Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Abstract

Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.

Vitamin D Deficiency in Rats Causes Cardiac Dysfunction by Inducing Myocardial Insulin Resistance

“…We observed significantly higher NF‐κB protein and TNF‐α and IL‐6 genes in the hearts of Con(‐) group. Oxidative stress is another cellular signaling component associated with insulin resistance in the heart, and we also observed significant downregulation of the endogenous antioxidant enzymes, SOD2, and catalase, in the hearts of Con(‐) group . Importantly, the severity of all the above changes in the heart was greater in Con(‐) hearts than in HFHFrD group.…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…114,151,152 Increased H 2 O 2 resulting from superoxide (O − 2 ) production at complex I has been observed in cardiac mitochondria from obese mice. 44,153,154 During ADP-driven respiration (coupled OXPHOS), H 2 O 2 production was found to be higher in atrial tissue from patients with T2DM, 107 and in obese mice with T2DM, 155 compared with non-diabetic controls. In contrast, lower ROS production was reported in high-fat-high-sugar diet fed rats.…”

“…Approximately 90% of cellular ROS is produced in the mitochondria mainly from complexes I and III . Increased H 2 O 2 resulting from superoxide () production at complex I has been observed in cardiac mitochondria from obese mice . During ADP‐driven respiration (coupled OXPHOS), H 2 O 2 production was found to be higher in atrial tissue from patients with T2DM, and in obese mice with T2DM, compared with non‐diabetic controls.…”

“…Increased expression of mitochondrial catalase in response to high‐fat diet was shown to prevent oxidative stress and rescue diet‐induced mitochondrial dysfunction . Furthermore, mitochondrial ROS scavenging was shown to improve cardiac insulin signalling and mitochondrial energetics . Perhaps focused studies to elucidate changes in redox buffering systems (ie thioredoxin and glutathione systems) in the heart associated with substrate availability and utilization could reveal origins of oxidative stress.…”

Insulin Signaling and Heart Failure

“…Second, it remains to be determined if strategies that will directly correct the changes in myocardial insulin signaling described above will reverse heart failure. Oxidative stress is a widely accepted mechanism for cardiac dysfunction in insulin resistant states and it was recently reported that targeted anti-oxidant therapy may partially restore abnormal insulin signaling and improve cardiac structure and function 152 . Combined treatment with polyphenols resveratrol and S17834 also significantly restored cardiac function in diet-induced heart failure in rodent models via multiple mechanisms including reducing oxidative stress, reversing oxidative modifications of proteins, reducing hyperinsulinemia and increasing circulating adiponectin concentrations 153 .…”