Assessing the Efficiency of the Diabetic Heart at Subcellular, Tissue and Organ Level

Abstract

In this review, we focus on the diabetic heart rather than the vascular complications of diabetes. Focus is further narrowed to a specific, but widely used, animal model: the diabetic rat heart in which diabetes has been induced by a single injection of streptozotocin. Our experimental approach is primarily biophysical and ranges from measurements made in isolated working whole-hearts, to those made from isolated left-ventricular tissues and mitochondria. Our interest is on the effect of severe diabetes on cardiac energetics, in terms of efficiency of cardiac work performance, ATP synthesis and oxygen consumption. By designing experiments to test the energetic performance of the heart and its trabeculae across a wide range of protocols, we have revealed the dependence of efficiency on afterload. This has allowed us to clarify a long-standing uncertainty in the literature; whereas the diabetic heart is unable to work against high afterloads, it nevertheless retains normal peak efficiency. But a further anomaly has been revealed. Whereas there is no evidence that the diabetic myocardium loses peak mechanical efficiency, its mitochondria demonstrate a decreased P:O ratio -i.e., a decreased bioenergetic efficiency. This decrease is consistent with an increase in the rate of production of reactive oxygen species, together with elevated proton leakage across the inner mitochondrial membrane at near maximal phosphorylating respiration states.Keywords: Cardiac oxygen consumption; Pressure-volume work; Myocardial heat production, Force-length work, Mitochondrial efficiency PreambleReaders of the Journal of General Practice will scarcely need to be reminded that diabetes is a leading cause of death in both the 'developed' and 'developing' world [1]. New Zealand is no exception. We do have something of a unique situation, however, since the burden falls disproportionately on the Maori & Polynesian populations, with both the prevalence and the death rates approaching double those of Pakeha (http://www.maoridiabetes.co.nz/). Given the strong link between obesity and diabetes, the high rates of obesity in New Zealand (31% of adults in 2013) is of increasing concern (http:// www.health.govt.nz/our-work/diseases-and-conditions/obesity/ obesity-key-facts-and-statistics).There have been a number of excellent reviews on the subject of diabetes [2][3][4][5], surely the most unique of which is that authored by Gottlieb [6], dealing with clinical and epidemiological issues. Since we are neither clinicians nor epidemiologists but rather, physiologists, biophysicists and bioengineers, we offer a different point-of-view. Our motivation commences from the knowledge that upwards of 80% of overall morbidity and mortality associated with diabetes is attributable to cardiovascular disease, involving both the arterial/arteriolar system and the myocardium per se. Specifically, we focus on the 'diabetic heart' first described by Rubler et al. [7] from four diabetic patients who had died of diabetic glomerulosclerosis and whose hearts w...