Overview
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.
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
Eligibility
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
