Nutritional and Metabolic Diseases, Prediabetes, Type 2 Diabetes
Conditions
Keywords
prediabetes, type 2 diabetes, healthy controls, mri, decision-making, lifestyle factors, ketones, nutritional and metabolic diseases
Brief summary
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.
Detailed description
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): * Identification of metabolic biomarkers and omics-based scores that predict individual glycemic response to food * Identification of general lifestyle patterns that distinguish individuals with prediabetes or T2D from those without prediabetes or T2D, as well as individuals with prediabetes from those with T2D * Identification of personal factors and differences in lifestyle patterns that predict individual glucose response to food Primary aims (LIME-B study): * Characterization of individual βHB and glucose responses to exogenous βHB supplementation and their association with glycemic status and individual metabolic and lifestyle phenotypes * Investigation of the effects of exogenous βHB supplementation on neurocognitive processes, cognitive functioning as well as avoidance and decision-making behavior in individuals with different glycemic status * Elucidation of neuronal, metabolic, and physiological mechanisms associated with specific lifestyle patterns
Interventions
DIETARY_SUPPLEMENTβHB drink (ketone ester)
Single oral dose of a βHB ester (0.3 g/kg body weight), consumed fasted during one of the two visits of module B
DIETARY_SUPPLEMENTCarbohydrate drink
Single oral dose of an equicaloric and taste-matched dextrose drink.
Sponsors
German Institute of Human Nutrition
Freie Universität Berlin, Center for Cognitive Neuroscience Berlin (CCNB)
German Center of Diabetes Research (DZD)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Within-subject crossover design: each participant receives both the βHB drink and the placebo drink at two visits in module B, separated by an interval of approximately two weeks, in randomized order, stratified by glycemic group
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Overweight or obese (BMI 25-40 kg/m²) * Good knowledge of German * Completion of the LIME screening visit; participants who do not take part in the further assessments of module A \[NCT07868601\] may still participate in module B Participants are classified into three groups based on the screening visit: * Group A (without Prediabetes or Type 2 Diabetes) Criteria: HbA1c \<5.7% and fasting plasma glucose \< 100 mg/dl * Group B (Prediabetes) Criteria: HbA1c 5.7-6.4%, or fasting plasma glucose 100-125 mg/dL * Group C (Type 2 Diabetes) Criteria: HbA1c ≥6.5%, fasting plasma glucose ≥ 126 mg/dl, or existing T2D diagnosis by physician, or T2D diagnosis based on an available result from standardized 75 g oral glucose tolerance test
Exclusion criteria
* Weight changes of more than 5% in the last 3 months * Night shift work * Travel across more than one time zone in the last month before and during study participation * Intensive regular physical activity of more than 2 hours per day * Current pregnancy or breastfeeding * Severe renal, liver or heart disease * Existing or past hematological malignancies, other malignant tumors, unless successfully treated more than 12 months before study start * Severe neurological or psychiatric disorders * Daily alcohol consumption of more than 20 grams or more than 150 grams per week * Use of illicit or legal drugs one week prior to study start and during study participation * Known systemic infections * Type 1 diabetes and rare forms of diabetes * Diabetes treatment with insulin or sulfonylureas or diabetes medication in the absence of manifest type 2 diabetes * Unstable thyroid dysfunction * Blood coagulation disorders or anticoagulation therapy that cannot be interrupted * Medications affecting nutrient absorption * Medications with immunosuppressants or steroids (oral or parenteral) * Current eating disorders, functional or structural digestive disorders or bariatric surgery * Food allergies or intolerances to ingredients of the test meals * Intermittent fasting or calorie-restricted diet four weeks prior to the start of the study or during the study * Ketogenic diet or ketogenic supplements four weeks prior to or during module B * Left-handedness * Severe claustrophobia * Electrical implants or non-removable metallic implants * Concurrent participation in another intervention study * Assessment by the study physician based on medical concerns precluding study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| βHB response to exogenous βHB supplementation | 3-16 weeks | 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 course of βHB concentrations | 3-16 weeks | 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 |
