HIGH TISSUE-SODIUM ASSOCIATES WITH SYSTEMIC INFLAMMATION AND INSULIN RESISTANCE IN OBESE INDIVIDUALS

Abstract

Background and Aims:

High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association.

Methods and Results:

In a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using ²³Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m² in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r=−0.45, p=0.01) and skin sodium (r=−0.46, p=0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction= 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction= 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction=0.01).

Conclusions:

Higher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies.

Introduction

Obesity affects approximately one third of the world’s population¹ and leads to the development of insulin resistance, type 2 diabetes and cardiovascular disease². While the exact underlying mechanisms are not completely understood, evidence from human and animal research suggest that chronic inflammation plays a causative link between obesity and insulin resistance^3–5.

Sodium content of the tissue, including skin and muscle, which can be quantified using sodium magnetic resonance imaging (²³Na-MRI)⁶. Recent animal studies have shown that high tissue sodium causes systemic inflammatory activation and subsequent development of cardiovascular end organ damage, suggesting that excess tissue sodium accumulation may play a role in the intricate relationship between sodium, inflammation, and cardiovascular disease⁷. It remains unknown whether excess tissue sodium plays a role in the development of obesity-related insulin resistance^8,9.

In this cross-sectional study, we hypothesized that the pro-inflammatory effects of excess tissue sodium accumulation may contribute to the development of obesity-related insulin resistance. To test this hypothesis, we examined the relationship between sodium content in the muscle and skin, and insulin sensitivity in obese individuals and compared with their non-obese counterparts. Tissue sodium was measured by ²³Na-MRI, and insulin sensitivity was assessed by glucose disposal rate (GDR) measured by hyperinsulinemic euglycemic clamp technique. GDR is a reflection of ability to efficiently utilize glucose in the setting of hyperinsulinemia, higher rate indicating more sensitivity, i.e. healthier metabolic state.

Methods

Study Population

A cross-sectional investigation was carried out in 83 study subjects who were recruited for a randomized clinical trial conducted at Vanderbilt University Medical Center from September 2014 to May 2018 (NCT02236520)¹⁰.Thirty (30) of the subjects were classified as obese based on the body mass index (BMI) cutoff of ≥30 kg/m² established in the National Institute of Health’s evidence report on the identification, evaluation and treatment of overweight and obesity in adults as well as in American College of Cardiology/American Heart Association Task Force on Practice Guidelines^11,12. Patients on antihypertensive or antidiabetic therapy or patients with acute cardiovascular events in the last 6 months, impaired kidney or liver function, morbid obesity or contraindications to magnetic resonance imaging were excluded. A total of 96 study subjects gave consent and 83 completed the study (Figure 1). All subjects provided informed consent and the study was approved by the institutional review board at Vanderbilt University Medical Center (VUMC).

Figure 1.

Consort flow diagram.

Hyperinsulinemic Euglycemic Clamp

Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp technique, adapted from the original work by DeFronzo et al.¹³ All clamp study procedures were carried out at the Clinical Research Center at VUMC after an overnight 8-hour fasting period. The detailed methodology of the clamp procedures can be found elsewhere¹⁴ and is briefly described here.

On the morning of the study day, peripheral intravenous access was obtained in for the infusion of insulin and dextrose. After baseline blood samples were obtained, primed infusion of regular human insulin at the concentration of 2.0 mU/kg/min was started and continued throughout the study to maintain hyperinsulinemia with a goal plasma insulin of 100 μU/mL. Plasma glucose concentration was monitored every 5 minutes. Dextrose 20% in water infusion was adjusted to reach and maintain the target plasma glucose levels of 90 ± 5 mg/dL. Once steady state was reached, the dextrose infusion rate was held constant for 30 minutes and insulin-mediated glucose disposal rate (GDR) (mg/kg/min) was calculated from samples taken during this period. GDR was normalized to body weight and used as the index of insulin sensitivity.

