Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development

Area of Science:

• Immunology
• Metabolic Diseases
• Pharmacology

Background:

• NLRP3 inflammasome activation by diabetes-related stressors is implicated in disease development.
• The therapeutic potential of targeting the NLRP3 inflammasome for diabetes remains uncertain.
• Nucleoside reverse-transcriptase inhibitors (NRTIs), used for HIV-1 and hepatitis B, are known to inhibit inflammasome activation.

Purpose of the Study:

• To investigate the association between NRTI exposure and incident diabetes risk.
• To explore the mechanistic role of NRTIs in modulating inflammasome activity and insulin sensitivity.

Main Methods:

• Analysis of five health insurance databases encompassing 128,861 patients with HIV-1 or hepatitis B.
• In vitro studies using human cells with induced diabetes or insulin resistance.
• In vivo studies using mice fed a high-fat diet.

Main Results:

• NRTI exposure was associated with a 33% lower adjusted risk of incident diabetes (aHR, 0.673; P < 0.0001).
• Lamivudine (an NRTI) improved insulin sensitivity and reduced inflammasome activation in cellular and murine models.
• Elevated inflammasome-activating short interspersed nuclear element (SINE) transcripts and reduced DICER1 were observed in diabetic/insulin-resistant models.

Conclusions:

• NRTI exposure is linked to a significantly reduced risk of developing diabetes.
• NRTIs, such as lamivudine, demonstrate potential in improving metabolic parameters and reducing inflammasome activity.
• Drug repurposing of NRTIs for diabetes prevention is a promising therapeutic strategy.