Mitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model

In a rat model of type 2 diabetes, treatment with the mitochondrial peptide MOTS-c lowered fasting blood glucose and the inflammatory marker C-reactive protein, and reduced signs of NLRP3 inflammasome activation in heart tissue. These findings suggest MOTS-c dampens both systemic and cardiac inflammation in diabetes.

Journal article — experimental animal study. Population: high-fat diet and streptozotocin-induced T2DM rats. Interventions: MOTS-c.

MOTS-c significantly reduced fasting blood glucose and circulating C-reactive protein. It selectively modulated plasma inflammatory cytokines, including IL-10 and IL-1β. In left ventricular tissue, levels of NLRP3, ASC, and cleaved caspase-1 were reduced after MOTS-c administration. Correlation analyses linked IL-18 and IL-1β with elevated markers such as low-density lipoprotein and uric acid.

This paper provides evidence that MOTS-c can suppress NLRP3 inflammasome activation in cardiac tissue in a diabetic rat model, supporting interest in MOTS-c for reducing diabetic cardiovascular risk. It does not establish efficacy in humans, nor does it provide dosing or a defined mechanism beyond reduced inflammasome components.

Key findings

• MOTS-c treatment significantly reduced fasting blood glucose in the diabetic rat model.
• MOTS-c treatment significantly reduced circulating C-reactive protein levels.
• MOTS-c selectively modulated plasma inflammatory cytokines, including IL-10 and IL-1β.
• MOTS-c reduced left ventricular levels of NLRP3, ASC, and cleaved caspase-1.
• IL-18 and IL-1β correlated with elevated low-density lipoprotein and uric acid levels.

Limitations

• Animal model findings may not translate to humans.
• Diabetes was experimentally induced with high-fat diet and streptozotocin, not naturally occurring T2DM.
• The abstract does not report sample size, treatment dose, or duration, limiting assessment of robustness.
• Correlation analyses cannot establish causality for cytokine–metabolic marker relationships.

The record

• Journal: Experimental physiology 111(8): 3742-3752
• Published: 2026-06-19
• PMID: 42321010 — DOI: 10.1113/ep093714
• MeSH terms: Myocardium, Animals, Rats, Rats, Sprague-Dawley, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Inflammation, Blood Glucose, C-Reactive Protein, Mitochondrial Proteins, Cytokines, Male, Interleukin-1beta, Diabetic Cardiomyopathies, Inflammasomes, Diet, High-Fat, NLR Family, Pyrin Domain-Containing 3 Protein
• Funding: Health Research Council of New Zealand; Heart Foundation of New Zealand Research Fellowship; Auckland Medical Research Foundation; Emerging Research First Grants
• Author countries: New Zealand

Peptide profiles: MOTS-c.

All indexed evidence: MOTS-c trials & papers.

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