3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Insulin-Resistance

Iron overload (IO) induces insulin resistance in H9c2 cardiomyoblast cells. Here, we used H9c2 cells overexpressing MitoNEET to examine the potential for protection against iron accumulation in the mitochondria and subsequent insulin resistance. In control H9c2 cells, IO was observed to increase mitochondrial iron content, reactive oxygen species (ROS) production, mitochondrial fission, and reduced insulin-stimulated Akt and ERK1/2 phosphorylation. IO did not significantly affect mitophagy, or mitochondrial content, however, an increase in peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein expression, a key regulator of mitochondrial biogenesis, was observed. MitoNEET overexpression was able to attenuate the effects of IO on mitochondrial iron content, reactive oxygen species, mitochondrial fission, and insulin signaling. MitoNEET overexpression also upregulated levels of PGC1α protein. The mitochondria-targeted antioxidant, Skq1, prevented IO-induced ROS production and insulin resistance in control cells, indicating mitochondrial ROS plays a causal role in the onset of insulin resistance. The selective mitochondrial fission inhibitor, Mdivi-1, prevented IO-induced mitochondrial fission, however, it did not alleviate IO-induced insulin resistance. Collectively, IO causes insulin resistance in H9c2 cardiomyoblasts and this can be averted by reduction of mitochondrial iron accumulation and ROS production by overexpression of the MitoNEET protein.

Topics: Humans; Insulin; Insulin Resistance; Iron; Iron Overload; Mitochondria; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reactive Oxygen Species

Dynamin-related protein-1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1-mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1-specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), is effective in alleviating skeletal muscle insulin resistance and improving whole-body metabolic health under the obese and insulin-resistant condition. We subjected C57BL/6J mice to a high-fat diet (HFD) or low-fat diet (LFD) for 5-weeks. HFD-fed mice received Mdivi-1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin-resistant humans were treated with Mdivi-1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H

Topics: Animals; Anti-Obesity Agents; Cells, Cultured; Diet, High-Fat; Dynamins; Glucose; Humans; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Quinazolinones

Obese insulin resistance impairs cardiac mitochondrial dynamics by increasing mitochondrial fission and decreasing mitochondrial fusion, leading to mitochondrial damage, myocardial cell death and cardiac dysfunction. Therefore, inhibiting fission and promoting fusion could provide cardioprotection in this pre-diabetic condition. We investigated the combined effects of the mitochondrial fission inhibitor (Mdivi1) and fusion promoter (M1) on cardiac function in obese insulin-resistant rats. We hypothesized that Mdivi1 and M1 protect heart against obese insulin-resistant condition, but also there will be greater improvement using Mdivi1 and M1 as a combined treatment. Wistar rats (n=56, male) were randomly assigned to a high-fat diet (HFD) and normal diet (ND) fed groups. After feeding with either ND or HFD for 12 weeks, rats in each dietary group were divided into groups to receive either the vehicle, Mdivi1 (1.2 mg/kg, i.p.), M1 (2 mg/kg, i.p.) or combined treatment for 14 days. The cardiac function, cardiac mitochondrial function, metabolic and biochemical parameters were monitored before and after the treatment. HFD rats developed obese insulin resistance which led to impaired dynamics balance and function of mitochondria, increased cardiac cell apoptosis and dysfunction. Although Mdivi1, M1 and combined treatment exerted similar cardiometabolic benefits in HFD rats, the combined therapy showed a greater reduction in mitochondrial reactive oxygen species (ROS). Mitochondrial fission inhibitor and fusion promoter exerted similar levels of cardioprotection in a pre-diabetic condition.

Topics: Animals; Apoptosis; Cardiotonic Agents; Diet, High-Fat; Insulin Resistance; Male; Mitochondria, Heart; Mitochondrial Dynamics; Obesity; Quinazolinones; Rats, Wistar; Reactive Oxygen Species