An interventional study of βHB drink (ketone ester) and Carbohydrate drink in Nutritional and Metabolic Diseases, Prediabetes and Type 2 Diabetes, sponsored by German Institute of Human Nutrition. Recruiting at 2 sites in Germany. Open to participants aged 40 Years to 75 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-10-22.
Sponsored by German Institute of Human Nutrition · Not applicable, Interventional, and Prevention
Glycemic responses vary significantly among individuals, even when consuming identical foods or meals, but the factors predicting individual glucose responses to food intake remain poorly investigated. The aim of the LIfestyle MEtabotype (LIME) study is to identify lifestyle-related and mechanistic factors which predict individual postprandial glucose fluctuations in individuals with different glycemic status (prediabetes, type 2 diabetes [T2D] and absence of prediabetes or T2D), using comprehensive lifestyle characterization and metabolic, molecular and neurocognitive phenotyping.
As part of this phenotyping, the LIME study also investigates the role of ketone bodies. Individuals with insulin resistance, prediabetes or T2D often show impaired cerebral glucose utilization. Ketone bodies, such as β-hydroxybutyrate (βHB) may serve as an alternative energy source for the brain. However, how exogenous βHB affects neurocognitive processes and decision-making in individuals with different glycemic status remains poorly understood.
This record describes module B of the LIME study. Module B investigates the effects of a single dose of exogenous βHB, compared with a carbohydrate-based placebo drink, on brain structure and function, decision-making behavior and physiological and metabolic responses. Module A comprises a comprehensive lifestyle and metabolic characterization of the same participants and is registered separately as an observational study (NCT07868601). Data from both modules will be integrated in joint analyses.
Studies show that glycemic responses vary significantly among individuals, even when consuming identical foods or meals. These varying glycemic responses are attributed to metabolic differences between individuals. Recently, machine learning models incorporating metabolic data (including microbiome composition) have been able to successfully predict individual blood glucose responses. Precision nutrition recommendations based on such predictions could facilitate better glycemic control and reduce the risk of diabetes. From this perspective, considering metabolic biomarkers, phenotype and genotype, as well as gut microbiome composition, could play a role in deriving dietary recommendations and thereby achieving the best possible health outcomes through nutrition. In addition to macronutrient composition, the timing, frequency and number of meals may also play a significant role in the glycemic response to diet. Finally, socioeconomic, cultural and personal lifestyle factors also have an influence on the glycemic response. Therefore, this study aims to characterize the personal lifestyle differences between individuals with prediabetes, T2D, and those without prediabetes or T2D.
Furthermore, ketone bodies, specifically β-hydroxybutyrate (βHB), are gaining importance, as they serve as both metabolic biomarkers and alternative energy sources in periods of low carbohydrate availability. In individuals with insulin resistance or prediabetes, cerebral glucose utilization is often impaired, leading to the use of ketone bodies as a compensatory energy source for the brain. Findings indicate that the individual ketone response to dietary interventions varies significantly between individuals and could thus itself be relevant as a metabolic phenotype marker in the context of precision nutrition. Therefore, the study also aims to further investigate the extent to which exogenous βHB supplementation influences neurocognitive processes and decision-making behavior, and whether characteristic neurocognitive phenotypes can be derived from this in metabolic risk groups.
This study will achieve its aims by completing a comprehensive lifestyle characterization and metabolic, molecular and neurocognitive phenotyping of individuals with different glycemic status (prediabetes, type 2 diabetes [T2D], and absence of prediabetes or T2D) in a German cohort. The study consists of modules A and B. This record represents a description of module B; module A has an observational design and is registered as a separate record (NCT07868601).
Module A will include a 14-days observational period at home and two visits (screening and phenotyping visits) of the study center at the German Institute of Human Nutrition Potsdam-Rehbrücke before and after the observational period, respectively. Study visits of module A will include an intensive characterization of participants, comprising questionnaires, anthropometric and metabolic assessments, as well as the collection of biological samples. In the observation period, food intake, sleep, activity, and interstitial glucose will be monitored during 14 days, and test meals will be consumed at two days at specific times within this period.
Module B has an interventional crossover design and will take place 1-12 weeks after module A (or after the screening visit for participants not taking part in module A). It includes two visits of the study center at the Freie Universität Berlin, separated by a two-week interval. Study visits of module B will focus on neurocognitive phenotyping, comprising structural and functional magnetic resonance imaging (MRI) of the brain and computer-based decision-making tasks, performed after consumption of either a βHB-containing drink or an equicaloric and taste-matched carbohydrate (dextrose) drink, referred to as placebo drink in the following (test and placebo visits). Data from module A (registered separately [NCT07868601]; e.g., anthropometric and body composition data, blood parameters, CGM-derived glycemic parameters, gut microbiome, lifestyle, metabolic and questionnaire data) will be integrated with module B outcomes to examine associations between individual metabolic and lifestyle phenotypes and neurocognitive, behavioral, affective, physiological and metabolic measures, as well as responses to βHB supplementation. Participants who do not complete the measurements of module A will complete continuous glucose monitoring, actigraphy, sleep and dietary records and stool sample collection between the two module B visits. Module B outcomes will be analyzed with respect to drink condition (βHB vs. placebo), glycemic group, and their interaction.
The aims of the study are as follows:
Primary aims of the LIME study (addressed primarily in module A [NCT07868601], with contributions from module B):
Primary aims (LIME-B study):
25 studies on the registry are indexed under Nutritional and Metabolic Diseases; 13 are open to participants now.
