectin modulators.
- To assess their impact on oxidative stress, inflammation, and related signaling pathways.
Main Methods:
- Experimentally induced type 2 diabetes mellitus in a suitable animal model.
- Administration of canagliflozin and indapamide.
- Assessment of glycemic control (blood glucose, HbA1c), insulin and adiponectin levels.
- Measurement of oxidative stress markers (MDA, TAC) and antioxidant gene expression (Nrf2).
- Evaluation of inflammatory markers (TNF-α, IL-10, NLRP3, NF-κB, CD68) and key metabolic signaling proteins (PPARγ, IRS1).
Main Results:
- T2DM induced hyperglycemia, reduced insulin and adiponectin, increased oxidative stress (MDA) and inflammation (TNF-α, NLRP3, NF-κB, CD68), and altered gene expressions (Nrf2, PPARγ, IRS1).
- Both CANA and INDA treatments improved glycemic control, increased adiponectin and insulin, reduced oxidative stress and inflammation.
- INDA showed comparable or superior effects to CANA in improving HbA1c, IRS1 expression, and reducing NF-κB and CD68.
- INDA modulated adiponectin/NLRP3/PPARγ crosstalk, suggesting a multifaceted therapeutic mechanism.
Conclusions:
- Indapamide exhibits significant anti-diabetic, antioxidant, and anti-inflammatory properties in experimental T2DM.
- Indapamide's therapeutic effects are comparable, and in some aspects superior, to canagliflozin.
- Indapamide represents a potential therapeutic agent for T2DM, acting through modulation of adiponectin signaling and inflammatory pathways.
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