Magnetic Resonance Imaging (MRI)

The quantification of peripheral tissue sodium content at the mid-calf area was measured as published previously^15,16. Briefly, subjects underwent an MRI exam using a 3.0 T MR scanner (Philips Healthcare, Best, The Netherlands) and a single-tuned receive-only quadrature sodium coil (Rapid Biomedical GmbH, Rimpar, Germany). Study subjects were positioned supine to image the leg at approximately the widest part of the calf. The left lower leg was placed over a holder containing four solutions of saline at physiologic tissue sodium concentrations (10, 20, 30, 40 mmol/L NaCl in milli-Q water). The leg and standards were positioned in the center of the coil such that the leg remained supported at the knee and ankle, and the posterior skin closely in contact with the phantom holder. Tissue sodium content at the mid-calf was calculated based on a linear calibration of ²³Na-MRI signal in the saline phantoms. Manual segmentations in the skin (posterior semi-perimeter only, because of tapering of the anterior leg across the slice thickness) and muscle (including all muscle groups) were performed as described previously^15,16.

Laboratory Analysis

All blood sampling was performed at the Clinical Research Center and analyzed at VUMC central laboratories. Leptin samples were analyzed at Vanderbilt’s Hormonal Lab Core. High molecular-weight adiponectin and interleukin 6 (IL-6) were measured by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). High-sensitivity C-reactive protein (hsCRP) was measured by high-sensitivity particle-enhanced turbidimetric UniCel DxI Immunoassay system (Beckman Coulter) at the Vanderbilt Clinical laboratory.

Dietary Recall

Data on dietary intake were collected and analyzed using Nutrition Data System for Research software version 2017 (Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN)¹⁷. Two 24-hour dietary recalls were obtained in-person and over telephone (one weekday and one weekend) and used to estimate a 7-day average.

Statistical Analysis

Descriptive statistics were expressed as median and interquartile range (IQR) for continuous variables and as frequencies (percentages) for categorical variables. Chi-square test and Wilcoxon rank-sum test were used for the comparison of descriptive statistics between obese versus/non-obese individuals as appropriate. Spearman’s rank correlation was used to evaluate the correlation of GDR and tissue sodium content in the obese and non-obese individuals. Linear regression analyses were performed to estimate associations between GDR and tissue sodium content. Scatter diagrams of GDR and tissue sodium and line of best fit (with 95% confidence intervals) were plotted for the obese subjects.

Multivariable linear regression models were fitted with GDR as the dependent variable in the obese individuals. Muscle and skin sodium content were the main independent variables. Models were further adjusted for demographics (age and sex). To examine potential effect modification of the associations between GDR and tissue sodium by inflammatory markers, linear models were fitted with tissue sodium and interaction terms, either sodium*hsCRP or sodium*IL-6. A similar analysis was utilized in the entire cohort to investigate the potential effect modification by leptin by fitting a linear model with tissue sodium-leptin product interaction terms, which were adjusted for BMI. GDR, tissue sodium content, hsCRP, IL-6 and leptin were log-transformed in all regression models.

There were 1 and 5 missing values for hsCRP in the obese and non-obese subjects, respectively. Dietary sodium data were missing in 4 non-obese individuals. Covariate data were assumed to be missing at random and given the small missingness proportions for most of the covariates. The models that included hsCRP or dietary sodium were fit without imputation of missing values. All analyses were performed using Stata version 16.

Results

Baseline Characteristics

Thirty obese and fifty-three non-obese study individuals were included in the analysis (Table 1). Females comprised 67.5% of participants and 41% were African American. Median (IQR) of BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m², in obese and non-obese groups, respectively. Median (IQR) GDRs were 6.4 (4.7, 8.2) in the obese and 10.6 (6.7, 13.4) mg/kg/min in the non-obese subjects. Compared to the non-obese, obese subjects had significantly lower GDR, higher serum leptin, hsCRP and IL-6 levels (Table 1). Muscle and skin sodium were 17.1 (15.6, 18.7) and 13.6 (12, 17.6) mmol/L in the obese; 15.8 (14.8, 19) and 12.3 (10.9, 15.5) in the non-obese subjects (Table 1 and Figure 2). There was no significant difference in tissue sodium contents between obese and non-obese subjects.

Table 1.

