Defining the Human Insulin Resistance Molecular Network; SIGNATURE

NCT07255807 | Not Yet Recruiting

• 2 other identifiers: SIGNATURENNF24OC0085866
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

Metabolic Health; Insulin Sensitivity/Resistance

Keywords

Insulin Resistance; Metabolic Health; Glucose Metabolism; Lifestyle Interventions; Physical Inactivity; High-Fat Diet; Molecular Mechanisms; Insulin Sensitivity; Metabolic Phenotyping; Human Intervention Study

Outcome Measures

Primary Outcomes (1)

• Whole-body insulin action

  Glucose disposal rates during hyperinsulinemic euglycemic conditions as a marker of whole-body insulin action

  Baseline characterization & immediately following intervention (either 14 days of physical inactivity or 3 days of hypercaloric high-fat diet)

Secondary Outcomes (3)

• Identification of proteins and posttranslational modification of proteins in blood as well as skeletal muscle and adipose tissue biopsies

  Baseline & immediately following the intervention (14 days of physical inactivity or 3 days of hypercaloric high-fat diet)

• Whole-Body Glucose Tolerance

  Baseline & immediately following the intervention (14 days of physical inactivity or 3 days of hypercaloric high-fat diet)

• Beta Cell Function

  Baseline & immediately following the intervention (14 days of physical inactivity or 3 days of hypercaloric high-fat diet)

Study Arms (2)

Baseline Characterization

NO INTERVENTION

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

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.

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

Interventions

Physical Inactivity 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.

Also known as: Reduced Activity

Lifestyle Interventions

Hypercaloric High-Fat Diet 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.

Also known as: Overeating

Lifestyle Interventions

Eligibility Criteria

• Age: 25 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Copenhagen: lead
• University of Sydney: collaborator
• Queen Mary University of London: collaborator
• Novo Nordisk A/S: collaborator

Study Sites (1)

August Krogh Building

Copenhagen, 2100, Denmark

Location

MeSH Terms

Conditions

Insulin Resistance; Sedentary Behavior

Interventions

Parenteral Nutrition

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Behavior

Intervention Hierarchy (Ancestors)

Feeding Methods; Therapeutics; Nutritional Support; Nutrition Therapy

Study Officials

• Jørgen F.P. Wojtaszewski, Ph.D.

  University of Copenhagen

  PRINCIPAL INVESTIGATOR

• Ylva Hellsten, Ph.D.

  University of Copenhagen

  PRINCIPAL INVESTIGATOR

• Henriette Pilegaard, Ph.D.

  University of Copenhagen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jørgen F.P. Wojtaszewski, Ph.D.

CONTACT

+45 28751625; jw@nexs.ku.dk

Kate A Wickham, Ph.D.

CONTACT

+45 30638013; kawi@nexs.ku.dk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: This study uses a parallel design involving 80 healthy participants who all undergo comprehensive baseline assessments, including physiological and metabolic phenotyping, habitual physical activity, and dietary intake evaluations. Following baseline characterization, 40 participants are assigned to one of two independent intervention arms: 14 days of reduced physical activity or 3 days of a hypercaloric high-fat diet. Each intervention group is studied in parallel, with outcomes compared to assess the specific effects on insulin sensitivity and molecular mechanisms. The parallel design was chosen due to the invasive and time-intensive nature of the interventions and testing procedures, making a crossover design impractical and burdensome for participants.

Study Record Dates

• First Submitted: August 6, 2025
• First Posted: December 1, 2025
• Study Start: December 1, 2025
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2038
• Last Updated: December 1, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)