Overfeeding Induced Fat-tissue Stimulation (OVID_FASTI)

Short-term High-fat Overnutrition Induces Insulin Resistance in White Adipose Tissue

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.

Study Overview

• Status: Recruiting
• Conditions: Lipid-induced Insulin Resistance
• Intervention / Treatment: Behavioral: High-fat overnutrition; Behavioral: Normocaloric macronutrient-balanced nutrition

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Theresia Sarabhai, MD; Phone Number: DDZ 0173-9473478; Email: theresia.sarabhai@ddz.de
• Study Contact Backup: Name: Sabine Kahl, MD; Phone Number: 698 0221-3382-; Email: sabine.kahl@ddz.de

Study Locations

• Germany
  • Nordrhein-Westfalen
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40225
      • Recruiting
      • Georgia Xourafa
      • Contact: Georgia Xourafa, MD; Phone Number: +492113382426; Email: georgia.xourafa@ddz.de
      • Contact: Theresia Sarabhai, MD; Phone Number: 0211-3382-0; Email: theresia.Sarabhai@ddz.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age between 18 and 40 years
• BMI < 29 kg/m2
• Sport inactive (<1x /week)
• Capacity to consent

Exclusion Criteria:

• 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
• Diseases or drugs affecting the immune system and allergies to drugs used in the study
• Drugs with potential metabolic effects
• Chronic liver disease (hepatitis, gallbladder disease, elevated liver enzymes (ALT > 300 U/L))
• Chronic inflammatory bowel diseases
• Rheumatic diseases
• Hyper- or hypothyroidism of the thyroid gland
• Renal insufficiency, administration of iodine-containing contrast media in the last 2 days
• Chronic lung diseases
• cancerous diseases
• Addictive diseases, psychiatric diseases
• Pregnancy, breastfeeding
• Shift workers
• Anemia (Hb <12 g/dl)
• Disorders of hemostasis
• Regular use of antithrombotic drugs
• Alcohol consumption, smoking
• Conditions that do not permit an MRI examination

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High-fat overnutrition; Lipid overnutrition: 40% higher lipid consumption per day than required over three weeks.	Behavioral: High-fat overnutrition; Overnutrition: 40% higher lipid consumption per day than required
Active Comparator: Normocaloric macronutrient-balanced nutrition; Normocaloric, macronutrient-balanced nutrition per day over three weeks	Behavioral: Normocaloric macronutrient-balanced nutrition; Normocaloric, macronutrient-balanced nutrition: Calories requirement for weight maintenance [(kcal/d) 55% carbohydrates, 15% proteins, 30% fat]

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 weeks intervention period each

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 weeks intervention time

Collaborators and Investigators

• Sponsor: German Diabetes Center
• Collaborators: Yale University
• Investigators: Study Director: Michael Roden, Prof., MD, German Diabetes Center

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: September 27, 2022
• First Submitted That Met QC Criteria: January 4, 2024
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: OVID-FASTI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No