Baseline characteristics of study subjects

Characteristic	Obese (n=30)	Non-Obese (n=53)	P-value
Age (years)	49 (38, 58)	48 (34, 55)	0.44
Female, n (%)	21 (70)	35 (66)	0.81
African American origin (%)	15 (50)	34 (64.2)	0.25
BMI (kg/m2)	33 (31.5, 36.3)	25 (23.5, 27.2)	<0.001*
SBP (mmHg)	128 (121, 134)	124 (118, 129)	0.047*
DBP (mmHg)	77.5 (72, 84)	74 (70, 81)	0.14
GDR (mg/kg/min)	6.4 (4.7, 8.2)	10.6 (6.7, 13.4)	<0.001*
Muscle Na+ (mmol/L)	17.1 (15.6, 18.7)	15.8 (14.8, 19)	0.30
Skin Na+ (mmol/L)	13.6 (12, 17.6)	12.3 (10.9, 15.5)	0.13
hsCRP (mg/dL)	2.6 (1.1, 3.8)	1 (0.5, 2.2)	0.01*
IL-6 (pg/mL)	2.1 (1.4, 2.9)	1.5 (1, 2.4)	0.04*
Leptin (ng/ml)	52 (29.3, 70.1)	22.0 (12.7, 33.4)	<0.001*
Adiponectin (μg/ml)	18.3 (7.1, 35.4)	21 (11.1, 35.5)	0.30
Dietary Na+ (mg)	2853 (2220, 3748)	2821 (2120, 3813)	0.58

Data are presented as median (IQR) unless stated otherwise.

^*Indicates two-sided p<0.05 meets significance criteria.

Figure 2.

Tissue sodium content in obese and non-obese subjects. (A) Representative ²³Na-MRI acquisitions and segmentations of the lower calf. A representative sample of an obese (top row) and a lean (bottom row) subject. Images include (from first to fourth column): ¹H MRI Dixon water-weighted image, ²³Na MRI quantification of tissue sodium content and sodium phantoms used for calibration of the sodium signal, quantified tissue sodium content maps utilizing the skin segmentation, and quantified tissue sodium content maps utilizing the muscle segmentation. Segmentations of skin and muscle were accomplished by assigning regions of interest the water-weighted image. The holes that are present in the muscle segment column reflect blood vessels that were removed to ensure accurate muscle tissue sodium quantification. The colorbar visualizes sodium levels ranging from 0–40 mmol/L in a perceptually uniform colormap (magma). (B) Dot plots of skin and muscle sodium content in non-obese and obese subjects.

Relationship of Dietary Sodium Intake with Tissue Sodium and GDR

The median (IQR) dietary sodium intake was 2827 (2183–3813) mg/day. There was no correlation between dietary sodium intake and skin or muscle sodium in the entire cohort (r=0.14, p=0.2 and r=0.07, p=0.6 for muscle and skin Na+, respectively). Furthermore, no correlation was found between dietary sodium intake and GDR in the obese and non-obese subjects (r= −0.14, p=0.46 and r=−0.03, p=0.87 for obese and non-obese subjects, respectively).

Relationship between GDR and Tissue Sodium

GDR negatively correlated with skin and muscle sodium in the obese subjects (r=−0.46, p=0.01 and r=0.45, p=0.01 for skin and muscle sodium, respectively) (Figure 3). In multivariate analysis adjusted for age and sex, the association of GDR with muscle Na⁺ remained significant whereas the association between GDR and skin Na+ was attenuated after adjustment for sex (Table 2). There was no correlation between GDR and muscle or skin sodium in the non-obese subjects (r=0.07, p=0.6 and r=−0.05,Effect of inflammatory markers on the relationship between GDR and p=0.7 for skin and muscle Na+, respectively). Effect of inflammatory markers on the relationship between GDR and Tissue Sodium in Obese Individuals

Figure 3.

The regression plots of skin (A) and muscle (B) sodium concentrations with GDR in obese subjects. Plots depict the linear regression line of best line of fit along with 95% confidence bands.

Table 2.

The associations between GDR and tissue sodium content in obese and non-obese subjects.

