Prediabetes is associated with a low grade chronic inflammation which increases the risk, not only for developing type 2 diabetes (T2DM), but also for suffering from cardiovascular disease (CVD)-related events. An elevated lipopolysaccharide (or endotoxin) concentrations, associated with dysbiosis of the intestinal microbiota, has been implicated in the development of both T2DM and CVD. Selective modulation of the intestinal microbiota with prebiotics reduces intestinal permeability and endotoxin concentrations, systemic and local inflammation, and metabolic dysfunction in rodent models. The effect of prebiotic supplementation on cardiometabolic function in prediabetic humans is not known. The general objectives of this R21 proposal are to: 1) determine the feasibility and establish proof-of-concept for the effects of supplementation with the prebiotic inulin on cardiometabolic function in prediabetic humans in order to conduct a larger, more comprehensive randomized double-blind placebo- controlled trial in the future;2) establish our proficiency with measurements of intestinal permeability and characterizing fecal bacterial composition;and 3) obtain preliminary data for effect size generation. To this end, we will randomize 48 prediabetic adults (50-75 yrs) to 4 weeks of prebiotic supplementation with inulin (10 g/day) or placebo (maltodextrin). Subjects will be provided with all of their food for the duration of the study from our metabolic kitchen to avoid potential confounding through differences in dietary intake between individuals. Measurements of intestinal permeability (sugar probes), serum endotoxin concentrations (Factor C Endotoxin Detection Assay), insulin sensitivity (intravenous glucose tolerance testing), skeletal muscle metabolic flexibility (ex vivo fatty acid, glucose and pyruvate oxidation), endothelial function (flow-mediated dilatation), arterial stiffness (applanation tonometry and high resolution ultrasound), and fecal bacterial composition (16S rDNA pyrosequencing) will be measured at baseline and following 4 weeks of treatment. This innovative integrative and translational physiological study will be conducted by an established P.I. and investigative team with extensive experience and a strong record of success performing intervention studies targeting cardiometabolic dysfunction. These studies have significant translational potential as they may advance basic science findings in rodents to humans. The identification of prebiotic supplementation with inulin as a simple and efficacious adjunctive strategy for reducing cardiometabolic risk in prediabetics could change clinical practice by informing dietary recommendations and increasing acceptance of prebiotics by the scientific and medical community.

Public Health Relevance

Lifestyle interventions do not prevent the progression of prediabetes in all individuals. Prebiotic supplementation may offer a simple and efficacious adjunctive therapy to reduce diabetes and CVD risk. The proposed investigation aims to determine the feasibility and establish proof of concept for conducting a larger, more comprehensive randomized double blind placebo-controlled trial on the effects of prebiotic supplementation with inulin on cardiometabolic function in prediabetic humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL118668-01A1
Application #
8644352
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Ershow, Abby
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$174,854
Indirect Cost
$62,354
Name
Virginia Polytechnic Institute and State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061