Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention

Ville M. Koistinen; Suvi Manninen; Marjo Tuomainen; Kirsikka Aittola; Elina Järvelä-Reijonen; Tanja Tilles-Tirkkonen; Reija Männikkö; Niina Lintu; Leila Karhunen; Marjukka Kolehmainen; Santtu Mikkonen; Marko Lehtonen; Janne Martikainen; Kaisa Poutanen; Ursula Schwab; Pilvikki Absetz; Jaana Lindström; Timo A. Lakka; Kati Hanhineva; Jussi Pihlajamäki

doi:10.1038/s41598-025-25749-z

Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention

Ville M. Koistinen
, Suvi Manninen
, Marjo Tuomainen
, Kirsikka Aittola
, Elina Järvelä-Reijonen
, Tanja Tilles-Tirkkonen
, Reija Männikkö
, Niina Lintu
, Leila Karhunen
, Marjukka Kolehmainen
, Santtu Mikkonen
, Marko Lehtonen
, Janne Martikainen
, Kaisa Poutanen
, Ursula Schwab
, Pilvikki Absetz
, Jaana Lindström
, Timo A. Lakka
, Kati Hanhineva
, Jussi Pihlajamäki^*

^*Corresponding author for this work

BA53 Industrial biotechnology and food

Research output: Contribution to journal › Article › Scientific › peer-review

Abstract

Type 2 diabetes can be prevented by lifestyle intervention. We aimed to identify metabolites that associate with glucose metabolism and respond to lifestyle intervention with evidence-based targets for nutrition and physical activity in individuals at high risk of type 2 diabetes. Standard oral glucose tolerance test (OGTT) was used to categorize 624 participants into those having normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), IGT with increased fasting glucose (IGT + IFG), and type 2 diabetes. Plasma LC-MS metabolomics was performed to reveal metabolic signatures. The baseline group differences were analysed with the Kruskal–Wallis test and the effect of intervention with a linear mixed-effects model. Significant differences in the metabolite signature were observed between the baseline groups, particularly in amino acids, acylcarnitines, and phospholipids. Fatty acid amides, phospholipids, amino acids, dimethylguanidinovaleric acid, and 5-aminovaleric acid betaine responded most to the lifestyle intervention. Lysophosphatidylcholines containing odd-chain fatty acids showed associations with improved glucose metabolism. Twenty-five metabolites differed between the baseline groups, responded to the intervention, and were associated with changes in glucose metabolism. The findings suggest a metabolite panel could be used in distinguishing individuals with varying degrees of glucose metabolism and in predicting response to lifestyle interventions.

Original language	English
Article number	39093
Journal	Scientific Reports
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41598-025-25749-z
Publication status	Published - 7 Nov 2025
MoE publication type	A1 Journal article-refereed

Funding

Mrs. Miia Reponen (School of Pharmacy, University of Eastern Finland) is acknowledged for technical assistance. We appreciate Biocentre Finland and Biocentre Kuopio for supporting LC-MS laboratory facility. We acknowledge the health and social care workers in the three participating regions (Hospital districts of North Savo, Päijät-Häme and South Karelia) and the stakeholders of the StopDia project (Ministry of Social Affairs and Health, Finnish Social Security Institute Kela, Regional councils of North Savo and Päijät-Häme, Cities of Kuopio, Varkaus, and Siilinjärvi, Ylä-Savon SOTE, Finnish Heart Association, Finnish Diabetes Association, Family Federation of Finland, Association of Finnish Pharmacies, Consumers’ Union of Finland, Etera Mutual Pension Insurance Company, Agency for Rural Affairs Mavi and its partner organisations, Self-care and Digital Value Services project ODA) for participating in planning the recruitment of the participants and the intervention. We acknowledge Juho Viitasalo and Juha Kekäläinen from the University of Eastern Finland for their extensive work in the development of the StopDia digital tools. We also acknowledge Tiina Laatikainen, Kennet Harald, Markku Peltonen, Pekka Jousilahti, Katri Hemiö, Maliheh Nekouei, Marvi Langari, Eeva Virtanen, and Riia Järvenpää from the National Institute for Health and Welfare; Saara Vanhatalo, Johanna Leväsluoto, Adil Umer, Juha Leppänen, Samuli Heinonen, and Eeva Rantala from the Technical Research Centre of Finland VTT; Kari Jalkanen and Matti Uusitupa from the University of Eastern Finland; and Jaakko Tuomilehto from the University of Helsinki for their role in the development of the StopDia protocols and for participating in the project. We also thank the international advisory board of the StopDia project, including professors Edith Feskens, Theresa Marteau, and Peter Schwarz. The LC-MS analysis was supported by Biocenter Finland.