	Obese		Non-obese
	Beta (CI 95%)	p-value	Beta (CI 95%)	p-value
Muscle Sodium
Unadjusted	−1.11 (−1.99, −0.24)	0.015*	−0.13 (−0.93, 0.66)	0.74
Adjusted for age	−1.08 (−1.97, −0.19)	0.020*	−0.04 (−0.84, 0.76)	0.91
Adjusted for sex	−0.99 (−1.9,−0.08)	0.034*	−0.14 (−0.94, 0.67)	0.74
Skin Sodium
Unadjusted	−0.45 (−0.83, −0.07)	0.022*	0.14 (−0.32, 0.59)	0.55
Adjusted for age	−0.47 (−0.92, −0.03)	0.037*	0.35 (−0.15, 0.85)	0.18
Adjusted for sex	−0.39 (−0.83,−0.05)	0.080	0.20 (−0.33, 0.73)	0.45

^*Indicates two-sided p<0.05 meets significance criteria.

To investigate the potential role of inflammation in the relationship between tissue sodium and obesity-related insulin resistance, further interaction analysis was conducted in the obese subjects. There was significant effect modification of the association of GDR and tissue sodium by the inflammatory markers. GDR changed more per unit changes in muscle or skin sodium at higher levels of hsCRP (p-interaction= 0.028 and 0.005 for muscle and skin Na+, respectively) and higher levels of IL-6 (p= 0.05 and 0.01 for muscle and skin Na+, respectively). For example, a 10% higher muscle sodium was associated with a 10.4 % lower GDR at a serum hsCRP of 2 mg/L, versus an up to 27.9 % lower GDR at a serum hsCRP level of 10 mg/L. Likewise, a 10% higher muscle sodium was associated with a 10.3% lower GDR at a serum IL-6 of 2 pg/ml, versus an up to 33.7% lower GDR at a serum IL-6 of 6 pg/ml. Figure 4A and 4B show the effect of changing levels of inflammatory markers on the relationship between GDR and muscle sodium. These effect modifications were not observed in non-obese individuals (data not shown).

Figure 4.

The interactions between tissue sodium, inflammatory markers and leptin levels. (A) Interaction between muscle Na+ and plasma hsCRP for the association with GDR in obese individuals. Subjects with very low hsCRP had higher GDR even with very high muscle Na+ concentrations. At higher hsCRP levels, there was a greater decrease in GDR per unit change in muscle Na+. P for interaction 0.028. (B) Interaction between muscle Na+ and plasma IL-6 for the association with GDR in obese individuals. Subjects with very low IL-6 had higher GDR even with very high muscle Na+ concentrations. At higher IL-6 levels, there was a greater decrease in GDR per unit change in muscle Na+. P for interaction p= 0.05. (C) Interaction between muscle Na+ and serum leptin for the association with GDR in the entire cohort. The association between GDR and muscle sodium was stronger with higher levels of leptin (p-interaction= 0.01).

Effect of leptin on the relationship between GDR and Tissue Sodium

In our study, significantly higher levels of serum leptin levels were observed in the obese subjects compared to non-obese object¹⁸. Therefore, multiple regression analysis was performed to determine the extent to which tissue sodium, BMI and serum leptin acted independently to determine insulin sensitivity in the overall cohort. Muscle sodium content, serum leptin and BMI were independently associated with the GDR. In the regression model utilizing skin sodium as the main predictor of interest, skin sodium and serum leptin were independently associated with the GDR (Table 3). To assess a potential effect modification by leptin on the association between tissue sodium and GDR, an interaction term between leptin and tissue sodium was subsequently included in the analysis. There was significant effect modification of serum leptin on the relationship of GDR with muscle sodium (p for interaction=0.01). For example, at a serum leptin of 110 ng/ml, 10% higher muscle sodium content was associated with 21% lower GDR (p=0.001). On the contrary, at a serum leptin of 10 ng/ml, muscle sodium was no longer significantly associated with GDR (p=0.6). The association between muscle sodium and GDR was significant only at serum leptin levels of 17.4 ng/ml and above. Figure 4C depicts the change in the relationship between muscle sodium and GDR with changing levels of serum leptin. No interaction was found between leptin and skin sodium in predicting GDR. In univariate analysis of the associations of tissue sodium with BMI, inflammatory markers and serum leptin (Supplemental Table 1), skin sodium was found to significantly decrease with increasing serum leptin.

Table 3.

The associations between GDR, tissue sodium and leptin in all subjects.

