Effects of Ketone Bodies on Insulin Sensitivity (KETO-SENSE)

KETO-SENSE - Effects of Ketone Bodies on Insulin Sensitivity

KETO-SENSE is a clinical research study investigating how ketone bodies affect energy metabolism and insulin sensitivity in humans. Ketone bodies are naturally produced by the liver during fasting or prolonged exercise and can serve as an alternative fuel for the brain, heart, and muscles.

In this study, ten overweight but otherwise healthy adults aged 55-70 years will participate in four study days at Aarhus University Hospital. Participants will receive one of four interventions in a randomized crossover design: 1) growth hormone (GH) and a ketone supplement, 2) GH and placebo, 3) a saline infusion with the ketone supplement, or 4) placebo (saline infusion and placebo supplement). The study uses advanced PET/CT imaging, indirect calorimetry, and tissue biopsies to measure how ketones influence fat breakdown, glucose uptake, and energy expenditure.

By understanding these mechanisms, the study aims to clarify whether oral ketone supplementation can improve insulin sensitivity and energy metabolism - findings that could be relevant for common conditions such as overweight, insulin resistance, and type 2 diabetes.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; Energy Metabolism; Obesity & Overweight; Ketone Body Metabolism
• Intervention / Treatment: Drug: Growth Hormone, Human; Dietary supplement: Oral ketone supplement (KetoAid®, KE4); Dietary supplement: Oral placebo drink; Drug: Saline infusion (placebo)

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Simon Bøggild Hansen, MD; Phone Number: +45 4111 1574; Email: simhan@clin.au.dk

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Contact: Simon Bøggild Hansen, MD; Phone Number: +45 4111 1574; Email: simhan@clin.au.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age range: 55-70 yr
• BMI: 25 - 35 kg/m2

Exclusion Criteria:

