Multi-parameter Comparison of a Standardized Mixed Meal Tolerance Test in Healthy and Type 2 Diabetic Subjects: the PhenFlex Challenge

Overview

Journal Genes Nutr

Publisher Biomed Central

Date 2017 Sep 2

PMID 28861127

Citations 52

Authors

Suzan Wopereis

Johanna H M Stroeve

Annette Stafleu

Gertruud C M Bakker

Jacobus Burggraaf

Marjan J van Erk

Linette Pellis

Ruud Boessen

Alwine A F Kardinaal

Ben van Ommen

Affiliations

Soon will be listed here.

Abstract

Background: A key feature of metabolic health is the ability to adapt upon dietary perturbations. Recently, it was shown that metabolic challenge tests in combination with the new generation biomarkers allow the simultaneous quantification of major metabolic health processes. Currently, applied challenge tests are largely non-standardized. A systematic review defined an optimal nutritional challenge test, the "PhenFlex test" (PFT). This study aimed to prove that PFT modulates all relevant processes governing metabolic health thereby allowing to distinguish subjects with different metabolic health status. Therefore, 20 healthy and 20 type 2 diabetic (T2D) male subjects were challenged both by PFT and oral glucose tolerance test (OGTT). During the 8-h response time course, 132 parameters were quantified that report on 26 metabolic processes distributed over 7 organs (gut, liver, adipose, pancreas, vasculature, muscle, kidney) and systemic stress.

Results: In healthy subjects, 110 of the 132 parameters showed a time course response. Patients with T2D showed 18 parameters to be significantly different after overnight fasting compared to healthy subjects, while 58 parameters were different in the post-challenge time course after the PFT. This demonstrates the added value of PFT in distinguishing subjects with different health status. The OGTT and PFT response was highly comparable for glucose metabolism as identical amounts of glucose were present in both challenge tests. Yet the PFT reports on additional processes, including vasculature, systemic stress, and metabolic flexibility.

Conclusion: The PFT enables the quantification of all relevant metabolic processes involved in maintaining or regaining homeostasis of metabolic health. Studying both healthy subjects and subjects with impaired metabolic health showed that the PFT revealed new processes laying underneath health. This study provides the first evidence towards adopting the PFT as gold standard in nutrition research.

Citing Articles

Multi-study feasibility analysis on a composite biomarker of inflammatory resilience to quantify the effects of energy restriction on low-grade inflammation in overweight and obese individuals.

Dessing M, van den Broek T, Hoevenaars F, van den Brink W, Rundle M, Frost G Eur J Nutr. 2025; 64(3):106.

PMID: 40035864 PMC: 11880040. DOI: 10.1007/s00394-025-03627-8.

Moderating carbohydrate digestion rate in mice promotes fat oxidation and metabolic flexibility revealed through a new approach to assess metabolic substrate utilization.

Hayes A, Swackhamer C, Quezada-Calvillo R, Butte N, Sterchi E, Nichols B Eur J Nutr. 2025; 64(2):83.

PMID: 39904882 PMC: 11908681. DOI: 10.1007/s00394-025-03585-1.

A toolkit for quantifying individual response to herbal extracts in metabolic and inflammatory stress.

Park S, Kwon O, van den Broek T, Bouwman J, Kim J NPJ Sci Food. 2025; 9(1):14.

PMID: 39900584 PMC: 11791183. DOI: 10.1038/s41538-024-00354-y.

Longitudinal Metabolomics Data Analysis Informed by Mechanistic Models.

Li L, Hoefsloot H, Bakker B, Horner D, Rasmussen M, Smilde A Metabolites. 2025; 15(1).

PMID: 39852345 PMC: 11766892. DOI: 10.3390/metabo15010002.

Two-dimensional Health State Map to define metabolic health using separated static and dynamic homeostasis features: a proof-of-concept study.

Wu Y, Zhang X, Sun L, Wu Q, Liu X, Deng Y Natl Sci Rev. 2025; 12(1):nwae425.

PMID: 39816947 PMC: 11734281. DOI: 10.1093/nsr/nwae425.

