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

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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.

Résumé

L'hyperinsulinémie et l'insulinorésistance ont été décrits il y a plus de 30 ans comme étant des facteurs importants contribuant à une pression artérielle (PA) élevée associée à l'obésité et au syndrome métabolique, également appelé syndrome X. Ce concept a été initialement soutenu par des études cliniques et démographiques montrant des corrélations entre l'hyperinsulinémie, l'insulinorésistance et une PA élevée chez les personnes atteintes du syndrome métabolique. Des études de court terme sur des animaux de laboratoire et chez l'Homme ont fourni des preuves supplémentaires que l'hyperinsulinémie peut provoquer une augmentation de l'activité du système nerveux sympathique (SNS) et de la rétention de sodium au niveau rénal qui, si elle est maintenue, pourrait augmenter la PA. Bien que les perfusions d'insuline puissent accroître l'activité du SNS et augmenter légèrement la PA chez les rongeurs, l'administration chronique d'insuline n'augmente pas significativement la PA chez les individus insulinorésistants maigres ou obèses, que ce soit chez les lapins, les chiens, les chevaux ou chez l’Homme. De multiples études chez l'Homme et les animaux de laboratoire ont également montré qu'une hyperinsulinémie et une insulinorésistance sévère peuvent survenir en absence de PA élevée. Ces observations amènent à se demander si l’insulinorésistance et l'hyperinsulinémie sont des facteurs majeurs liant l'obésité et le syndrome métabolique à l'hypertension. D'autres mécanismes, tels que la compression physique des reins, l'activation du système rénine-angiotensine-aldostérone, l'hyperleptinémie, la stimulation du système à mélanocortine du cerveau et l'activation du SNS, semblent jouer un rôle plus critique dans l'initiation de l'hypertension chez les sujets obèses atteints d'un syndrome métabolique. Cependant, les effets métaboliques de l'insulinorésistance, notamment l'hyperglycémie et la dyslipidémie, semblent interagir en synergie avec l'augmentation de la PA pour provoquer des lésions vasculaires et rénales qui peuvent exacerber l'hypertension et les dommages associés aux reins et au système cardiovasculaire.

Section snippets

Epidemiological evidence associating insulin resistance and hyperinsulinemia with hypertension

More than 30 years ago investigators observed that people with high plasma insulin concentration and insulin resistance often had higher BP compared with those with normal insulin levels.12, 13, 14, 15, 16, 17 The majority of people with insulin resistance and hyperinsulinemia also exhibited a cluster of other metabolic abnormalities, including elevated serum triglycerides, dyslipidemia with low HDL and high low-density lipoproteins, among other factors. This “metabolic syndrome” included

Mechanisms That Initiate Hypertension in Obesity and Metabolic Syndrome

The list of additional factors, besides insulin resistance and hyperinsulinemia, that have been postulated to mediate hypertension on obesity/metabolic syndrome is extensive and includes various adipokines from adipose tissue, abnormal gut microbiota, SNS activation, excess antinatriuretic hormones, deficiency of natriuretic hormones, vascular and kidney dysfunction, and other mechanisms that have been previously reviewed.84, 85, 86, 87 For many of these factors, however, clear cause and effect

Conclusions

Obesity/metabolic syndrome is a major risk factor for multiple chronic diseases including CV diseases. Many hypotheses have been proposed to explain how excess adiposity increases SNS activity, impairs kidney function, and elevates BP. One hypothesis that gained traction more than 30 years ago is that hyperinsulinemia and insulin resistance are major contributors to hypertension in people with obesity/metabolic syndrome. This hypothesis is mainly supported by epidemiologic studies showing

Funding Sources

The authors’ research was supported by National Heart, Lung, and Blood Institute (P01 HL51971), National Institute of General Medical Sciences (P20 GM104357 and U54 GM115428), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK121411 and R00 DK113280), and the American Heart Association.

Disclosures

The authors have no conflicts of interest to disclose.

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