N-acetylcysteine combined with insulin attenuates myocardial injury in canines with type 1 diabetes mellitus by modulating TNF-α-mediated apoptotic pathways and affecting linear ubiquitination

Abstract

The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1β-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.