Dr. Ron’s Research Review – July 31, 2013

© 2013

This week’s research review focuses on Salt.

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-alpha and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of experimental autoimmune encephalomyelitis, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells. (Kleinewietfeld, Manzel et al. 2013)

Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. (Lastra, Dhuper et al. 2010)

Low-salt diet, however, increases insulin resistance in healthy subjects (Garg, Williams et al. 2011)

Dr. Ron


Articles

Low-salt diet increases insulin resistance in healthy subjects

            (Garg, Williams et al. 2011) Download

Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium <20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium >150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 +/- 12.5 years (range, 18-65) and with body mass index of 25.3 +/- 4.0 kg/m(2), were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 +/- 1.6 vs 2.4 +/- 1.7, P < .01). Serum aldosterone (21.0 +/- 14.3 vs 3.4 +/- 1.5 ng/dL, P < .001), 24-hour urine aldosterone (63.0 +/- 34.0 vs 9.5 +/- 6.5 mug/d, P < .001), and 24-hour urine norepinephrine excretion (78.0 +/- 36.7 vs 67.9 +/- 39.8 mug/d, P < .05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation.

Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells

         (Kleinewietfeld, Manzel et al. 2013) Download

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-alpha and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

Salt, aldosterone, and insulin resistance: impact on the cardiovascular system

            (Lastra, Dhuper et al. 2010) Download

Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.


References

Garg, R., G. H. Williams, et al. (2011). "Low-salt diet increases insulin resistance in healthy subjects." Metabolism 60(7): 965-8. [PMID: 21036373]

Kleinewietfeld, M., A. Manzel, et al. (2013). "Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells." Nature 496(7446): 518-22. [PMID: 23467095]

Lastra, G., S. Dhuper, et al. (2010). "Salt, aldosterone, and insulin resistance: impact on the cardiovascular system." Nat Rev Cardiol 7(10): 577-84. [PMID: 20697411]