Insulin Resistance, Obesity & Overweight, Energy Metabolism, Ketone Body Metabolism
Conditions
Keywords
insulin resistance, Overweight, Growth hormone, Ketone bodies, Lipolysis, Energy metabolism
Brief summary
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.
Interventions
Continuous intravenous infusion of growth hormone (30 ng·kg-¹·min-¹) for approximately 7 hours to induce physiological lipolysis.
DIETARY_SUPPLEMENTOral ketone supplement (KetoAid®, KE4)
Oral administration of D-β-hydroxybutyrate ester (R-1,3-butanediol β-hydroxybutyrate).
Continuous IV infusion of isotonic saline as placebo for growth hormone.
DIETARY_SUPPLEMENTOral placebo drink
Oral administration of an isocaloric placebo drink.
Sponsors
University of Aarhus
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
55 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tissue-specific oxidation of β-hydroxybutyrate and palmitate measured by PET/CT imaging | During four experimental study days conducted over approximately 12 weeks | 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. |
| Energy expenditure | During four experimental study days conducted over approximately 12 weeks | Measurement of resting and insulin-stimulated energy expenditure using indirect calorimetry and analysis of respiratory exchange ratio (RER). |
| Cardiac output measured by PET/CT imaging | During four experimental study days conducted over approximately 12 weeks | 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. |
| Myocardial glucose and fatty acid uptake rates | During four experimental study days conducted over approximately 12 weeks | 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. |
| Insulin-stimulated glucose uptake in skeletal muscle and organs measured by [¹⁸F]-FDG PET | During four experimental study days conducted over approximately 12 weeks | 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. |
| Tissue-specific uptake of β-hydroxybutyrate and palmitate measured by PET/CT imaging | During four experimental study days conducted over approximately 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative mRNA expression of GH-responsive genes (SOCS1-3, CISH, IGF-I) in skeletal muscle and adipose tissue | During four experimental study days conducted over approximately 12 weeks | 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. |
| Skeletal muscle mitochondrial oxidative phosphorylation capacity | During four experimental study days conducted over approximately 12 weeks | Assessment of mitochondrial oxidative phosphorylation capacity in permeabilized muscle fibers obtained from vastus lateralis biopsies, measured by high-resolution respirometry (Oroboros Oxygraph-2k). |
| Expression levels of GH-regulated proteins (GHR, JAK2, STAT5, BCL6) in skeletal muscle and adipose tissue | During four experimental study days conducted over approximately 12 weeks | Quantification of GH-regulated proteins (GHR, JAK2, STAT5, BCL6) in muscle and adipose biopsies using capillary electrophoresis immunoassay for each intervention condition. |
| Muscle glycogen content | During four experimental study days conducted over approximately 12 weeks | Measurement of skeletal-muscle glycogen stores to assess substrate utilization and glucose storage during growth-hormone and ketone interventions. |
| Skeletal muscle pyruvate dehydrogenase (PDHa) enzymatic activity | During four experimental study days conducted over approximately 12 weeks | 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. |
| Adipose tissue lipoprotein lipase (LPL) enzymatic activity | During four experimental study days conducted over approximately 12 weeks | 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. |
| Expression levels of lipolytic regulatory proteins in adipose tissue | During four experimental study days conducted over approximately 12 weeks | Expression of regulators of lipolysis to assess GH- and BHB-mediated effects on lipid metabolism. |
| Phosphorylation levels of insulin-regulated proteins in skeletal muscle | During four experimental study days conducted over approximately 12 weeks | Quantification of phosphorylation levels of insulin-regulated proteins in skeletal-muscle biopsies. |
| Expression levels of insulin-regulated proteins in skeletal muscle | During four experimental study days conducted over approximately 12 weeks | Quantification of protein expression levels of insulin-regulated proteins in skeletal-muscle biopsies. |
Countries
Denmark
Contacts
CONTACTSimon Bøggild Hansen, MD
Outcome results
None listed