A vascular mechanism for high-sodium-induced insulin resistance in rats

Abstract

Aims/hypothesis High sodium (HS) effects on hypertension are well established. Recent evidence implicates a relationship between HS intake and insulin resistance, even in the absence of hypertension. The aim of the current study was to determine whether loss of the vascular actions of insulin may be the driving factor linking HS intake to insulin resistance. Methods Sprague Dawley rats were fed a control (0.31% wt/wt NaCl) or HS (8.00% wt/wt NaCl) diet for 4 weeks and subjected to euglycaemic-hyperinsulinaemic clamp (10 mU min) or constant-flow pump-perfused hindlimb studies following an overnight fast. A separate group of HS rats was given quinapril during the dietary intervention and subjected to euglycaemichyperinsulinaemic clamp as above. Results HS intake had no effect on body weight or fat mass or on fasting glucose, insulin, endothelin-1 or NEFA concentrations. However, HS impaired whole body and skeletal muscle glucose uptake, in addition to a loss of insulin-stimulated microvascular recruitment. These effects were present despite enhanced insulin signalling (Akt) in both liver and skeletal muscle. Constant-flow pump-perfused hindlimb experiments revealed normal insulin-stimulated myocyte glucose uptake in HS-fed rats. Quinapril treatment restored insulin-mediated microvascular recruitment and muscle glucose uptake in vivo.Conclusions/interpretation HS-induced insulin resistance is driven by impaired microvascular responsiveness to insulin, and is not due to metabolic or signalling defects within myocytes or liver. These results imply that reducing sodium intake may be important not only for management of hypertension but also for insulin resistance, and highlight the vasculature as a potential therapeutic target in the prevention of insulin resistance.

Regulation of microvascular flow and metabolism: An overview

“…It is important to note that most animal models used to investigate insulin resistance develop both myocyte and microvascular insulin resistance. However, we and others have evidence demonstrating that the microvasculature can become insulin resistant prior to changes in myocyte insulin sensitivity suggesting the vasculature is an early contributor to development of insulin resistance …”

“…We have recently characterised two dietary animal models that develop microvascular insulin resistance . In the first model dietary fat in rats is moderately increased from 5% to 9% wt./wt., rather than the more common 5‐ to 7‐fold increase employed in many studies .…”

“…In the first model dietary fat in rats is moderately increased from 5% to 9% wt./wt., rather than the more common 5‐ to 7‐fold increase employed in many studies . The second model we have characterised is the high salt‐fed rat in which dietary NaCl is increased from 0.3% to 8.0% wt./wt . After a 4‐week dietary intervention, both of these animal models develop whole body, skeletal muscle and microvascular insulin resistance in vivo when compared to control rats.…”

High-Salt Diet Gets Involved in Gastrointestinal Diseases through the Reshaping of Gastroenterological Milieu

“…An insulin decrease has also been observed with HSD-fed Wistar rats [26,51]. HSD-induced insulin resistance (IR) was found to be driven by impaired microvascular responsiveness to insulin [52] and linked with decreased insulin sensitivity, phosphatidylinositol (PI) 3-kinase or Akt activation [53], and AT hypoxia [54]. Further study indicated that HSD and IR, alone or combined, might have a strong relationship with obesity-related metabolic disorders [55].…”

Muscle microvascular blood flow responses in insulin resistance and ageing

“…In our laboratory we have recently characterised two dietary animal models of insulin resistance (Premilovac et al . , ). Both of these models support the concept that microvascular insulin resistance develops before, and contributes to, reduced muscle glucose uptake in vivo .…”