| Fasting and postprandial glucose and insulin response | 3-16 weeks | 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 |
| Concentration of inflammatory markers | 3-16 weeks | 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 |
| Metabolic and stress-responsive hormones | 3-16 weeks | 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 |
| Gut and appetite-regulating hormones | 3-16 weeks | 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 |
| Lipolysis and energy metabolites | 3-16 weeks | Free fatty acids, triglycerides, lactate and amino acids in fasting and postprandial blood samples, compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Oxidative stress markers | 3-16 weeks | 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 |
| Avoidance behavior | 3-16 weeks | 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 |
| Risky decision-making | 3-16 weeks | 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 |
| Dual-task performance | 3-16 weeks | Reaction times, accuracy and dual-task costs in an auditory-visual dual-task paradigm, compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Heart rate and heart rate variability (HRV) | 3-16 weeks | Heart rate and heart rate variability (HRV) from electrocardiography, compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Skin conductance response | 3-16 weeks | Electrodermal activity (EDA) measured via electrodermal activity electrodes, compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Respiration rate | 3-16 weeks | 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 |
| Pulse | 3-16 weeks | Pulse measured via pulse oximetry during MRI, compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Gastric myoelectric activity | 3-16 weeks | Gastric rhythm and power assessed by electrogastrography (EGG), compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Brain Structure | 3-16 weeks | 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 |
| White matter micro- and macrostructure | 3-16 weeks | White matter micro- and macrostructure assessed by diffusion-weighted imaging (DWI), compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Resting-state functional connectivity | 3-16 weeks | Functional connectivity between brain regions assessed by resting-state functional MRI (rs-fMRI), compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Task-related brain activity | 3-16 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Module A phenotyping data as predictors, moderators and controls | 2 weeks and 3-16 weeks | 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 |
| Body height | 3-16 weeks | Body height measured using a calibrated wall-mounted measuring tape |
| Body weight | 3-16 weeks | Body weight measured by scale weight |
| Waist and hip circumference | 3-16 weeks | Waist and hip circumference measured using a measuring tape |
| Body Mass Index (BMI) | 3-16 weeks | BMI \[kg/m2\], calculated as weight/square height |
| Subjective state during visits | 3-16 weeks | 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 |
| Affective state | 3-16 weeks | Positive and Negative Affect Scale (PANAS; Janke et al., 2014) compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Anxiety | 3-16 weeks | State-Trait Anxiety Inventory (STAI; Grimm et al., 2009) compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Perceived stress | 3-16 weeks | Perceived Stress Questionnaire (PSQ; Fliege et al., 2001) compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Flow state | 3-16 weeks | Flow State Scale (FSS; Rheinberg et al., 2003) compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Food craving | 3-16 weeks | Food Cravings Questionnaire (FCQ; Meule et al., 2012) |
| Subjective hypoglycaemic symptoms | 3-16 weeks | Subjective hypoglycaemic symptom list (SHSL; Meyhöfer et al. 2022; Mitrakou et al. 1993) compared between drink conditions (βHB vs. placebo) and glycemic groups |
| Other hormones and metabolites (exploratory) | 3-16 weeks | 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 \[SHBG\]) |
Countries
Germany
Contacts
CONTACTSoyoung Q Park, Prof. Dr.
CONTACTEva Fröhlich, Dr.
PRINCIPAL_INVESTIGATOROlga Ramich, Prof. Dr.
German Institute of Human Nutrition Potsdam-Rehbrücke and the Charité - Universitätsmedizin Berlin
PRINCIPAL_INVESTIGATORSoyoung Q Park, Prof. Dr.
German Institute of Human Nutrition Potsdam-Rehbrücke and the Charité - Universitätsmedizin Berlin
Outcome results
None listed