Azoramide improves mitochondrial dysfunction in palmitate-induced insulin resistant H9c2 cells

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Metabolic Disorders

Background:

• Azoramide is a novel compound with potential benefits for endoplasmic reticulum (ER) folding capacity and type 2 diabetes mellitus (T2DM).
• Limited studies suggest azoramide may improve insulin sensitivity in obese mice, but its direct effects on cardiac insulin signaling are unclear.

Purpose of the Study:

• To investigate the direct impact of azoramide on insulin signaling pathways in insulin-resistant (IR) cardiomyocytes.
• To evaluate azoramide's protective effects against mitochondrial dysfunction and cellular damage in an in vitro model of cardiac insulin resistance.

Main Methods:

• An in vitro model of insulin resistance was established in H9c2 ventricular cardiomyocytes using palmitic acid incubation.
• Insulin resistance was confirmed by reduced glucose uptake (2-DG6P).
• Treated cells were assessed for glucose uptake, ATP production, reactive oxygen species (ROS) levels, mitochondrial membrane potential, mitochondrial fusion proteins, and insulin signaling pathway components (IRS1, Akt, GLUT4).

Main Results:

• Azoramide treatment fully prevented the decrease in glucose uptake in IR cardiomyocytes.
• Azoramide preserved cellular ATP levels, reduced elevated ROS production, and maintained mitochondrial membrane potential in IR cells.
• Azoramide treatment restored the phosphorylation of IRS1 and Akt, and normalized GLUT4 and Akt protein levels, indicating recovery of the insulin signaling pathway.

Conclusions:

• Azoramide demonstrates a significant protective role in insulin-resistant cardiomyocytes, primarily through its action on mitochondria.
• Azoramide can offer direct cardioprotection in the insulin-resistant heart by modulating mitochondrial function.
• Azoramide is a promising candidate for treating insulin resistance-associated cardiovascular disorders.