Altered mitochondrial metabolism in the insulin‐resistant heart

Abstract

Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

Harnessing the protective role of OPA1 in diabetic cardiomyopathy

“…OPA1 is located on both the inner mitochondrial membrane as well as the intermembrane space, depending on its processing, and induces fusion in concert with the outer GTPases, Mitofusins 1 and 2 1 . Mitochondrial dysfunction is a pathological hallmark of diabetic cardiomyopathy characterized by lower capacity for oxidative phosphorylation (OXPHOS), oxidative stress and abrogated mitochondrial quality control, 3 although the role of OPA1 in this setting is relatively unexplored. In experimental models of diabetes, observations of increased mitochondrial fragmentation in the heart are linked to both increased fission processes and impaired fusion processes 3 .…”

“…Mitochondrial dysfunction is a pathological hallmark of diabetic cardiomyopathy characterized by lower capacity for oxidative phosphorylation (OXPHOS), oxidative stress and abrogated mitochondrial quality control, 3 although the role of OPA1 in this setting is relatively unexplored. In experimental models of diabetes, observations of increased mitochondrial fragmentation in the heart are linked to both increased fission processes and impaired fusion processes 3 . Mitochondrial fragmentation under these conditions may occur as a protective mechanism to limit the consequences of local areas of dysfunction by disconnecting damaged parts of the mitochondrial reticulum.…”

“…A hallmark of diabetic cardiomyopathy is diastolic dysfunction (left ventricular stiffness and impaired relaxation) 3 . Ding et al 2 demonstrate marked diastolic dysfunction in the STZ‐diabetic rat heart, in the absence of dilation, and likewise improvement in diastolic function following OPA1‐targeted treatment.…”

Adipose tissue—more than just fat

“…A number of articles addressing basic mechanisms related to obesity have recently appeared in Acta physiologica. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] One area of clinical relevance for obese patients is the immune system. Duan et al 20 recapitulate the connections between a high-fat diet and diseases.…”

“…11 Recently Makrecka-Kuka et al summarized mitochondrial dysfunction in association with altered metabolic function in the diabetic heart. 13 Glucagon and insulin are two major hormones balancing glucose utilization, production, and its uptake from blood into adipose as well as muscle tissue. The trans membrane protein GLUT4 is a main insulin-sensitive transporter responsible for glucose uptake.…”