This study's planned enrollment of 300 is above the median of 107 across 20 interventional studies indexed under Nutritional and Metabolic Diseases.
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Participants are classified into three groups based on the screening visit:
Exclusion Criteria:
Participants receive a single dose of a βHB ester drink (0.3 g/kg body weight) at one of the two module B visits
Dietary Supplement: βHB drink (ketone ester)
Carbohydrate drink Participants receive an equicaloric and taste-matched carbohydrate drink (placebo drink) at the other visit of module B
Dietary Supplement: Carbohydrate drink
Single oral dose of a βHB ester (0.3 g/kg body weight), consumed fasted during one of the two visits of module B
Single oral dose of an equicaloric and taste-matched dextrose drink.
βHB response to exogenous βHB supplementation
βHB area under the curve (AUC) from fasting and repeated postprandial blood samples after drink intake, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Time course of βHB concentrations
Fasting concentrations and time course of βHB concentrations at individual time points including derived metrics (e.g., peak concentration, time to peak, rate of change), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Fasting and postprandial glucose and insulin response
Fasting concentrations and postprandial time course of glucose, insulin and C-peptide in repeated blood samples after drink intake, including derived metrics (e.g., incremental area under the curve \[iAUC\], incremental peak, time to peak, amplitude, nadir, rate of change) and indices of insulin sensitivity (e.g., HOMA-IR), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Concentration of inflammatory markers
Interleukin-6 (IL-6) and hsCRP levels measured in fasting blood samples; IL-6 additionally in postprandial blood samples after drink intake, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Metabolic and stress-responsive hormones
Growth differentiation factor 15 (GDF15), fibroblast growth factor 21 (FGF21) and cortisol concentrations in fasting and postprandial blood samples, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Gut and appetite-regulating hormones
Glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), ghrelin and leptin concentrations in fasting and postprandial blood samples, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Lipolysis and energy metabolites
Free fatty acids, triglycerides, lactate and amino acids in fasting and postprandial blood samples, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Oxidative stress markers
Oxidative stress markers such as Malondialdehyde and 3-Nitrotyrosine in fasting and postprandial blood samples, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Avoidance behavior
Time spent in less safe areas and exploratory movement in two virtual reality scenarios (elevated platform, dark maze), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Risky decision-making
Choice behavior in a lottery task during fMRI (e.g., proportion of risky choices, risk attitude), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Dual-task performance
Reaction times, accuracy and dual-task costs in an auditory-visual dual-task paradigm, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Heart rate and heart rate variability (HRV)
Heart rate and heart rate variability (HRV) from electrocardiography, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Skin conductance response
Electrodermal activity (EDA) measured via electrodermal activity electrodes, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Respiration rate
Task-based and resting-state respiration rate, measured via a respiration belt pulse (pulse oximetry during MRI), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Pulse
Pulse measured via pulse oximetry during MRI, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Gastric myoelectric activity
Gastric rhythm and power assessed by electrogastrography (EGG), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Brain Structure
Brain morphology (e.g., regional gray matter volume and density) assessed by T1-weighted structural MRI, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
White matter micro- and macrostructure
White matter micro- and macrostructure assessed by diffusion-weighted imaging (DWI), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Resting-state functional connectivity
Functional connectivity between brain regions assessed by resting-state functional MRI (rs-fMRI), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Task-related brain activity
Brain activity during a risk-based decision-making task (lottery task) assessed by functional MRI (fMRI), compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Module A phenotyping data as predictors, moderators and controls
All outcome measures registered for module A \[NCT07868601\] (e.g., body composition, blood parameters, CGM-derived glycemic parameters, gut microbiome, dietary intake, sleep and activity, questionnaire data) integrated with module B outcomes in joint analyses; if not obtained in module A, CGM, actigraphy, sleep, dietary records and stool samples are collected between the two module B visits
Time frame: 2 weeks and 3-16 weeks
Body height
Body height measured using a calibrated wall-mounted measuring tape
Time frame: 3-16 weeks
Body weight
Body weight measured by scale weight
Time frame: 3-16 weeks
Waist and hip circumference
Waist and hip circumference measured using a measuring tape
Time frame: 3-16 weeks
Body Mass Index (BMI)
BMI \[kg/m2\], calculated as weight/square height
Time frame: 3-16 weeks
Subjective state during visits
Repeated ratings of stress, hunger, thirst, anxiety and well-being and subjective hypoglycemia symptoms during the visits, including during the virtual reality task, compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Affective state
Positive and Negative Affect Scale (PANAS; Janke et al., 2014) compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Anxiety
State-Trait Anxiety Inventory (STAI; Grimm et al., 2009) compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Perceived stress
Perceived Stress Questionnaire (PSQ; Fliege et al., 2001) compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Flow state
Flow State Scale (FSS; Rheinberg et al., 2003) compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Food craving
Food Cravings Questionnaire (FCQ; Meule et al., 2012)
Time frame: 3-16 weeks
Subjective hypoglycaemic symptoms
Subjective hypoglycaemic symptom list (SHSL; Meyhöfer et al. 2022; Mitrakou et al. 1993) compared between drink conditions (βHB vs. placebo) and glycemic groups
Time frame: 3-16 weeks
Other hormones and metabolites (exploratory)
Exploratory analysis of additional hormones and metabolites in stored blood samples (e.g., sex hormones such as testosterone, estradiol, progesterone and sex hormone-binding globulin \[SHBG\])
Time frame: 3-16 weeks
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Studies of the drug tested here: Beta-hydroxybutyrate-1,3-butanediol monoester
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