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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
80
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.
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.
August Krogh Building
Copenhagen, Denmark
Whole-body insulin action
Glucose disposal rates during hyperinsulinemic euglycemic conditions as a marker of whole-body insulin action
Time frame: Baseline characterization & immediately following intervention (either 14 days of physical inactivity or 3 days of hypercaloric high-fat diet)
Identification of proteins and posttranslational modification of proteins in blood as well as skeletal muscle and adipose tissue biopsies
The obtained skeletal muscle samples will be subjected to mass spectrometry-based proteomic and phosphoproteomic analyses. These measurements show protein abundance and posttranslational modifications that regulates protein function. Ultimately, revealing the signalling network underlying the interventions studied. Unit of measure is log2-transformed arbitrary units.
Time frame: Baseline & immediately following the intervention (14 days of physical inactivity or 3 days of hypercaloric high-fat diet)
Whole-Body Glucose Tolerance
Whole-body glucose tolerance will be assessed by an oral glucose tolerance test (OGTT). Blood glucose and insulin concentrations will be measured at multiple time points following oral glucose ingestion to determine glucose and insulin responses. Glucose and insulin areas under the curve (AUC) values will be used to evaluate changes in glucose tolerance.
Time frame: Baseline & immediately following the intervention (14 days of physical inactivity or 3 days of hypercaloric high-fat diet)
Beta Cell Function
Beta cell function will be evaluated using an intravenous glucose tolerance test (IVGTT). Following intravenous glucose administration, arterial glucose and insulin concentrations will be measured at multiple time points to assess first-phase insulin secretion and beta cell responsiveness.
Time frame: Baseline & immediately following the intervention (14 days of physical inactivity or 3 days of hypercaloric high-fat diet)
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