Defining the Human Insulin Resistance Molecular Network; SIGNATURE

University of Copenhagen

Status: Not yet enrolling

Conditions: Insulin Sensitivity/Resistance; Metabolic Health

Treatments: Behavioral: Hypercaloric High-Fat Diet; Behavioral: Physical Inactivity

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT07255807

NNF24OC0085866 (Other Grant/Funding Number)

SIGNATURE

Details and patient eligibility

About

The goal of this intervention study is to learn more about what causes insulin resistance in otherwise healthy adults, and how short-term changes in physical activity or diet may influence it. The study includes healthy male and female participants aged 25 to 55 years, who meet specific health criteria.

The main questions it aims to answer are:

Does the cause of insulin resistance vary between individuals due to their genes and lifestyle?

Can the investigators identify different types (sub-phenotypes) of insulin resistance at the molecular level?

Researchers will compare groups who either reduce their physical activity for 14 days or consume a high-fat diet for 3 days, to see how these changes affect insulin sensitivity and related biological markers.

Participants will:

• Complete a health screening and be assessed for eligibility
• Undergo baseline testing to measure insulin sensitivity, physical activity, diet, and metabolic health
• Be randomly assigned to one of two short-term interventions (14 days of reduced physical activity, or 3 days of a high-fat, high-calorie diet)
• Repeat selected tests after the intervention to assess changes

This study will help researchers better understand how lifestyle and biology interact in the development of insulin resistance, even in people who are otherwise healthy.

Full description

This intervention study aims to uncover the molecular mechanisms that underlie insulin resistance in otherwise healthy adults and to explore how short-term lifestyle changes may influence these mechanisms. Insulin resistance is a key feature in the development of type 2 diabetes and other metabolic diseases, but it does not arise uniformly across individuals. The overarching hypothesis is that insulin resistance has multiple underlying causes that differ between individuals, depending on genetic variation and modifiable lifestyle factors such as physical activity and diet.

A total of 80 healthy participants-40 males and 40 females aged between 25 and 55 years-will be recruited. All participants must have a body mass index (BMI) between 18 and 30 and meet strict inclusion and exclusion criteria to minimize confounding variables. Participants will be free of chronic disease, non-smokers, have limited alcohol intake, and not engage in high levels of physical activity. This controlled approach ensures a more accurate assessment of the variables under investigation.

At baseline, all participants will undergo comprehensive phenotyping, including assessments of habitual physical activity, dietary intake, glucose tolerance, and whole-body insulin sensitivity. This will allow the researchers to categorize sub-phenotypes of insulin resistance at both the physiological and molecular level.

Following baseline testing, 40 of the 80 participants will undergo one of two short-term interventions designed to stress metabolic pathways associated with insulin sensitivity:

• Reduced physical activity: Participants will significantly decrease their daily physical activity for 14 days.
• High-fat diet: Participants will consume a hypercaloric high-fat diet for 3 consecutive days.

The aim of these interventions is to test how short-term negative lifestyle changes impact insulin action and related molecular markers, and whether these responses vary between individuals with different phenotypic and genetic profiles.

After the intervention period, selected metabolic tests will be repeated to assess changes in insulin sensitivity and molecular signaling. The primary outcome measure is whole-body insulin action, assessed using gold-standard physiological methods. Exploratory outcomes include identifying cellular and molecular mechanisms contributing to insulin resistance, and understanding the interaction between gene expression and lifestyle responses.

By combining deep phenotyping with short-term interventions, this study will generate new insights into the biological diversity of insulin resistance. Ultimately, this may contribute to the development of more individualized strategies for the prevention and treatment of metabolic diseases.

Enrollment: 80 estimated patients

Sex: All

Ages: 25 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Age: 25-55 years
• Body Mass Index (BMI): 18-30 kg/m²
• Healthy (no diagnosed chronic diseases)
• Able and willing to comply with study procedures

Exclusion criteria

• Smoking or nicotine use, current or within the past 5 years
• Alcohol intake exceeding 10 units per week
• Hemoglobin A1c (HbA1c) > 48 mmol/mol (indicative of diabetes or prediabetes)
• Chronic diseases (e.g., cardiovascular disease, diabetes, etc.)
• Chronic medication use, including hormonal treatments
• High physical activity levels (more than 3 hours per week of moderate to vigorous exercise)
• Pregnancy or within 3 months postpartum
• Breastfeeding or within 3 months of cessation
• Abnormal routine blood markers (as defined in lab screening)
• Blood donation within the past 2 months

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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80 participants in 2 patient groups

Baseline Characterization

No Intervention group

Description:

All participants (N=80) undergo extensive baseline characterization over three study visits. This includes assessments of insulin sensitivity, glucose tolerance, metabolic and physiological phenotyping, habitual physical activity, and dietary intake. No intervention is applied during this phase; the purpose is to establish baseline measures and characterize individual variation in insulin resistance and metabolic profiles. Participants complete detailed clinical, physiological, and behavioral assessments without any experimental manipulation. This includes: * Measurement of insulin action and glucose tolerance * Dietary and physical activity profiling * Collection of biospecimens for molecular analyses

Lifestyle Interventions

Experimental group

Description:

A subset of 40 participants are randomized into one of two experimental interventions following baseline assessment: * 14 days of reduced physical activity (\<1,500 steps/day), or * 3 days of a hypercaloric high-fat diet The aim is to evaluate how short-term lifestyle stressors affect insulin sensitivity and related molecular markers. Assessments from visits 4 and 5 are compared to baseline to determine within-subject changes. Intervention Names: 1. Reduced Physical Activity \- Participants limit daily steps to \<1,500 for 14 days 2. High-Fat Diet * Participants consume a hypercaloric, high-fat diet for 3 days Description of Intervention: Participants undergo one of the two lifestyle interventions with strict monitoring and support. Selected baseline tests are repeated post-intervention to evaluate metabolic and molecular responses.

Treatment:

Behavioral: Physical Inactivity

Behavioral: Hypercaloric High-Fat Diet