Insulin Resistance: Metabolic Mechanisms and Consequences in the Heart

Abstract

Insulin resistance is a characteristic feature of obesity and Type 2 diabetes 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. 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 utilizing 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 discuss potential new areas for investigating novel mechanisms that contribute to insulin resistance in the heart.

Examining the Role of Insulin in the Regulation of Cardiovascular Health

“…As in skeletal muscle, insulin stimulates GLUT4-mediated glucose uptake in the heart via the PI3K-Akt and CAP-Cbl pathways and also stimulates glucose oxidation [5,11]. Insulin also reduces fatty acid oxidation and utilization, despite increasing fatty acid uptake, allowing a switch from fatty acid to glucose oxidation upon insulin stimulation.…”

“…Insulin also reduces fatty acid oxidation and utilization, despite increasing fatty acid uptake, allowing a switch from fatty acid to glucose oxidation upon insulin stimulation. This metabolic flexibility for ATP production in the heart is important to permit it to respond to the fluctuations in energy substrate supply that occur during intense exercise and the switch between fed and fasted states [1,11].…”

“…Furthermore, insulin stimulation of the PI3K-Akt pathway has been reported to regulate numerous other cardiac processes, including hypertrophy, apoptosis and autophagy, as reviewed elsewhere [11,15]. Insulin infusion is used in the clinical setting to improve outcomes in acute coronary patients, yet the mode of action and efficacy of this is still uncertain [15].…”

Heart Failure as a Comorbidity of Diabetes: Role of Dipeptidyl Peptidase 4

“…Indeed, type 1 diabetic rodents generated by streptozotocin-induced insulin deficiency exhibits myocardial atrophy 30) . The myocardium possesses an insulin receptor that determines its innate insulin signaling pathway connecting to metabolic 31) and mitochondrial remodeling [31][32][33] . It gains consensus that an abnormal excess of insulin signaling exerts vicious effects on the cardiovascular sys-induced impaired Ca 2 homeostasis 61) .…”

Fatty Acid Chain Elongation in Palmitate-perfused Working Rat Heart

“…The crucial role of palmitate conversion to stearate for the emergence of insulin resistance in liver raises the question of a similar effect in other tissues, such as the heart. If this exists, then cardiac Elovl6 could be a viable target to affect insulin resistance of the heart and impacts the heart in many ways (24).…”