	Beta (CI 95%)	p-value
Muscle Sodium
Muscle Sodium	−0.57 (−1.150, −0.001)	0.05*
Leptin	−0.17 (−0.30, −0.045)	0.009*
BMI	−0.02 (−0.04, −0.005)	0.015*
Skin Sodium
Skin Sodium	−0.45 (−0.77, −0.12)	0.007*
Leptin	−0.25 (−0.39, −0.11)	0.001*
BMI	−0.02 (−0.04, 0.002)	0.084

Muscle sodium, skin sodium and leptin are log-transformed.

Discussion

We investigated the relationship between tissue sodium accumulation and insulin resistance in obese individuals. Our results show a significant direct correlation of muscle and skin sodium contents with obesity-related insulin resistance. As a potential mechanism, we found that the association between tissue sodium and insulin resistance was modified by circulating inflammatory markers and was significant only at higher levels of inflammatory markers.

The association between insulin resistance and sodium content of muscle was previously shown in subjects on maintenance hemodialysis¹⁹. Muscle sodium content was found to inversely associate with GDR as well as leucine disposal rate, a measure of whole-body protein kinetics, suggesting that high sodium microenvironment within the muscle may interfere with insulin signaling and energy metabolism¹⁹. Skeletal muscle is responsible of approximately 80% of insulin mediated glucose uptake, making it the major regulator of whole-body glucose metabolism²⁰. Therefore, insulin resistance in the skeletal muscle is central to the development of systemic insulin resistance and type 2 diabetes mellitus²¹. The strong inverse association between GDR and muscle sodium found in the current study introduces excess tissue sodium accumulation as a potential risk factor for the development of obesity-related insulin resistance and calls for further studies to investigate whether high interstitial sodium accumulation interferes with insulin action in the muscle and contributes to the development of insulin resistance in obesity.

A notable finding in our study was the significant effect modification of serum inflammatory markers on the relationship between tissue sodium and insulin resistance implying that systemic immune activation may play a role in the relationship between tissue sodium accumulation and obesity-related insulin resistance. Obese adipose tissue is a significant source of inflammatory mediators and chronic inflammation²², which in turn is a major driver of insulin resistance in obesity²³. Inflammation in adipocytes disrupts free fatty acid metabolism that can induce insulin resistance in the muscle and liver²⁴. This inflammatory cascade is further aggravated by infiltration of the adipose tissue by macrophages and T lymphocytes, inducing a chronic systemic inflammatory status and systemic insulin resistance²⁵. Accordingly, inflammatory markers, including hsCRP and IL-6, strongly correlate with higher glucose intolerance^23,26. Importantly, excess tissue sodium is also intricately linked with inflammation²³. Recent data suggest that high extracellular sodium, equivalent to the concentrations that can be found in the human skin , acts as a proinflammatory stimulus²⁷. At high concentrations, extracellular sodium enters antigen presenting cells and triggers T cell activation and release of various proinflammatory cytokines, including IL-1β and IL-6. The resulting local and systemic inflammatory state participates in the development of hypertension and cardiovascular end organ damage. Skin is a key reservoir of antigen presenting cells and Barbaro et al. recently showed that monocytes isolated from individuals with high skin sodium exhibit markers of sodium-induced activation²⁸. Based on our observation that the association between tissue sodium and insulin resistance was dependent on the presence of higher levels of systemic inflammation, it can be hypothesized that high salt-induced inflammation may have an additive effect on obesity-associated inflammation and, in turn, aggravate insulin resistance^22–26. Skin sodium storage is seen with increased content and sulfation of glycosaminoglycans (GAGs), which are negatively charged polyanions²⁹. While binding of positively charged sodium cations to GAGs results in osmotically inactive sodium storage in the interstitium³⁰, excess sodium can be stored both intracellular or extracellularly³¹ and the location of high tissue sodium content measured via NaMRI remains undetermined^32,33. While animal studies suggest that sodium storage in muscle may predominantly be intracellular space,³⁴. it is unclear whether intracellular storage is paralleled by extracellular storage. More detailed studies are needed to investigate the precise location of excess sodium and how this relates to the interplay between insulin resistance, tissue sodium and inflammation.

