About this trial
Type 2 diabetes is the most common metabolic disease worldwide, characterized by hyperglycemia, decreased whole body insulin sensitivity, and white adipose tissue (WAT) dysfunction. A key factor in its development is chronic overnutrition, usually with a high-fat diet (HFD), leading to disturbances of glucose and lipid metabolism. However, the mechanism of short-term HFD-induced tissue-specific insulin resistance remains poorly understood. This project aims to further unravel the underlying mechanisms of short-term HFD overnutrition-mediated WAT insulin resistance. The model described here corresponds to a randomized, single- blinded parallel-grouped trial, consisting of two interventions: a macronutrient-balanced diet and or a hypercaloric diet over three weeks in order to investigate differences in interorgan fatty acid and glucose metabolism between the studied groups. Based on recent studies, the hypothesis is that 21-day hypercaloric HFD induces WAT insulin resistance via a diacylglycerol, novel protein kinase C-insulin receptor signaling model in both fasting and insulin-stimulated states.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Age between 18 and 40 years
BMI < 29 kg/m2
Sport inactive (<1x /week)
Capacity to consent
Disqualifiers
Diabetes mellitus disease
Acute coronary heart syndrome (myocardial infarction, unstable angina pectoris, stroke or transient ischemic attack in the last 3 months before study participation)
Acute infectious disease
Taking blood glucose-lowering drugs
Trial design
Parallel
Treatments tested in this trial
High-fat overnutrition
BehavioralOvernutrition: 40% higher lipid consumption per day than required
Normocaloric macronutrient-balanced nutrition
BehavioralNormocaloric, macronutrient-balanced nutrition: Calories requirement for weight maintenance \[(kcal/d) 55% carbohydrates, 15% proteins, 30% fat\]
Treatment groups
Trial outcomes
Primary outcomes
Whole-body insulin sensitivity and WAT insulin sensitivity
Hyperinsulinemica-euglycemia clamp tests with deuterated glucose to measure fasting and insulin-stimulated whole-body insulin sensitivity and measurement of the index ADIPO-IR (fasting insulin x free fatty acid concentration) before and after dietary intervention period.
Secondary outcomes
WAT insulin signaling pathways
Adipose tissue biopsies are planned to be taken during the fasting and insulin-stimulated state before and after the dietary intervention period. DAG and ceramide subcellular fractionation assay is planned to be performed. Expressionanalyses for activation /membrane translocation of novel and atypical protein kinase C isoforms will be done. Determination of the degree of phosphorylation of various components of the insulin pathway via Western blot are planned.
Sponsors and contacts
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German Diabetes Center
Lead sponsor
Yale University
Collaborator