The PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study: Rationale, Design and Preliminary Screening Results

Anouk Gijbels, Inez Trouwborst, Kelly M Jardon, Gabby B Hul, Els Siebelink, Suzanne M Bowser, Dilemin Yildiz, Lisa Wanders, Balázs Erdos, Dick H J Thijssen, Edith J M Feskens, Gijs H Goossens, Lydia A Afman, Ellen E Blaak, Anouk Gijbels, Inez Trouwborst, Kelly M Jardon, Gabby B Hul, Els Siebelink, Suzanne M Bowser, Dilemin Yildiz, Lisa Wanders, Balázs Erdos, Dick H J Thijssen, Edith J M Feskens, Gijs H Goossens, Lydia A Afman, Ellen E Blaak

Abstract

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism. Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes. Methods: In total, 240 overweight/obese (BMI 25 - 40 kg/m2) men and women (age 40 - 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either "No MIR/LIR," "MIR," "LIR," or "combined MIR/LIR." Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet. Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR. Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT03708419, clinicaltrials.gov as NCT03708419.

Keywords: dietary intervention study; glucose homeostasis; insulin resistance; metabolic phenotype; obesity; personalized nutrition; precision nutrition; randomized clinical trial.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Gijbels, Trouwborst, Jardon, Hul, Siebelink, Bowser, Yildiz, Wanders, Erdos, Thijssen, Feskens, Goossens, Afman and Blaak.

Figures

Figure 1
Figure 1
Study design of the PERSON study. Tissue-specific insulin resistance (MIR, muscle insulin resistance; LIR, liver insulin resistance) is assessed at screening using a 7-point oral glucose tolerance test and eligible participants with MIR or LIR are randomized to follow either their hypothesized optimal (dark purple) or suboptimal (light purple) diet for 12 weeks. Before and after the intervention, participants are extensively phenotyped during a “characterization week” in a controlled laboratory setting as well as in daily life. BMI, body mass index; MUFA, monounsaturated fatty acid.
Figure 2
Figure 2
Graphical overview of the pre- and post-intervention characterization week. The characterization week contains multiple clinical test days, during which participants are extensively phenotyped. In addition, blood glucose and physical activity are continuously monitored. At home, participants record their dietary intake and feelings of well-being, collect a fecal sample and 24-h urine, and consume a standardized breakfast on day 4, and on day 5, participants have a full day of standardized meals and snacks, including the standardized breakfast. In a subgroup of the study population, additional measurements are performed. DXA, dual-energy X-ray absorptiometry; MRI, magnetic resonance imaging; 1H-MRS, proton magnetic resonance spectroscopy; AGEs, advanced glycation endproducts; CAR, carotid artery reactivity; OGTT, oral glucose tolerance test; GI, gastrointestinal; scAT, subcutaneous adipose tissue; SM, skeletal muscle.
Figure 3
Figure 3
Overview of all measurements performed within the PERSON study. *Performed in a subgroup of the study population. SCR, screening visit; CW, characterization week; DIW, dietary intervention week.
Figure 4
Figure 4
Graphical overview of the oral glucose tolerance test and the high-fat mixed-meal (HFMM) test that are performed during the pre- and post-intervention characterization week. Participants are instructed to drink the glucose drink or HFMM within 5 min, and fasting and postprandial blood samples are drawn at the indicated timepoints for determination of the indicated metabolites. CHO, carbohydrates; HbA1c, hemoglobin A1c; FFA, free fatty acids; TAG, triglycerides; GLP-1, glucagon-like peptide 1; PYY, peptide YY; NMR, nuclear magnetic resonance; HDL, high-density lipoprotein; SCFA, short-chain fatty acids; PBMCs, peripheral blood mononuclear cells.
Figure 5
Figure 5
Flowchart of participant enrollment and eligibility from March 2018 to March 2020.
Figure 6
Figure 6
Plasma glucose (A–C) and insulin (D–F) concentrations during an oral glucose tolerance test according to insulin resistance phenotype. (A,D): data are geometric means with 95% confidence intervals; significant differences for MIR vs. LIR as analyzed using estimated marginal means from linear mixed-effects models with adjustment for sex and Bonferroni post-hoc pairwise comparisons are denoted with *(p < 0.05) or ***(p < 0.001). (B,C,E,F): data are adjusted geometric means with 95% confidence intervals. Different letters (a, b, c, d) indicate significant differences (p < 0.05) between IR phenotypes, as tested using ANCOVA with adjustment for sex and Bonferroni post-hoc pairwise comparisons.
Figure 7
Figure 7
HOMA-IR (A), HOMA-β (B), Matsuda index (C), disposition index (D), muscle insulin sensitivity index (E), and hepatic insulin resistance index (F) according to insulin resistance (IR) phenotype. Data are adjusted geometric means with 95% confidence intervals. Different letters (a, b, c, d) indicate significant differences (p < 0.05) between IR phenotypes, as tested using ANCOVA with adjustment for sex and Bonferroni post-hoc pairwise comparisons.

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