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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
10
Lactate and ketone body ester (one equivalent of S-lactate and one equivalent of 1,3-butanediol / D-β-hydroxybutyrate)
Taste and appearance matched noncaloric placebo
Steno Diabetes Center Aarhus
Aarhus, Denmark
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.
Time frame: Throughout the cross-over design, approximately 12 weeks
Differences in lipolysis rate
Measured as differences in palmitate flux
Time frame: 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)
Time frame: Throughout the cross-over design, approximately 12 weeks
Differences in gastric emptying rate
Evaluated by using the acetaminophen test
Time frame: 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)
Time frame: Throughout the cross-over design, approximately 12 weeks
Left Ventricular Ejection Fraction (LVEF)
Echocardiographic changes
Time frame: Throughout the cross-over design, approximately 12 weeks
Tricuspid annular plane systolic excursion (TAPSE)
Echocardiographic changes
Time frame: Throughout the cross-over design, approximately 12 weeks
Global Longitudinal Strain (GLS)
Echocardiographic changes
Time frame: Throughout the cross-over design, approximately 12 weeks
Mitral inflow velocities (E and A)
Echocardiographic changes
Time frame: Throughout the cross-over design, approximately 12 weeks
Mitral plane velocities in the lateral mitral annulus (e' and s')
Echocardiographic changes
Time frame: Throughout the cross-over design, approximately 12 weeks
Global work index (GWI)
Echocardiographic changes
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of 3-OHB
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of lactate
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of free fatty acids
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of glucose
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of insulin
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in plasma concentrations of growth/differentiation factor 15 (GDF-15)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of gastric inhibitory polypeptide (GIP)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of ghrelin
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of glucagon
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of liver-expressed antimicrobial peptide 2 (LEAP-2)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of C-peptide
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of triglycerides
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of cholesterol
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of brain-derived neurotrophic factor (BDNF)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of N-lactoyl-phenylalanine (Lac-Phe)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Fibrosis-4 (FIB-4)
Blood sampling of alanine aminotransferase (ALAT), aspartate transaminase (ASAT), and thrombocytes
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of erythrocyte volume fraction (EVF)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of Erythropoietin (EPO)
Blood sampling
Time frame: Throughout the cross-over design, approximately 12 weeks
Changes in blood concentrations of inflammation markers
Blood sampling of C reactive protein (CRP) and leucocytes
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: Throughout the cross-over design, approximately 12 weeks
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