References

Huber M, Bakker M, Dijk W, Prins H, Wiegant F . The challenge of evaluating health effects of organic food; operationalisation of a dynamic concept of health. J Sci Food Agric. 2012; 92(14):2766-73. DOI: 10.1002/jsfa.5563. View

Kardinaal A, van Erk M, Dutman A, Stroeve J, van de Steeg E, Bijlsma S . Quantifying phenotypic flexibility as the response to a high-fat challenge test in different states of metabolic health. FASEB J. 2015; 29(11):4600-13. DOI: 10.1096/fj.14-269852. View

Shaham O, Wei R, Wang T, Ricciardi C, Lewis G, Vasan R . Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol. 2008; 4:214. PMC: 2538910. DOI: 10.1038/msb.2008.50. View

Wopereis S, Wolvers D, van Erk M, Gribnau M, Kremer B, van Dorsten F . Assessment of inflammatory resilience in healthy subjects using dietary lipid and glucose challenges. BMC Med Genomics. 2013; 6:44. PMC: 4015956. DOI: 10.1186/1755-8794-6-44. View

van Ommen B, Wopereis S . Next-Generation Biomarkers of Health. Nestle Nutr Inst Workshop Ser. 2016; 84:25-33. DOI: 10.1159/000436949. View

Pellis L, van Erk M, van Ommen B, Bakker G, Hendriks H, Cnubben N . Plasma metabolomics and proteomics profiling after a postprandial challenge reveal subtle diet effects on human metabolic status. Metabolomics. 2012; 8(2):347-359. PMC: 3291817. DOI: 10.1007/s11306-011-0320-5. View

Thomsen C, Rasmussen O, Christiansen C, Pedersen E, Vesterlund M, Storm H . Comparison of the effects of a monounsaturated fat diet and a high carbohydrate diet on cardiovascular risk factors in first degree relatives to type-2 diabetic subjects. Eur J Clin Nutr. 1999; 53(10):818-23. DOI: 10.1038/sj.ejcn.1600855. View

Esposito K, Nappo F, Giugliano F, Di Palo C, Ciotola M, Barbieri M . Meal modulation of circulating interleukin 18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus. Am J Clin Nutr. 2003; 78(6):1135-40. DOI: 10.1093/ajcn/78.6.1135. View

Rasmussen M, Ho K, Kjems L, Hilsted J . Serum growth hormone-binding protein in obesity: effect of a short-term, very low calorie diet and diet-induced weight loss. J Clin Endocrinol Metab. 1996; 81(4):1519-24. DOI: 10.1210/jcem.81.4.8636361. View

10.

Cruz-Teno C, Perez-Martinez P, Delgado-Lista J, Yubero-Serrano E, Garcia-Rios A, Marin C . Dietary fat modifies the postprandial inflammatory state in subjects with metabolic syndrome: the LIPGENE study. Mol Nutr Food Res. 2012; 56(6):854-65. DOI: 10.1002/mnfr.201200096. View

11.

Morris C, OGrada C, Ryan M, Roche H, Gibney M, Gibney E . Identification of differential responses to an oral glucose tolerance test in healthy adults. PLoS One. 2013; 8(8):e72890. PMC: 3749984. DOI: 10.1371/journal.pone.0072890. View

12.

Suhre K . Metabolic profiling in diabetes. J Endocrinol. 2014; 221(3):R75-85. DOI: 10.1530/JOE-14-0024. View

13.

Bondia-Pons I, Nordlund E, Mattila I, Katina K, Aura A, Kolehmainen M . Postprandial differences in the plasma metabolome of healthy Finnish subjects after intake of a sourdough fermented endosperm rye bread versus white wheat bread. Nutr J. 2011; 10:116. PMC: 3214176. DOI: 10.1186/1475-2891-10-116. View

14.

Huber M, Knottnerus J, Green L, van der Horst H, Jadad A, Kromhout D . How should we define health?. BMJ. 2011; 343:d4163. DOI: 10.1136/bmj.d4163. View

15.

Stroeve J, van Wietmarschen H, Kremer B, van Ommen B, Wopereis S . Phenotypic flexibility as a measure of health: the optimal nutritional stress response test. Genes Nutr. 2015; 10(3):13. PMC: 4404421. DOI: 10.1007/s12263-015-0459-1. View

16.

van Ommen B, van der Greef J, Ordovas J, Daniel H . Phenotypic flexibility as key factor in the human nutrition and health relationship. Genes Nutr. 2014; 9(5):423. PMC: 4172643. DOI: 10.1007/s12263-014-0423-5. View

17.

Song Y, Manson J, Tinker L, Howard B, Kuller L, Nathan L . Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women's Health Initiative Observational Study. Diabetes Care. 2007; 30(7):1747-52. PMC: 1952235. DOI: 10.2337/dc07-0358. View

18.

van Ommen B, Keijer J, Heil S, Kaput J . Challenging homeostasis to define biomarkers for nutrition related health. Mol Nutr Food Res. 2009; 53(7):795-804. DOI: 10.1002/mnfr.200800390. View

19.

Marathe C, Rayner C, Jones K, Horowitz M . Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes Care. 2013; 36(5):1396-405. PMC: 3631884. DOI: 10.2337/dc12-1609. View

20.

Hanson R, Pratley R, Bogardus C, Narayan K, Roumain J, Imperatore G . Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol. 2000; 151(2):190-8. DOI: 10.1093/oxfordjournals.aje.a010187. View