Metabolic Flexibility and Ketone Production During Energy Deficit (MetaFlex)

Indices of Metabolic Flexibility and Ketone Production During Short-Term Energy Deficit With and Without Dietary Carbohydrate Restriction

This randomized, interventional study examines the effects of short-term carbohydrate restriction, with and without caloric restriction, on indices of metabolic flexibility in healthy adults. Participants are randomly assigned to either a low-carbohydrate diet or a standard diet under energy balance, followed by the same diet under controlled caloric restriction. Primary outcomes include measures of carbon dioxide production, breath ketones and interstitial glucose. Secondary outcomes include blood and urinary ketones, body weight, body composition, and selected metabolic biomarkers.

Study Overview

• Status: Completed
• Conditions: Dietary Carbohydrate Restriction, Energy Deficit
• Intervention / Treatment: Other: Low-Carbohydrate Diet; Other: Standard Diet With Caloric Restriction

Detailed Description

This is a monocentric, randomized, open-label nutrition intervention conducted in healthy adults aged 18 to 40 years. The study investigates the effects of short-term carbohydrate and caloric restriction on indices of metabolic flexibility.

After screening and baseline assessments, participants undergo an initial period of energy balance with a standardized diet, followed by a 2-week intervention phase. Participants are randomly assigned in a 1:1 ratio to either a low-carbohydrate diet or a standard mixed diet. Participants are instructed to maintain their habitual physical activity throughout the study. During the first week of the intervention period, energy intake is equivalent to estimated energy requirements. During the second week, energy intake is reduced by ~500 kcal/d.

Metabolic outcomes are assessed using repeated laboratory and remote measurements. Primary outcomes include breath-based measures of carbon dioxide and acetone production, as well as continuous glucose monitoring. Secondary outcomes include urinary and capillary blood ketones, body weight, body composition, resting metabolic rate, plasma glucose and selected biomarkers (leptin, insulin, triiodothyronine, GLP-1, HbA1c).

Data are collected at baseline, during the intervention, and post-intervention. The total participation time per participant is approximately three weeks. The study aims to characterize short-term metabolic responses to dietary carbohydrate manipulation and energy deficit under controlled conditions.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • München, Bavaria, Germany, 80809
      • Technical University of Munich

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18-40 years
• Body mass index (BMI) 18.5-27 kg/m²
• Regular exercise or vigorous physical activity at least once per week
• Willing and able to comply with the dietary intervention and study procedures
• For female participants: non-pregnant and using hormonal contraception

Exclusion Criteria:

• Acute or chronic illness
• Metabolic disorders or conditions associated with altered glucose or lipid metabolism (exclusion of pre-diabetes and diabetes via HbA1c measurement)
• Use of medications known to interfere with study outcomes
• Intolerance or allergy to components of the study diets
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-Carbohydrate Diet; Participants assigned to this arm follow a low-carbohydrate diet. Daily carbohydrate intake is reduced to approximately 75-125 g per day (about 15% of total energy intake), with remaining energy derived primarily from fat (~70%) and protein (~15%). Diets are individually tailored to meet estimated energy and micronutrient requirements. Participants are instructed to maintain their habitual physical activity throughout the study.	Other: Low-Carbohydrate Diet; Participants receive a low-carbohydrate diet. All meals are provided and individually tailored based on estimated energy requirements. Carbohydrate intake is restricted to 75-125 g per day, with the remaining energy intake derived from fat and protein. The intervention is administered for 14 days.
Active Comparator: Standard Diet; Participants assigned to this arm follow a standard mixed diet combined. The diet consists of approximately 50-55% carbohydrates, 25-35% fat, and 15% protein. Diets are individually tailored to meet estimated energy and micronutrient requirements. Participants are instructed to maintain their habitual physical activity throughout the study.	Other: Standard Diet With Caloric Restriction; Participants receive a standard mixed diet. All meals are provided and individually tailored based on estimated energy requirements. The macronutrient distribution consists of approximately 50-55% carbohydrates, 25-35% fat, and 15% protein. The intervention is administered for 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Carbon dioxide production and breath acetone concentration	Carbon dioxide production and breath acetone concentration are assessed using portable breath analysis devices during standardized daily measurements and timepoints.	Baseline, during the energy-deficit intervention period, and post-intervention (over approximately 3 weeks)
Interstitial glucose concentration assessed by continuous glucose monitoring	Continuous glucose monitoring is used to assess interstitial glucose concentration, including average glucose levels, glucose variability, and time in glycemic ranges.	Continuously assessed throughout the study period (approximately 3 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary ketone concentration	Urinary ketone concentration is assessed once daily using reagent test strips and self-reported by participants.	Daily during the study period (approximately 3 weeks)
Capillary blood ketone concentration	Capillary blood ketone concentration is measured once daily in the fasting state using a handheld ketone meter.	Daily during the study period (approximately 3 weeks)
Fasting capillary blood glucose concentration	Fasting blood glucose concentration is measured once daily using a capillary blood glucose meter.	Daily during the study period (approximately 3 weeks)
Body weight	Body weight is measured daily using a Bluetooth-enabled electronic scale.	Daily during the study period (approximately 3 weeks)
Fat Mass	Fat mass is assessed using bioelectrical impedance analysis and air displacement plethysmography.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Fat-Free Mass	Fat-free mass is assessed using bioelectrical impedance analysis and air displacement plethysmography.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Body Fat Percentage	Body fat percentage is assessed using bioelectrical impedance analysis and air displacement plethysmography.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Resting metabolic rate	Resting metabolic rate is assessed by indirect calorimetry during laboratory visits.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Plasma Leptin Concentration	Blood samples are collected to assess plasma leptin concentration.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Plasma Insulin Concentration	Blood samples are collected to assess plasma insulin concentration.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Plasma Triiodothyronine (T3) Concentration	Blood samples are collected to assess plasma triiodothyronine (T3) concentration.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)
Plasma Glucagon-Like Peptide-1 (GLP-1) Concentration	Blood samples are collected to assess plasma glucagon-like peptide-1 (GLP-1) concentration.	Baseline (Day 1), mid-intervention (approximately Day 14), and post-intervention (approximately Day 21)

Collaborators and Investigators

• Sponsor: Technical University of Munich
• Collaborators: Metaflow Ltd.
• Investigators: Principal Investigator: Karsten Köhler, Prof. Dr., Professorship for Exercise, Nutrition and Health, Technical University of Munich

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2023
• Primary Completion (Actual): March 11, 2024
• Study Completion (Actual): April 26, 2024

Study Registration Dates

• First Submitted: February 10, 2026
• First Submitted That Met QC Criteria: February 17, 2026
• First Posted (Actual): February 24, 2026

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Continuous Glucose Monitoring; Low Carbohydrate Diet; Caloric Restriction; Metabolic Flexibility; Ketone Production
• Additional Relevant MeSH Terms: Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; Energy Intake; Caloric Restriction; Diet, Carbohydrate-Restricted
• Other Study ID Numbers: MetaFlex

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Individual participant data will be shared upon reasonable request in accordance with the Technical University of Munich's data sharing policy and applicable data protection regulations

Drug and device information, study documents

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