Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic db/db Mice

Objective@#Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice. @*Methods@#A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions. @*Results@#Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment. @*Conclusion@#AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.

Mitochondrial Mechanisms in Diabetic Cardiomyopathy

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca²⁺ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.

Established and Emerging Mechanisms of Diabetic Cardiomyopathy

Diabetes mellitus increases the risk for the development of heart failure even in the absence of coronary artery disease and hypertension, a cardiac entity termed diabetic cardiomyopathy (DC). Clinically, DC is increasingly recognized and typically characterized by concentric cardiac hypertrophy and diastolic dysfunction, ultimately resulting in heart failure with preserved ejection fraction (HFpEF) and potentially even heart failure with reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie the alterations in myocardial structure and function in DC, many of which show similar alterations in the failing heart. Well investigated and established mechanisms of DC include increased myocardial fibrosis, enhanced apoptosis, oxidative stress, impaired intracellular calcium handling, substrate metabolic alterations, and inflammation, among others. In addition, a number of novel mechanisms that receive increasing attention have been identified in recent years, including autophagy, dysregulation of microRNAs, epigenetic mechanisms, and alterations in mitochondrial protein acetylation, dynamics and quality control. This review aims to provide an overview and update of established underlying mechanisms of DC, as well as a discussion of recently identified and emerging mechanisms that may also contribute to the structural and functional alterations in DC.