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

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.

Keywords: Cardiometabolic disease; Endotoxemia; Inflammation; Insulin sensitivity; Isoflavone; LPS; Soy.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Copyright © 2014 Elsevier B.V. All rights reserved.

Figures

Figure 1. Overview of the Discovery and Validation/Extension studies

The relationship between dietary isoflavone intake with inflammatory markers and insulin resistance was assessed in the GENE-LPS Diet Study sample (N=215). Findings were supported by complementary analyses in the MECHE Study (N=129) and the NHANES 2005–2006 sample (N=884).

Figure 2. The cytokine response to LPS in individuals with moderate-high (>1.48mg/day, N=65) or low-no (

Individuals with moderate-high isoflavone intake had a higher inflammatory response across multiple cytokines post-LPS, as measured by peak TNFα levels (A. P=0.009), peak IL-1RA levels (B. P=0.09) and peak IL-6 levels (C. P=0.2). P Value from ANCOVA analysis adjusted for age, sex, race, BMI.

Figure 3. Insulin response to Oral Glucose Tolerance Test (OGTT) differs by soy consumption in MECHE

In the MECHE study, soy consumers (N=20) had a significantly lower overall insulin response to glucose bolus during OGTT (A) (ΔAUC P=0.03), despite similar glucose curves (B) to soy non-consumers (N=109).

Figure 4. Fasting insulin and glucose, and 2-hour glucose post-OGTT in NHANES are lower in EA soy consumers than soy non-consumers

Fasting insulin was significantly lower in soy consumers (A. P=0.028 N=121 consumer, N=517 non-consumer), while fasting glucose trended towards being lower (B. P=0.091) and glucose 2-hours post-OGTT was significantly lower (C. P<0.0001).