Association between insulin resistance and the development of cardiovascular disease

Abstract

For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.

Keywords: Cardiovascular disease; Dyslipidemia; Hyperinsulinemia; Insulin resistance; Metabolism.

Fig. 1

A simplified model of insulin resistance. The loss of suppressive effects of insulin on lipolysis in adipocytes increases free fatty acids. Increased free fatty acids flux to the liver stimulates the assembly and secretion of VLDL resulting in hypertriglyceridemia. Triglycerides (TG) in VLDL are transferred to both HDL and LDL through the action of cholesteryl ester transfer protein (CETP). This process results in a triglyceride-enriched HDL and LDL particle. Triglyceride-enriched HDL is more rapidly cleared from the circulation by the kidney, leaving fewer HDL particles to accept cholesterol from the vasculature. In the glucose metabolism, the insulin resistance results in decreased hepatic glycogen synthesis, owing to decreased activation of glycogen synthase, increased hepatic gluconeogenesis, and glucose delivery by the liver

Fig. 2

Mechanisms implicated in the development of diabetic cardiomyopathy. Normally, the insulin signaling regulates the glucose and lipids metabolism in heart. Insulin resistance produces a metabolic derangement that results in high lipid oxidation and low of glucose oxidation. The activation of the renin–angiotensin–aldosterone system (RAAS) can cause mitochondrial dysfunction, endoplasmic reticulum stress and oxidative stress. This can results in abnormal Ca²⁺ handling and low ATP production leading to cardiomyocyte death. ER endoplasmic reticulum, FFA free fatty acids