Metabolic dysfunction in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is defined as cardiac disease independent of vascular complications during diabetes. The number of new cases of DCM is rising at epidemic rates in proportion to newly diagnosed cases of diabetes mellitus (DM) throughout the world. DCM is a heart failure syndrome found in diabetic patients that is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction, occurring in the absence of hypertension and coronary artery disease. DCM and other diabetic complications are caused in part by elevations in blood glucose and lipids, characteristic of DM. Although there are pathological consequences to hyperglycemia and hyperlipidemia, the combination of the two metabolic abnormalities potentiates the severity of diabetic complications. A natural competition exists between glucose and fatty acid metabolism in the heart that is regulated by allosteric and feedback control and transcriptional modulation of key limiting enzymes. Inhibition of these glycolytic enzymes not only controls flux of substrate through the glycolytic pathway, but also leads to the diversion of glycolytic intermediate substrate through pathological pathways, which mediate the onset of diabetic complications. The present review describes the limiting steps involved in the development of these pathological pathways and the factors involved in the regulation of these limiting steps. Additionally, therapeutic options with demonstrated or postulated effects on DCM are described.

Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study

“…As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 6 0.7 vs. 8.4 6 0.5 mmol/L), lower PDH flux (0.005 6 0.001 vs. 0.017 6 0.002 s -1 ), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9] 12.2 6 0.8 vs. 20 6 2), which are in keeping with early diabetic cardiomyopathy.…”

“…Although some of this risk can be attributed to increased coronary artery disease and hypertension, it is becoming clear that patients with type 2 diabetes are also at risk for the development of "diabetic cardiomyopathy" (2-5), which manifests across a spectrum from subclinical left ventricular (LV) diastolic dysfunction (i.e., transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9]) to overt systolic failure (6). As the incidence of type 2 diabetes is rapidly increasing, understanding the pathophysiology behind diabetic cardiomyopathy and developing new treatment strategies is of increasing clinical importance.Cardiac metabolism and altered substrate use are now emerging as candidate mechanisms underpinning diabetic cardiomyopathy and, as such, are targets for novel treatments (7,8). The cardiac metabolic changes in type 2 diabetes are linked to an increase in circulating fatty acid levels that results from insulin insensitivity and a failure to suppress adipose tissue hormone-sensitive lipase (9).…”

“…Cardiac metabolism and altered substrate use are now emerging as candidate mechanisms underpinning diabetic cardiomyopathy and, as such, are targets for novel treatments (7,8). The cardiac metabolic changes in type 2 diabetes are linked to an increase in circulating fatty acid levels that results from insulin insensitivity and a failure to suppress adipose tissue hormone-sensitive lipase (9).…”

Analysis of Endogenous Antioxidant Peptides and Oxidative Stress Levels in Diabetic Cardiomyopathy

“…The earlier performance of diabetic cardiomyopathy is asymptomatic diastolic dysfunction, eventually lead to a decrease in ventricle compliance, impaired contractile function, which eventually lead to congestive heart failure. The mechanism of diabetic cardiomyopathy is unknown, it mainly involves several factors, including disorder of calcium balance, elevation of renin-angiotensin system activity, mitochondria disorder,abnormal metabolic substrate utility [9][10][11] , enhanced oxidative stress is the central nodes of these factors [12,13] . Oxidative stress induced myocardial cells injury in diabetic, the treatment of exogenous antioxidant should be provided, but the curative effect is not so good by its toxic and side effect.…”

Complications Associated with Diabetes: A Case Study

“…Patients with DM have nerve damage hence unable to feel any kind of trauma [14] and diabetic cardiomyopathy [15].…”