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

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.

Keywords: Hypertension; Insulin signaling; Metabolism; Obesity; Vascular Biology.

Figure 1. Enrollment, randomization, and dropout of participants.

Figure 2. MAP, M/I value, and IMMR on a low-salt, as compared with a high-salt, diet in the total study population.

(A) MAP: low salt: n = 40 (20 lean and 20 abdominally obese individuals) vs. high salt: n = 40 (20 lean and 20 abdominally obese individuals. (B) M/I value: low salt: n = 39 (19 lean; no insulin levels available in 1 participant and 20 abdominally obese individuals) vs. high salt: n = 40 (20 lean and 20 abdominally obese individuals). (C) IMMR: low salt: n = 40 (20 lean and 20 abdominally obese individuals) vs. high salt: n = 39 (20 lean and 19 abdominally obese individuals; IMMR data unavailable in 1 participant). MAP was assessed with 24-hour ambulatory blood pressure measurement (ABPM), M/I value with a hyperinsulinemic-euglycemic clamp, and IMMR with contrast-enhanced ultrasound before and during hyperinsulinemia, on both a low-salt (50 mmol/24 h) and high-salt (250 mmol/24 h) diet during 7 days in randomized order. Data are presented as median (black line), first and third quartiles (box edges), and minimum and maximum (whiskers). Data were analyzed with repeated-measures ANCOVA, adjusted for group, age, and sex.

Figure 3. Association of Ln IMMR with MAP on a low-salt diet in lean and abdominally obese individuals.

MAP was assessed with 24-hour ABPM and IMMR with contrast-enhanced ultrasound before and during hyperinsulinemia, on a low-salt diet (50 mmol/24 h) during 7 days. (A) Association of Ln IMMR with MAP on a low-salt diet in lean individuals (n = 20). (B) Association of Ln IMMR with MAP on a low-salt diet in abdominally obese individuals (n = 20). Standardized regression coefficients (sβ; derived from multiple linear regression analyses) are adjusted for age and sex; P lean vs. abdominally obese = 0.084. Lean (○): n = 20; abdominally obese (●): n = 20.

Figure 4. Association of Ln urine cortisol with Ln M/I value on a low- and a high-salt diet.

Standardized regression coefficients (derived from multiple linear regression analyses) are adjusted for group (lean/obese), age, and sex. Low salt (●): n = 39; high salt (○): n = 40. Urinary cortisol excretion was measured by supported liquid extraction (SLE⁺) followed by liquid chromatography tandem mass spectrometry detection (LC-MS/MS), and M/I value was assessed with a hyperinsulinemic-euglycemic clamp, on both a low-salt (50 mmol/24 h) and high-salt (250 mmol/24 h) diet during 7 days in randomized order.

Figure 5. Schematic proposal of basal functional muscle microvascular density, IMMR (i.e., microvascular insulin sensitivity), and the association of IMMR with M/I value (i.e., metabolic insulin sensitivity) during low-, ad libitum– and high-salt intake in lean compared with abdominally obese individuals.

The continuous line represents the insulin-mediated increase of muscle microvascular density, relative to basal density (represented with the dashed line).