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<p>Insulin resistance (IR), which involves impaired insulin signaling diminished insulin sensitivity in skeletal muscle, is closely associated with chronic low-grade inflammation. A key mediator of this process is the NLRP3 inflammasome, which activates Gasdermin D (GSDMD). Upon cleavage, the N-terminal fragment of GSDMD (GSDMD-NT) forms membrane pores that facilitate interleukin-1β (IL-1β) release. Disulfiram (DSF), an FDA-approved drug that also inhibits GSDMD-NT pore formation, has emerged as a potential therapeutic for inflammasome-mediated inflammation. However, the role of GSDMD in skeletal muscle during IR remains poorly understood. This study evaluated whether GSDMD-NT-mediated IL-1β release contributes to skeletal muscle inflammation and IR, and whether DSF can restore insulin sensitivity. Male C57BL/6 mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks; a subgroup of HFD-fed mice received intraperitoneal DSF (50&#xa0;mg/kg) for 3 weeks. The flexor digitorum brevis (FDB) and gastrocnemius muscles were collected for single-fiber isolation, quantitative PCR, immunoblotting, and immunofluorescence. IL-1β levels were measured by ELISA. Insulin sensitivity was assessed via 2-NBDG uptake, Akt phosphorylation, and glucose tolerance tests (IPGTT). HFD-fed mice exhibited increased GSDMD-NT and oligomer levels, localized to the sarcolemma and T-tubules, along with elevated IL-1β in skeletal muscle. DSF administration reduced weight gain, fasting glycemia, IPGTT, and systemic IL-1β, while enhancing insulin-stimulated 2-NBDG uptake and Akt phosphorylation in FDB. Moreover, DSF reduced GSDMD-NT oligomerization and IL-1β release in the gastrocnemius muscle. These findings suggest a novel pathogenic role for GSDMD in skeletal muscle IR and support DSF as a potential candidate for metabolic disease intervention.</p>

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Disulfiram inhibits Gasdermin D pores formation and improves insulin-dependent glucose uptake and glucose homeostasis in skeletal muscle of obesity-induced insulin-resistant mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Cynthia Cadagan,
  • Javier Russell-Guzmán,
  • Luan Américo-Da-Silva,
  • Paula Montaña,
  • Genaro Barrientos,
  • Sonja Buvinic,
  • Gladys Tapia,
  • Manuel Estrada,
  • Paola Llanos

摘要

Insulin resistance (IR), which involves impaired insulin signaling diminished insulin sensitivity in skeletal muscle, is closely associated with chronic low-grade inflammation. A key mediator of this process is the NLRP3 inflammasome, which activates Gasdermin D (GSDMD). Upon cleavage, the N-terminal fragment of GSDMD (GSDMD-NT) forms membrane pores that facilitate interleukin-1β (IL-1β) release. Disulfiram (DSF), an FDA-approved drug that also inhibits GSDMD-NT pore formation, has emerged as a potential therapeutic for inflammasome-mediated inflammation. However, the role of GSDMD in skeletal muscle during IR remains poorly understood. This study evaluated whether GSDMD-NT-mediated IL-1β release contributes to skeletal muscle inflammation and IR, and whether DSF can restore insulin sensitivity. Male C57BL/6 mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks; a subgroup of HFD-fed mice received intraperitoneal DSF (50 mg/kg) for 3 weeks. The flexor digitorum brevis (FDB) and gastrocnemius muscles were collected for single-fiber isolation, quantitative PCR, immunoblotting, and immunofluorescence. IL-1β levels were measured by ELISA. Insulin sensitivity was assessed via 2-NBDG uptake, Akt phosphorylation, and glucose tolerance tests (IPGTT). HFD-fed mice exhibited increased GSDMD-NT and oligomer levels, localized to the sarcolemma and T-tubules, along with elevated IL-1β in skeletal muscle. DSF administration reduced weight gain, fasting glycemia, IPGTT, and systemic IL-1β, while enhancing insulin-stimulated 2-NBDG uptake and Akt phosphorylation in FDB. Moreover, DSF reduced GSDMD-NT oligomerization and IL-1β release in the gastrocnemius muscle. These findings suggest a novel pathogenic role for GSDMD in skeletal muscle IR and support DSF as a potential candidate for metabolic disease intervention.