Insulin resistance: metabolic mechanisms and consequences in the heart

Abstract

Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus and impacts the heart in various ways. Impaired insulin-mediated glucose uptake is a uniformly observed characteristic of the heart in these states, although changes in upstream kinase signaling are variable and dependent on the severity and duration of the associated obesity or diabetes mellitus. The understanding of the physiological and pathophysiological role of insulin resistance in the heart is evolving. To maintain its high energy demands, the heart is capable of using many metabolic substrates. Although insulin signaling may directly regulate cardiac metabolism, its main role is likely the regulation of substrate delivery from the periphery to the heart. In addition to promoting glucose uptake, insulin regulates long-chain fatty acid uptake, protein synthesis, and vascular function in the normal cardiovascular system. Recent advances in understanding the role of metabolic, signaling, and inflammatory pathways in obesity have provided opportunities to better understand the pathophysiology of insulin resistance in the heart. This review will summarize our current understanding of metabolic mechanisms for and consequences of insulin resistance in the heart and will discuss potential new areas for investigating novel mechanisms that contribute to insulin resistance in the heart.

Figure 1

Proposed scheme linking metabolic and signaling pathways to insulin resistance in the heart. Enhanced supply of fatty acids results in enhanced fatty acid uptake into the heart, which in turn, leads to an increase in mitochondrial uptake of long chain fatty acyl CoA . β-oxidation of long chain acyl CoA in the heart is increased in insulin resistance, and may exceed the capacity of the TCA cycle and the electron transport chain to utilize β-oxidation products, leading to increased oxidative stress and ROS production. A mismatch between β-oxidation and the TCA cycle and electron transport chain leads to a buildup of products of incomplete β-oxidation. ROS and products of incomplete oxidation impact signaling cascade such as PKC, JNK and IKK, as well as that of IRS-1 and downstream signaling mediators in the insulin signaling pathway, such as PI3 kinase, Akt and AS160, resulting in reduced GLUT4 translocation and consequently a decrease in glucose uptake in to the heart. However, GLUT4 translocation has also been shown to be impaired in the heart in insulin resistant states in the absence of defects in PI3K and Akt signaling. In these circumstances, hyperactivation of Akt may further exacerbate lipotoxicity by increasing the translocation of CD36 to the plasma membrane. Increased β-oxidation leads to increased production of acetyl-CoA, NADH, AND FADH₂, and citrate, which inhibit PDH and PFK respectively. Generation of Advanced glycation end product (AGE) precursors and AGEs due to increased flux of glucose via the aldose reductase pathway, are an unexplored pathway in insulin resistance. These pathways have been shown to impact signaling via PKC and PI3K/Akt and ROS generation.