Keywords

Acylcarnitines
Amino acids
Fatty acid amides
Impaired glucose metabolism
Metabolomics
Personalized treatment
Phospholipids
Life Style
Glucose Tolerance Test
Humans
Middle Aged
Blood Glucose/metabolism
Metabolome
Male
Glucose Intolerance/metabolism
Phospholipids/blood
Exercise
Female
Diabetes Mellitus, Type 2/metabolism
Adult
Aged
Glucose/metabolism
Metabolomics/methods

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Koistinen, V. M., Manninen, S., Tuomainen, M., Aittola, K., Järvelä-Reijonen, E., Tilles-Tirkkonen, T., Männikkö, R., Lintu, N., Karhunen, L., Kolehmainen, M., Mikkonen, S., Lehtonen, M., Martikainen, J., Poutanen, K., Schwab, U., Absetz, P., Lindström, J., Lakka, T. A., Hanhineva, K., & Pihlajamäki, J. (2025). Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention. Scientific Reports, 15(1), Article 39093. https://doi.org/10.1038/s41598-025-25749-z

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abstract = "Type 2 diabetes can be prevented by lifestyle intervention. We aimed to identify metabolites that associate with glucose metabolism and respond to lifestyle intervention with evidence-based targets for nutrition and physical activity in individuals at high risk of type 2 diabetes. Standard oral glucose tolerance test (OGTT) was used to categorize 624 participants into those having normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), IGT with increased fasting glucose (IGT + IFG), and type 2 diabetes. Plasma LC-MS metabolomics was performed to reveal metabolic signatures. The baseline group differences were analysed with the Kruskal–Wallis test and the effect of intervention with a linear mixed-effects model. Significant differences in the metabolite signature were observed between the baseline groups, particularly in amino acids, acylcarnitines, and phospholipids. Fatty acid amides, phospholipids, amino acids, dimethylguanidinovaleric acid, and 5-aminovaleric acid betaine responded most to the lifestyle intervention. Lysophosphatidylcholines containing odd-chain fatty acids showed associations with improved glucose metabolism. Twenty-five metabolites differed between the baseline groups, responded to the intervention, and were associated with changes in glucose metabolism. The findings suggest a metabolite panel could be used in distinguishing individuals with varying degrees of glucose metabolism and in predicting response to lifestyle interventions.",

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Koistinen, VM, Manninen, S, Tuomainen, M, Aittola, K, Järvelä-Reijonen, E, Tilles-Tirkkonen, T, Männikkö, R, Lintu, N, Karhunen, L, Kolehmainen, M, Mikkonen, S, Lehtonen, M, Martikainen, J, Poutanen, K, Schwab, U, Absetz, P, Lindström, J, Lakka, TA, Hanhineva, K & Pihlajamäki, J 2025, 'Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention', Scientific Reports, vol. 15, no. 1, 39093. https://doi.org/10.1038/s41598-025-25749-z

TY - JOUR

T1 - Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention

AU - Koistinen, Ville M.

