Role of Hyperinsulinemia and Insulin Resistance in Hypertension: Metabolic Syndrome Revisited

Abstract

Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance, and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin-resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation, appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury that can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.

Figure 1 -. Main actions of insulin on BP regulation.

This figure summarizes the main effects of hyperinsulinemia on blood pressure regulation that have been proposed and the evidence from studies in humans and several experimental animal models supporting or refuting these hypothesized effects. BP, blood pressure; Na+, sodium; SNS, sympathetic nervous system.

Figure 2 -. Potential mechanisms of hypertension and cardiovascular and renal injury in obesity.

Obesity, particularly visceral obesity, triggers activation of the renin-angiotensin-aldosterone system (RAAS) which together with increased sympathetic nervous system (SNS) activity increases renal sodium reabsorption and blood pressure. Physical compression of the kidneys caused by increased fat in and around the kidneys may also stimulate renal sodium reabsorption and contribute to RAAS activation in obesity. When obesity is sustained, progressive metabolic impairments including insulin resistance, compensatory hyperinsulinemia, and accompanying hyperglycemia and dyslipidemia may contribute to inflammation and atherosclerosis and interact with hypertension to cause further injury to the kidneys and cardiovascular system that worsens the hypertension and creates a vicious cycle.