Novel Anti-Inflammatory Effects of Repaglinide in Rodent Models of Inflammation

Abstract

Background: Repaglinide is an FDA-approved treatment for type 2 diabetes mellitus. The anti-inflammatory effect of repaglinide in the absence of diabetes has not been reported previously. It is the objective of this set of studies to investigate the potential anti-inflammatory effects of repaglinide. Method: The in vivo anti-inflammatory effects of repaglinide were studied in two different models of delay type hyperreactivity (DTH) response induced by sheep red blood cells (sRBC) and 2,5′-dinitrofluorobenzene (DNFB), and in two different rodent models of lipopolysaccharide (LPS) challenge. Results: In mice systemically sensitized with sRBC, which subsequently received a local injection of sRBC in the footpad, local swelling occurred within 24 h after challenge. Repaglinide was efficacious in attenuating this response. In an orthogonal DTH model using DNFB as the antigen, the animals received topical sensitization with DNFB on their shaved backs, followed by topical challenge on the left ears. Repaglinide efficaciously downregulated the resulting ear swelling response. In mice challenged systemically or intratracheally with LPS, repaglinide significantly decreased serum tumor necrosis factor α level and bronchial alveolar lavage fluid MCP-1 levels, respectively. Conclusion: This set of data suggests novel anti-inflammatory effects of repaglinide in nondiabetic animals. However, the high dose required for an efficacious effect would make this application impractical in the clinic.

Hypoglycemic agents and potential anti-inflammatory activity

“…Repaglinide efficaciously downregulated the resulting ear swelling response with sheep red blood cells and decreased serum TNF-α level and bronchial alveolar lavage fluid MCP-1 levels in LPS-challenged animals. 67 In addition, change of treatment from glimepiride to repaglinide in Japanese patients with T2DM reduced the levels of plasminogen activator inhibitor-1, hsCRP, and urinary 8-hydroxydeoxyguanosine. 68 Similarly, a study by Assaloni et al showed that controlling postprandial hyperglycemia with meglitinide significantly improves the cluster of oxidative stress (reduces nitrotyrosine, malondialdehyde, and oxidized low-density lipoprotein levels) and inflammation markers (decreases IL-6, IL-18, and TNF-α) that are increased in the postprandial state in patients with diabetes.…”

“…Although novel anti-inflammatory effects of repaglinide in nondiabetic animals were established, the high doses required for an efficacious effect would make this application impractical in the clinic. 67 Repaglinide was studied in two different models of delay-type hyperreactivity response induced by sheep red blood cells and 2,5′-dinitrofluorobenzene, and in two different rodent models of LPS challenge. Repaglinide efficaciously downregulated the resulting ear swelling response with sheep red blood cells and decreased serum TNF-α level and bronchial alveolar lavage fluid MCP-1 levels in LPS-challenged animals.…”

Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K+) channel activity

“…It is noteworthy that Kir6 inhibitors tested here are used as short acting insulin secretagogues that have also been shown to reduce systemic inflammation [22,42] and Assloni et al [43] showed that controlling post-prandial hyperglycemia by mitiglinide improves cluster of oxidative and inflammatory markers in diabetic patients. However, it remains unclear whether these effects are direct or reduction in inflammation is an indirect consequence of reduced glucose levels [44].…”

Evaluation of the effects of acarbose on weight and metabolic, inflammatory, and cardiovascular markers in patients with obesity and overweight

“…[ 19 20 ] Newer sulfonylurea drugs such as gliclazide and glimepiride are more efficient in reducing inflammatory markers compared to other drugs of this group. [ 21 22 23 ] Some studies have demonstrated that acarbose can reduce blood pressure, lipid, body weight, inflammatory markers, and cardiovascular adverse events. [ 12 13 14 ] A study of these effects concluded that in diabetic patients who received acarbose, insulin resistance index, interleukin 6 (IL-6), and interleukin 1β (IL-1β) showed no significant reduction after 3 months of treatment.…”