AU - Manninen, Suvi

AU - Tuomainen, Marjo

AU - Aittola, Kirsikka

AU - Järvelä-Reijonen, Elina

AU - Tilles-Tirkkonen, Tanja

AU - Männikkö, Reija

AU - Lintu, Niina

AU - Karhunen, Leila

AU - Kolehmainen, Marjukka

AU - Mikkonen, Santtu

AU - Lehtonen, Marko

AU - Martikainen, Janne

AU - Poutanen, Kaisa

AU - Schwab, Ursula

AU - Absetz, Pilvikki

AU - Lindström, Jaana

AU - Lakka, Timo A.

AU - Hanhineva, Kati

AU - Pihlajamäki, Jussi

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/11/7

Y1 - 2025/11/7

N2 - Type 2 diabetes can be prevented by lifestyle intervention. We aimed to identify metabolites that associate with glucose metabolism and respond to lifestyle intervention with evidence-based targets for nutrition and physical activity in individuals at high risk of type 2 diabetes. Standard oral glucose tolerance test (OGTT) was used to categorize 624 participants into those having normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), IGT with increased fasting glucose (IGT + IFG), and type 2 diabetes. Plasma LC-MS metabolomics was performed to reveal metabolic signatures. The baseline group differences were analysed with the Kruskal–Wallis test and the effect of intervention with a linear mixed-effects model. Significant differences in the metabolite signature were observed between the baseline groups, particularly in amino acids, acylcarnitines, and phospholipids. Fatty acid amides, phospholipids, amino acids, dimethylguanidinovaleric acid, and 5-aminovaleric acid betaine responded most to the lifestyle intervention. Lysophosphatidylcholines containing odd-chain fatty acids showed associations with improved glucose metabolism. Twenty-five metabolites differed between the baseline groups, responded to the intervention, and were associated with changes in glucose metabolism. The findings suggest a metabolite panel could be used in distinguishing individuals with varying degrees of glucose metabolism and in predicting response to lifestyle interventions.

AB - Type 2 diabetes can be prevented by lifestyle intervention. We aimed to identify metabolites that associate with glucose metabolism and respond to lifestyle intervention with evidence-based targets for nutrition and physical activity in individuals at high risk of type 2 diabetes. Standard oral glucose tolerance test (OGTT) was used to categorize 624 participants into those having normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), IGT with increased fasting glucose (IGT + IFG), and type 2 diabetes. Plasma LC-MS metabolomics was performed to reveal metabolic signatures. The baseline group differences were analysed with the Kruskal–Wallis test and the effect of intervention with a linear mixed-effects model. Significant differences in the metabolite signature were observed between the baseline groups, particularly in amino acids, acylcarnitines, and phospholipids. Fatty acid amides, phospholipids, amino acids, dimethylguanidinovaleric acid, and 5-aminovaleric acid betaine responded most to the lifestyle intervention. Lysophosphatidylcholines containing odd-chain fatty acids showed associations with improved glucose metabolism. Twenty-five metabolites differed between the baseline groups, responded to the intervention, and were associated with changes in glucose metabolism. The findings suggest a metabolite panel could be used in distinguishing individuals with varying degrees of glucose metabolism and in predicting response to lifestyle interventions.

KW - Acylcarnitines

KW - Amino acids

KW - Fatty acid amides

KW - Impaired glucose metabolism

KW - Metabolomics

KW - Personalized treatment

KW - Phospholipids

KW - Life Style

KW - Glucose Tolerance Test

KW - Humans

KW - Middle Aged

KW - Blood Glucose/metabolism

KW - Metabolome

KW - Male

KW - Glucose Intolerance/metabolism

KW - Phospholipids/blood

KW - Exercise

KW - Female

KW - Diabetes Mellitus, Type 2/metabolism

KW - Adult

KW - Aged

KW - Glucose/metabolism

KW - Metabolomics/methods

UR - https://www.scopus.com/pages/publications/105021068042

U2 - 10.1038/s41598-025-25749-z

DO - 10.1038/s41598-025-25749-z

M3 - Article

C2 - 41203831

AN - SCOPUS:105021068042

SN - 2045-2322

VL - 15

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 39093

ER -

Metabolites associated with abnormal glucose metabolism responding to primary care lifestyle intervention

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