Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers

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Abstract

Background and aims

Consumption of foods that modulate inflammatory stress in genetically-prone individuals may influence development of cardiometabolic diseases. Isoflavones in soy-derived foods function as phytoestrogens, have antioxidant and anti-inflammatory activity, inhibit protein-tyrosine kinase activity, and may be atheroprotective. We examined the relationship between soy food consumption and inflammatory responses to endotoxemia, postprandial responses to oral lipid tolerance test (OLTT), and insulin sensitivity from frequently sampled intravenous tolerance tests (FSIGTT).

Methods and results

We administered low-dose endotoxin (LPS 1 ng/kg) to induce transient endotoxemia in young, healthy volunteers (N = 215) of African (AA), and European (EA) ancestry as part of the GENE Study. We further supported these findings in two independent samples: the MECHE Study and NHANES. Soy food consumption was a significant predictor of peak cytokine response following LPS. Individuals with moderate-high (>1.48 mg/day, N = 65) vs. low-no (<1.48 mg/day, N = 150) isoflavone consumption had significantly higher tumor necrosis factor alpha (TNFα) post-LPS (AUC, P = 0.009). Further, high-isoflavone consumers were protected against inflammation-induced decline in insulin sensitivity (SI) in GENE. We observed significant differences by soy consumption in the interferon gamma (IFNγ) response to OLTT, and the insulin response to OGTT in MECHE, as well as significantly lower fasting insulin, and 2-hour glucose post-OGTT in EA NHANES subjects.

Conclusion

We demonstrate that soy consumption may influence inflammatory and metabolic responses. In research of nutritional exposures, measuring evoked phenotypes may be more informative than describing resting characteristics.

The GENE Study was registered under NCT00953667 and the MECHE Study under NCT01172951, both at clinicaltrials.gov.

Introduction

Inflammation is a key component of several cardiometabolic diseases, including obesity, type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD) [1]. While many factors, including genetic, environmental and microbial, influence the development of a pro-inflammatory state, habitual diet may be a key inflammatory regulator [2]. We utilize evoked endotoxemia (LPS) in healthy individuals as a model of physiological responses to inflammatory stimuli, inflammation-induced insulin resistance, and cardiometabolic risk [3], [4], [5], with relevance to postprandial metabolic endotoxemia [6]. Dietary components which modulate response to LPS may influence transient postprandial inflammatory stress, affect ability to appropriately resolve inflammatory stimuli, and influence chronic cardiometabolic disease and diet-induced obesity.

Bioactive food compounds may have important health-modulating effects. Dietary plant-derived phytochemicals have anti-inflammatory and antioxidant properties that may be protective against disease development [7]. Isoflavones, primarily genistein (∼50–60%), daidzein (∼30–40%), and glycitein (∼5–10%), are found in high concentrations in soy-derived foods [8]. Isoflavones function as phytoestrogens [9], inhibit protein-tyrosine kinase activity [10], and may have an anti-proliferative effect on cancer cells [11]. Although human epidemiological and interventional data remain inconclusive, mounting evidence suggests that isoflavones may be atheroprotective [12], [13].

As part of the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study [4], we administered a low dose of endotoxin (LPS 1 ng/kg) to induce a controlled inflammatory response. We found that dietary isoflavone intake was associated with the inflammatory response to endotoxemia, and with endotoxemia-induced changes in insulin sensitivity. The findings were supported by complementary analyses in two independent samples; the MECHE study (www.ucd.ie/jingo/) and NHANES (www.cdc.gov/nchs/nhanes.htm).

Section snippets

GENE study population

Details of the GENE Study have been published previously [4]. Briefly, healthy volunteers (N = 294), non-smokers, age 18–45, BMI 18–30 kg/m2, African American (AA) or European (EA) ancestry were recruited to an inpatient endotoxin challenge (1 ng/kg LPS), and frequently sampled intravenous glucose tolerance tests (FSIGTT) pre- and post-LPS at the University of Pennsylvania (UPenn) Clinical and Translational Research Center (CTRC). Subjects who completed dietary records (N = 215) were analyzed

Dietary isoflavone intake is a predictor of inflammatory response in the GENE study

Baseline anthropomorphic and inflammatory characteristics for GENE Study subjects (N = 215, 50% female, 32% AA, 68% EA) are presented in Table 1A, stratified by the upper vs. lower 2 tertiles of isoflavone intake. Dietary composition is presented in Table 1B.

Using multiple linear regression models, we assessed the relationship between macronutrients (carbohydrate, protein, saturated, monounsaturated and polyunsaturated fatty acids) as well as other bioactive dietary nutrients (beta-carotene,

Discussion

We investigated the effects of dietary isoflavone consumption on evoked phenotypes of relevance to inflammatory cardiometabolic disease. Isoflavone consumption was associated with an increased cytokine response to evoked endotoxemia in young healthy subjects and an increased inflammatory response to an oral lipid load in a general population sample. Isoflavone consumers were somewhat protected against inflammation-induced insulin resistance, and soy consumers had lower fasting glucose and

Funding

The GENE Study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000003 as well as a NIH-NHLBI SCCOR Project grant (P50-HL-083799) to MPR. JFF is supported by a postdoctoral fellowship grant from the American Heart Association (12POST11840017). MPR is also supported by R01-HL-111694, R01-HL-113147, R01-DK-090505, U01-HL-108636 and K24-HL-107643. HMR is supported by SFI PI

Authors' contributions to manuscript

JFF and MPR designed the research. JFF conducted research in the GENE Study. MFR, ERG, LB and HMR conducted research in the MECHE Study. JFF analyzed data and wrote the paper. All authors read and approved the final manuscript.

Conflict of interest

The authors have no conflicts of interest to disclose.

Acknowledgments

We would like to thank the participants of the GENE, MECHE, and NHANES studies, the staff at the UPenn Clinical Translational Research Center and the support of the UPenn Nutrition Core Dietary Assessment Unit.

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