- Any evidence of acute or chronic illnesses, apart from well-controlled hypertension, that is judged by the investigators to impact the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GH infusion + oral ketone supplement; Participants receive a continuous intravenous infusion of growth hormone (30 ng·kg-¹·min-¹) combined with oral ketone supplementation.	Drug: Growth Hormone, Human; Continuous intravenous infusion of growth hormone (30 ng·kg-¹·min-¹) for approximately 7 hours to induce physiological lipolysis.; Dietary supplement: Oral ketone supplement (KetoAid®, KE4); Oral administration of D-β-hydroxybutyrate ester (R-1,3-butanediol β-hydroxybutyrate).
Experimental: GH infusion + oral placebo; Participants receive a continuous intravenous infusion of growth hormone (30 ng·kg-¹·min-¹) combined with oral placebo	Drug: Growth Hormone, Human; Continuous intravenous infusion of growth hormone (30 ng·kg-¹·min-¹) for approximately 7 hours to induce physiological lipolysis.; Dietary supplement: Oral placebo drink; Oral administration of an isocaloric placebo drink.
Experimental: Saline infusion + oral ketone supplement; Participants receive an intravenous saline infusion combined with oral ketone supplementation.	Dietary supplement: Oral ketone supplement (KetoAid®, KE4); Oral administration of D-β-hydroxybutyrate ester (R-1,3-butanediol β-hydroxybutyrate).; Drug: Saline infusion (placebo); Continuous IV infusion of isotonic saline as placebo for growth hormone.
Placebo Comparator: Saline infusion + oral placebo; Participants receive a continuous intravenous infusion of saline combined with oral placebo	Dietary supplement: Oral placebo drink; Oral administration of an isocaloric placebo drink.; Drug: Saline infusion (placebo); Continuous IV infusion of isotonic saline as placebo for growth hormone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin-stimulated glucose uptake in skeletal muscle and organs measured by [¹⁸F]-FDG PET	Quantification of insulin-stimulated glucose uptake rates in skeletal muscle and selected organs using dynamic [¹⁸F]-FDG PET during a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity.	During four experimental study days conducted over approximately 12 weeks
Tissue-specific uptake of β-hydroxybutyrate and palmitate measured by PET/CT imaging	Quantification of tissue-specific uptake of β-hydroxybutyrate (BHB) and palmitate in skeletal muscle, adipose tissue, and myocardium using dynamic PET/CT imaging with [¹¹C]-OHB and [¹¹C]-palmitate tracers.	During four experimental study days conducted over approximately 12 weeks
Tissue-specific oxidation of β-hydroxybutyrate and palmitate measured by PET/CT imaging	Quantification of oxidation rates of β-hydroxybutyrate (BHB) and palmitate in skeletal muscle, adipose tissue, and myocardium using dynamic PET/CT imaging with [¹¹C]-OHB and [¹¹C]-palmitate tracers to assess tissue-specific substrate utilization.	During four experimental study days conducted over approximately 12 weeks
Energy expenditure	Measurement of resting and insulin-stimulated energy expenditure using indirect calorimetry and analysis of respiratory exchange ratio (RER).	During four experimental study days conducted over approximately 12 weeks
Cardiac output measured by PET/CT imaging	Quantification of cardiac output in the basal state and during the hyperinsulinemic-euglycemic clamp using dynamic PET/CT imaging to evaluate hemodynamic effects of GH and β-hydroxybutyrate.	During four experimental study days conducted over approximately 12 weeks
Myocardial glucose and fatty acid uptake rates	Assessment of myocardial substrate metabolism using dynamic PET/CT imaging with [¹⁸F]-FDG and [¹¹C]-palmitate tracers during the basal period and the hyperinsulinemic-euglycemic clamp to quantify myocardial utilization of glucose and fatty acids.	During four experimental study days conducted over approximately 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skeletal muscle pyruvate dehydrogenase (PDHa) enzymatic activity	Assessment of skeletal-muscle PDHa enzymatic activity determined from the rate of acetyl-CoA production using a radioactivity-based assay and normalized to creatine content in the muscle homogenate.	During four experimental study days conducted over approximately 12 weeks
Adipose tissue lipoprotein lipase (LPL) enzymatic activity	Determination of heparin-releasable LPL activity in subcutaneous adipose-tissue and muscle biopsies using the glycerol-stabilized method to evaluate triglyceride-derived fatty-acid uptake.	During four experimental study days conducted over approximately 12 weeks
Expression levels of lipolytic regulatory proteins in adipose tissue	Expression of regulators of lipolysis to assess GH- and BHB-mediated effects on lipid metabolism.	During four experimental study days conducted over approximately 12 weeks
Phosphorylation levels of insulin-regulated proteins in skeletal muscle	Quantification of phosphorylation levels of insulin-regulated proteins in skeletal-muscle biopsies.	During four experimental study days conducted over approximately 12 weeks
Expression levels of insulin-regulated proteins in skeletal muscle	Quantification of protein expression levels of insulin-regulated proteins in skeletal-muscle biopsies.	During four experimental study days conducted over approximately 12 weeks
Expression levels of GH-regulated proteins (GHR, JAK2, STAT5, BCL6) in skeletal muscle and adipose tissue	Quantification of GH-regulated proteins (GHR, JAK2, STAT5, BCL6) in muscle and adipose biopsies using capillary electrophoresis immunoassay for each intervention condition.	During four experimental study days conducted over approximately 12 weeks
Relative mRNA expression of GH-responsive genes (SOCS1-3, CISH, IGF-I) in skeletal muscle and adipose tissue	Quantification of GH-responsive gene expression (SOCS1-3, CISH, IGF-I) in muscle and adipose biopsies using RT-PCR. Relative mRNA expression will be reported as fold change for each intervention condition.	During four experimental study days conducted over approximately 12 weeks
Skeletal muscle mitochondrial oxidative phosphorylation capacity	Assessment of mitochondrial oxidative phosphorylation capacity in permeabilized muscle fibers obtained from vastus lateralis biopsies, measured by high-resolution respirometry (Oroboros Oxygraph-2k).	During four experimental study days conducted over approximately 12 weeks
Muscle glycogen content	Measurement of skeletal-muscle glycogen stores to assess substrate utilization and glucose storage during growth-hormone and ketone interventions.	During four experimental study days conducted over approximately 12 weeks

Collaborators and Investigators

• Sponsor: University of Aarhus

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: January 15, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Overweight; insulin resistance; Ketone bodies; Growth hormone; Energy metabolism; Lipolysis
• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Hyperinsulinism; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity; Insulin Resistance; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Pituitary Hormones; Growth Hormone; Pituitary Hormones, Anterior; Human Growth Hormone
• Other Study ID Numbers: KETO-SENSE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared due to the small sample size, risk of indirect participant identification, and national data protection regulations (GDPR and Danish Data Protection Act). Aggregated and anonymized summary data will be available upon reasonable request.

Drug and device information, study documents

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