Metabolic Effects of Four-week Lactate-ketone Ester Supplementation

Study Overview
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Brief Summary
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Recent research reveals intriguing results concerning the role of exogenous lactate and the ketone body 3-hydroxybutyrate (3-OHB) as therapeutic tools to combat obesity and related conditions. Thus, oral administration of lactate and 3-OHB have separately been shown to suppress appetite sensations and slow gastric emptying while administered orally. Both seem to inhibit lipolysis while oral 3-OHB administration have shown direct insulin sensitizing effects. Furthermore, both substrates can be used as fuel for the heart. The goal of this placebo-controlled randomized crossover design is to test exogenous lactate and the ketone body 3-hydroxybutyrate (3-OHB) in healthy, non-diabetic, obese adults. The main questions it aims to answer are if chronic administration of LaKe ester affect or improve the following endpoints: Insulin sensitivity Appetite sensations Gastric emptying Lipolysis Cardiac output Left Ventricular Ejection Fraction Global Longitudinal Strain and other echocardiographic measures listed below Participants will ingest a combined lactate and ketone body ester (LaKe ester) or placebo twice a day for 28 days before experimental days.

Official Title
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Metabolic Effects of Four-week Lactate-ketone Ester Supplementation

Conditions
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Obesity

Intervention / Treatment
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* Dietary Supplement: LaKe Ester
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 30-60 years BMI range 30-40 Glycated haemoglobin (HbA1c) < 48 mmol/mol Otherwise 'healthy' Written and oral consent Exclusion Criteria: Medication that affect energy or glucose metabolism, eg metformin, insulin or Glucagon-like peptide-1 receptor (GLP-1) agonists Specific diets (eg practicing ketogenic diets) Cardiac arrhythmias (eg atrial fibrillation) Ongoing acute/chronic serious diseases (eg, anemia, chronic kidney or liver disease) Inability to understand Danish or English

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LaKe arm<br>Ingestion of a combined lactate and ketone body ester, 25 ml twice daily for 28 days. | Dietary Supplement: LaKe Ester<br>* Lactate and ketone body ester (one equivalent of S-lactate and one equivalent of 1,3-butanediol / D-β-hydroxybutyrate)<br>|
| Placebo Comparator: Placebo arm<br>Placebo treatment | Dietary Supplement: Placebo<br>* Taste and appearance matched noncaloric placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity expressed as an M-value | On all study days, a hyperinsulinemic-euglycemic clamp is used to determine insulin sensitivity: continuous infusion of insulin (1 milliunit · kg lean body mass-1 · min-1) for 2 hours. The blood glucose is clamped at 5 mmol/l. | Throughout the cross-over design, approximately 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in lipolysis rate | Measured as differences in palmitate flux | Throughout the cross-over design, approximately 12 weeks | 
| Differences in body weight and composition | Dual-energy X-ray absorptiometry (DEXA) scan to assess total fat mass (kg), lean body mass (kg), and bone mass (kg) | Throughout the cross-over design, approximately 12 weeks | 
| Differences in gastric emptying rate | Evaluated by using the acetaminophen test | Throughout the cross-over design, approximately 12 weeks | 
| Cardiac Output (CO) | Echocardiographic changes in left ventricular outflow tract (LVOT), velocity time integral (VTI) and heart rate (HR) | Throughout the cross-over design, approximately 12 weeks | 
| Left Ventricular Ejection Fraction (LVEF) | Echocardiographic changes | Throughout the cross-over design, approximately 12 weeks | 
| Tricuspid annular plane systolic excursion (TAPSE) | Echocardiographic changes | Throughout the cross-over design, approximately 12 weeks | 
| Global Longitudinal Strain (GLS) | Echocardiographic changes | Throughout the cross-over design, approximately 12 weeks | 
| Mitral inflow velocities (E and A) | Echocardiographic changes | Throughout the cross-over design, approximately 12 weeks | 
| Mitral plane velocities in the lateral mitral annulus (e' and s') | Echocardiographic changes | Throughout the cross-over design, approximately 12 weeks | 
| Global work index (GWI) | Echocardiographic changes | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of 3-OHB | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of lactate | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of free fatty acids | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of glucose | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of insulin | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in plasma concentrations of growth/differentiation factor 15 (GDF-15) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of gastric inhibitory polypeptide (GIP) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of ghrelin | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of glucagon | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of liver-expressed antimicrobial peptide 2 (LEAP-2) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of C-peptide | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of triglycerides | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of cholesterol | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of brain-derived neurotrophic factor (BDNF) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of N-lactoyl-phenylalanine (Lac-Phe) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Fibrosis-4 (FIB-4) | Blood sampling of alanine aminotransferase (ALAT), aspartate transaminase (ASAT), and thrombocytes | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of erythrocyte volume fraction (EVF) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of Erythropoietin (EPO) | Blood sampling | Throughout the cross-over design, approximately 12 weeks | 
| Changes in blood concentrations of inflammation markers | Blood sampling of C reactive protein (CRP) and leucocytes | Throughout the cross-over design, approximately 12 weeks | 
| Mood, assessed by Major Depression Inventory score (MDI) | Change in MDI score measured by Major Depression Inventory. The theoretical sum score ranges from 0 (no depression) to 50 (maximum depression). | Throughout the cross-over design, approximately 12 weeks | 
| Anxiety Symptom Scale questionnaire (ASS) | Change in the Anxiety Symptom Scale questionnaire to screen for anxiety disorders. The theoretical sum score ranges from 0 (no anxiety) to 60 (maximum anxiety). | Throughout the cross-over design, approximately 12 weeks | 
| Supplement tolerability | Assessed using a symptom questionnaire covering every organ system, including GI symptoms measured through the validated Beverage Tolerability Questionnaire. Participants will rate the frequency of each item on a scale from 0 (no symptoms) to 5 (severe symptoms). | Throughout the cross-over design, approximately 12 weeks | 
| Control of Eating Questionnaire (CoEQ) | The CoEQ has been used in clinical trials as a multi-dimensional measure of appetite, craving and mood regulation. Based on the previous 7 days, subjects will be asked to answer 21 questions (20 rated on a 100 mm visual analogue scale and one open-ended). | Throughout the cross-over design, approximately 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin sensitivity, Lipolysis, Appetite