Metabolism, hypoxia and the diabetic heart

Abstract

The diabetic heart becomes metabolically remodelled as a consequence of exposure to abnormal circulating substrates and hormones. Fatty acid uptake and metabolism are increased in the type 2 diabetic heart, resulting in accumulation of intracellular lipid intermediates and an increased contribution of fatty acids towards energy generation. Cardiac glucose uptake and oxidation are decreased, predominantly due to increased fatty acid metabolism, which suppresses glucose utilisation via the Randle cycle. These metabolic changes decrease cardiac efficiency and energetics in both humans and animal models of diabetes. Diabetic hearts have decreased recovery following ischemia, indicating a reduced tolerance to oxygen-limited conditions. There is evidence that diabetic hearts have a compromised hypoxia signalling pathway, as hypoxia-inducible factor (HIF) and downstream signalling from HIF are reduced following ischemia. Failure to activate HIF under oxygen-limited conditions results in less angiogenesis, and an inability to upregulate glycolytic ATP generation. Given that glycolysis is already suppressed in the diabetic heart under normoxic conditions, the inability to upregulate glycolysis in response to hypoxia may have deleterious effects on ATP production. Thus, impaired HIF signalling may contribute to metabolic and energetic abnormalities, and impaired collateral vessel development following myocardial infarction in the type 2 diabetic heart.

Introduction

Type 2 diabetes is becoming an epidemic in the Western world, and is increasingly prevalent in developing countries, due to changes in diet, increased sedentary lifestyles, escalating obesity and an ageing population; all features of modern living. In the United Kingdom, 2.6 million people are affected by type 2 diabetes, accounting for £9 billion of government National Health Service spending each year or 10% of the total healthcare budget [1], [2]. Type 2 diabetes is a consequence of an imbalance between insulin responsiveness and insulin production. One of the first clinical signs is glucose intolerance, due to insulin resistance of peripheral organs, including liver, fat and muscle, and is initially compensated by increased pancreatic β-cell insulin secretion. Depending on the plasticity of the β-cells, the hyperinsulinaemic drive may be sustained indefinitely, or β-cell dysfunction may develop leading to hypoinsulinaemia, hyperglycaemia and insulin-dependent diabetes [3]. As a consequence, diabetes is a highly heterogenous disease with many systemic effects.

Heart failure is the leading cause of mortality in people with type 2 diabetes [4]. There is growing evidence that the increased risk of heart failure may occur independently of accelerated coronary artery disease and hypertension, suggesting other mechanisms associated with diabetes underlie the cardiomyopathy [5]. Several mechanisms have been postulated, including impaired cardiac calcium homeostasis, upregulation of the renin–angiotensin system and abnormal cardiac metabolism [5]. Systemic metabolic changes that occur in diabetes modify metabolism in the heart, culminating in abnormal cardiac substrate utilisation, impaired cardiac efficiency and decreased energy generation [6], [7], [8]. Such changes limit the ability of the diabetic heart to alter metabolic substrate selection to match the changing demands of the cardiomyocyte, in response to changes in workload, hormonal stimulation and oxygen availability.

Continuous cardiac contraction requires the synthesis of large amounts of ATP, predominantly generated by oxygen-dependent mitochondrial oxidative phosphorylation. As a consequence, the heart is exquisitely sensitive to changes in oxygen concentration, as can occur under physiological and pathological conditions. Decreases in oxygen concentration result in activation of the evolutionarily-conserved hypoxia-inducible factor (HIF) system, which alters transcription of genes that modify metabolism to increase glycolytic ATP generation and suppress fatty acid oxidation [9], [10], [11]. There is evidence that the HIF system is compromised in the diabetic heart, which may contribute to the metabolic dysfunction and decreased recovery post-infarction [12], [13]. This article will give an overview of substrate metabolism in the healthy heart, and the cardiac metabolic remodelling that occurs in type 2 diabetes. We will discuss the impaired ability of the diabetic heart to upregulate HIF signalling pathways, highlighting the potential impact of an impaired HIF system on metabolism, angiogenesis and the response to ischemia.