Glucocorticoids affect metabolic but not muscle microvascular insulin sensitivity following high versus low salt intake.

Hanneke E Niessen,Monica T.J Schütten,Peter W De Leeuw,Alfons J.H.M Houben,Casper G Schalkwijk,Jean L.J.M Scheijen,Jos Op ’T Roodt,Yvo H.A.M Kusters,Coen D.A Stehouwer,Marjo P Van De Waardenburg

doi:10.1172/jci.insight.127530

Abstract

BACKGROUNDSalt-sensitive hypertension is often accompanied by insulin resistance in obese individuals, but the underlying mechanisms are obscure. Microvascular function is known to affect both salt sensitivity of blood pressure and metabolic insulin sensitivity. We hypothesized that excessive salt intake increases blood pressure and decreases insulin-mediated glucose disposal, at least in part by impairing insulin-mediated muscle microvascular recruitment (IMMR).METHODSIn 20 lean and 20 abdominally obese individuals, we assessed mean arterial pressure (MAP; 24-hour ambulatory blood pressure measurements), insulin-mediated whole-body glucose disposal (M/I value; hyperinsulinemic-euglycemic clamp technique), IMMR (contrast-enhanced ultrasound), osmolyte and water balance, and excretion of mineralocorticoids, glucocorticoids, and amino and organic acids after a low- and high-salt diet during 7 days in a randomized, double-blind, crossover design.RESULTSOn a low-, as compared with a high-salt, intake, MAP was lower, M/I value was lower, and IMMR was greater in both lean and abdominally obese individuals. In addition, natural logarithm IMMR was inversely associated with MAP in lean participants on a low-salt diet only. On a high-salt diet, free water clearance decreased, and excretion of glucocorticoids and of amino acids involved in the urea cycle increased.CONCLUSIONOur findings imply that hemodynamic and metabolic changes resulting from alterations in salt intake are not necessarily associated. Moreover, they are consistent with the concept that a high-salt intake increases muscle glucose uptake as a response to high salt-induced, glucocorticoid-driven muscle catabolism to stimulate urea production and thereby renal water conservation.TRIAL REGISTRATIONClinicalTrials.gov, NCT02068781.

Highlights

In obesity, an increased susceptibility to the hypertensive effects of salt is often seen in parallel with impaired insulin-mediated glucose disposal (1–6)
In 20 lean and 20 abdominally obese individuals, we assessed mean arterial pressure (MAP; 24-hour ambulatory blood pressure measurements), insulin-mediated whole-body glucose disposal (M/I value; hyperinsulinemic-euglycemic clamp technique), insulin-mediated muscle microvascular recruitment (IMMR), osmolyte and water balance, and excretion of mineralocorticoids, glucocorticoids, and amino and organic acids after a low- and high-salt diet during 7 days in a randomized, double-blind, crossover design
Natural logarithm IMMR was inversely associated with MAP in lean participants on a low-salt diet only

Summary

Introduction

An increased susceptibility to the hypertensive effects of salt (salt sensitivity) is often seen in parallel with impaired insulin-mediated glucose disposal (insulin resistance) (1–6). The exact underlying mechanisms for the association of salt-sensitive hypertension with insulin resistance in obese individuals have not been clarified, several explanations have been proposed, including inappropriate activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, sodium-induced elevation of circulating free fatty acids, and insulin-mediated sodium retention (2, 7, 8). We and others (9–13) have proposed that impairment of microvascular function may contribute to the detrimental effects of salt on blood pressure and insulin sensitivity, in obesity. (skin) capillary recruitment capacity during reactive hyperemia has been shown to be inversely associated with salt sensitivity of blood pressure in normotensive and hypertensive individuals (10). We hypothesized that excessive salt intake increases blood pressure and decreases insulin-mediated glucose disposal, at least in part by impairing insulin-mediated muscle microvascular recruitment (IMMR)

Methods

Results

Conclusion