Pathogenesis and pathophysiology of the cardiometabolic syndrome

Abstract

The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption, leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Noninfectious systemic inflammation associated with adipocyte and adipose tissue macrophage cytokine production can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very low-density lipoprotein triglyceride production, leading to dyslipidemia.

Figures

Figure 1

Physiologic interrelationships between fatty acid metabolism, insulin resistance, and features of the cardiometabolic syndrome. CETP indicates cholesterol ester transfer protein; VLDL, very low‐density lipoprotein triglyceride; HDL, high‐density lipoprotein; TG, triglyceride; FFA, free fatty acid.

Figure 2

 Potential cellular mechanisms for fatty acid–induced insulin resistance. IRS indicates insulin receptor substrate; PI 3 kinase, phosphoinositide 3‐kinase; PKC, protein kinase C; TG, triglyceride; ROS, reactive oxygen species; IKK‐β, I‐kappa B kinase β; NFκB, nuclear factor kappa B. Adapted from Shulman.