We also found that serum leptin was a significant predictor of insulin sensitivity independent of BMI and modified the interaction between muscle sodium and insulin sensitivity in the entire cohort including both obese and non-obese subjects. No interaction was found between skin sodium and leptin in their association with insulin sensitivity. Leptin is produced by adipose tissue and functions as the key regulator of body weight and energy balance³⁵. Leptin receptors are expressed in skeletal muscle, where it functions to modulate insulin sensitivity of the tissue by increasing glucose uptake and oxidation^36–38. Circulatory leptin levels rise dramatically with increasing adiposity and are associated with the development of insulin resistance³⁹. Obese individuals are characterized by hyperleptinemia due to tissue specific insensitivity to leptin’s actions, defined as leptin resistance¹⁸. This obesity-related leptin resistance impairs cellular metabolism in the key regulators of glucose homeostasis including the skeletal muscle⁴⁰. In our cohort, obese subjects had substantially higher leptin levels as expected, and muscle sodium associated more strongly with insulin resistance among individuals with hyperleptinemia. There are various potential mechanisms that can explain such interaction. In normal physiology, leptin’s favorable actions in the myocyte may counteract the detrimental effects of high extracellular sodium on insulin signaling. Patients with leptin resistance, who are characterized by high circulating levels of the hormone, may be more vulnerable to these effects of high sodium. Leptin also has a key role in immune modulation directly via the leptin receptor in immune cells and has been implicated in the development of obesity-associated inflammation⁴¹. Leptin is known to have proinflammatory actions on both antigen presenting cells and CD4+ T cells^42–45, which are the major drivers of sodium-induced inflammation⁴⁶. Therefore, hyperleptinemia may also promote the harmful effects of high tissue sodium by potentiating immune activation. Further studies are necessary to reveal the mechanisms by which leptin may play a role in the relationship between muscle sodium accumulation and insulin sensitivity. Despite the lack of an interaction skin sodium and leptin in their association with insulin sensitivity, skin sodium was found to be negatively associated with leptin. Leptin has been shown to stimulate proliferation of keratinocytes and fibroblasts and promote collagen synthesis⁴⁷, therefore may influence GAG content in the skin. The nature of the association between leptin and skin sodium requires further research.

Our study has several strengths and limitations. We used hyperinsulinemic-euglycemic clamp, which is considered the gold-standard method to assess insulin sensitivity. Although we examined several potential factors that may play a role in the association between tissue sodium and insulin resistance, including inflammatory markers and adipocytokine levels, the cross-sectional design of this study limits the ability to determine a causality. Dietary salt intake was measured by two 24-hour dietary recalls. Since diet can vary substantially day to day⁴⁸, the accuracy of the recalls to estimate long-term dietary salt intake is limited. Additionally, our sample size is relatively small, further limiting the power to establish inference. Data from large prospective studies and complimentary assessments are required to characterize the nature of such association and the involved pathophysiological pathways. It is noteworthy that the sodium content in skin and muscle did not differ between obese and non-obese subjects and did not associate with BMI in supplemental univariate analysis that included the entire study population. That said, our results highlight the changing risk profile in the setting of obesity and high tissue sodium content suggesting that the exaggerated insulin resistance in this setting could be the culprit for worsening overall metabolic miliue.

In conclusion, the results of this cross-sectional study suggest that high tissue sodium may be linked with the development of insulin resistance in the obese population. Our results underscore the complexity between tissue sodium accumulation and associated metabolic adverse events. Is elevated tissue sodium accumulation a driver or a consequence of dysmetabolism; how does it relate with increased adiposity and the resulting hormonal and inflammatory milieu; could intervention against such accumulation lead to clinically significant improvements? We have not answered these questions, but we present them for subsequent investigations.

Highlights for “High Tissue-Sodium Associates with Systemic Inflammation and Insulin Resistance in Obese Individuals”.

• High tissue sodium associates with increased insulin resistance in obese individuals.

• This association is stronger with increasing levels of serum inflammatory markers.

• This association is stronger with increasing levels of leptin resistance.

• Systemic inflammation and leptin dysregulation may be implicated in the association between tissue sodium and insulin sensitivity.