Defining the Human Insulin Resistance Molecular Network; SIGNATURE

NCT ID: NCT07255807

Last Updated: 2025-12-01

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-01
• Study Completion Date: 2038-06-30

Brief Summary

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.

Detailed 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.

Conditions

Metabolic Health; Insulin Sensitivity/Resistance

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Baseline Characterization

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Lifestyle Interventions

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.

Group Type: EXPERIMENTAL

Physical Inactivity

Intervention Type: BEHAVIORAL

Participants assigned to the physical inactivity intervention will reduce their daily physical activity to fewer than 1,500 steps per day for 14 consecutive days. This strict limitation significantly decreases overall movement and muscle activity, mimicking a sedentary lifestyle. The aim is to assess the short-term effects of reduced physical activity on insulin sensitivity and related metabolic processes. Compliance will be monitored using activity trackers and daily logs. Baseline metabolic and physiological assessments will be repeated after the intervention to evaluate changes.

Hypercaloric High-Fat Diet

Intervention Type: BEHAVIORAL

Participants assigned to the high-fat diet intervention will consume a hypercaloric diet rich in fat for 3 consecutive days. The diet is designed to significantly increase caloric intake and fat consumption beyond habitual levels to induce short-term metabolic stress. This intervention aims to assess how a brief period of high-fat overfeeding affects insulin sensitivity and related molecular pathways. Participants' dietary intake will be carefully controlled and monitored to ensure adherence. Baseline metabolic and physiological assessments will be repeated after the intervention to evaluate changes.

Interventions

Physical Inactivity

Participants assigned to the physical inactivity intervention will reduce their daily physical activity to fewer than 1,500 steps per day for 14 consecutive days. This strict limitation significantly decreases overall movement and muscle activity, mimicking a sedentary lifestyle. The aim is to assess the short-term effects of reduced physical activity on insulin sensitivity and related metabolic processes. Compliance will be monitored using activity trackers and daily logs. Baseline metabolic and physiological assessments will be repeated after the intervention to evaluate changes.

Intervention Type: BEHAVIORAL

Hypercaloric High-Fat Diet

Participants assigned to the high-fat diet intervention will consume a hypercaloric diet rich in fat for 3 consecutive days. The diet is designed to significantly increase caloric intake and fat consumption beyond habitual levels to induce short-term metabolic stress. This intervention aims to assess how a brief period of high-fat overfeeding affects insulin sensitivity and related molecular pathways. Participants' dietary intake will be carefully controlled and monitored to ensure adherence. Baseline metabolic and physiological assessments will be repeated after the intervention to evaluate changes.

Intervention Type: BEHAVIORAL

Other Intervention Names

Reduced Activity; Overeating

Eligibility Criteria

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

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Sydney

OTHER

Sponsor Role: collaborator

Queen Mary University of London

OTHER

Sponsor Role: collaborator

Novo Nordisk A/S

INDUSTRY

Sponsor Role: collaborator

University of Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Jorgen FP Wojtaszewski

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jørgen F.P. Wojtaszewski, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of Copenhagen

Ylva Hellsten, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of Copenhagen

Henriette Pilegaard, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of Copenhagen

Locations

August Krogh Building

Copenhagen, , Denmark

Countries

Denmark

Central Contacts

Jørgen F.P. Wojtaszewski, Ph.D.

Role: CONTACT

jw@nexs.ku.dk

+45 28751625

Kate A Wickham, Ph.D.

Role: CONTACT

kawi@nexs.ku.dk

+45 30638013

Facility Contacts

Kate A Wickham, Ph.D.

Role: primary

kawi@nexs.ku.dk

+45 30638013

Other Identifiers

NNF24OC0085866

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

SIGNATURE

Identifier Type: -

Identifier Source: org_study_id