Maintaining well-controlled blood glucose concentrations is essential in the prevention of chronic cardiometabolic diseases. The blood glucose response to dietary and/or lifestyle patterns may vary between individuals. Insulin resistance in specific metabolic organs such as skeletal muscle, adipose tissue or the liver may underlie differential blood glucose responses. This dietary intervention study aims to obtain insight into the metabolic and lifestyle determinants of postprandial blood glucose responses, and to establish the effect of macronutrient manipulation of a 12-week dietary intervention on blood glucose homeostasis in metabolically different subgroups an its relationship to physical and mental performance and well-being.
Study design: this study is a double-blinded, randomised, controlled, parallel design dietary intervention study. The study will be conducted at Maastricht University and Wageningen University and Research, the Netherlands. Study population: the study population will consist of 240 men and women between 40-75 years old, with a BMI 25-40 kg/m2. Participants will be either muscle insulin resistant (MIR) or liver insulin resistant (LIR), as classified by an oral glucose tolerance test (OGTT) during the screening procedure. A subgroup of 80 participants will be selected for detailed metabolic phenotyping. Intervention: for 12 weeks, participants will receive either a diet optimal for MIR (high in mono-unsaturated fatty acids) or a diet optimal for LIR (high in protein and fiber, low in fat) with respect to changes in disposition index. Participants will be randomly allocated to one of the two diets. Detailed laboratory and daily life phenotyping will be done pre- and post intervention.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
242
Based on a 7-points OGTT, participants will be classified as MIR or LIR. The hypothesized optimal diet for MIR has a moderate fat content which is high in mono- unsaturated fatty acids (HMUFA) with a macronutrient breakdown of 38 E% from fat (20% MUFA, 10% polyunsaturated fatty acids (PUFA), 8% saturated fatty acids (SFA)), 48 E% from carbohydrates (CHO, 35% complex), and 14 E% from protein (35-40% plant protein). The hypothesized optimal diet for LIR is low in fat, high in protein (LFHP) and increased fiber with a macronutrient breakdown of \<28 E% from fat (10% MUFA, 10% PUFA, 8% SFA), 48 E% from CHO (35% complex), and 24 E% from protein (35-40% plant protein), and an additional supplement of 6g of soluble fiber per day. Participants wil be randomly allocated to one of the two diets.
The optimal diet for the other metabolic phenotype will be considered as "suboptimal"/ control diet. For the MIR phenotype this is the high protein, high fiber, low fat diet; for the LIR phenotype this is the high monounsaturated fatty acid diet. See the description above.
Department of Human Biology, Maastricht University Medical Centre
Maastricht, Netherlands
Wageningen University and Research
Wageningen, Netherlands
Disposition index
The primary objective of this study is to establish the effect of a metabolically targeted, optimal versus suboptimal macronutrient manipulated 12-week dietary intervention on the change in disposition index, a composite marker of first phase insulin secretion and insulin sensitivity during a 2-hour 7-points oral glucose tolerance test (OGTT). Disposition index will be calculated as follows: \[Insulin sensitivity index (ISI) \* (AUC30 min insulin / AUC30 min glucose)\], where AUC30 min is the area under the curve between 0 and 30 minutes of the OGTT for insulin (pmol/l) and glucose (mmol/l), respectively, and ISI is defined as: \[10,000 ÷ square root of (fasting plasma glucose (mmol/l) x fasting insulin (pmol/l)) x (mean glucose (mmol/l) x mean insulin (pmol/l))\]. Higher values represent a higher insulin sensitivity.
Time frame: Change from baseline at week 12 dietary intervention
Mean 24h glucose concentrations
Optimal versus suboptimal diet. The mean 24h glucose concentrations will be measured continuously with the iPro2 device and Enlite Glucose Sensor (Medtronic) and expressed as mmol/L.
Time frame: Change from baseline at week 12 dietary intervention
Glucose incremental area under the curve (iAUC)
Optimal versus suboptimal diet. The iAUC will be calculated using the trapezoid rule from data obtained from the iPro2 device and Enlite Glucose Sensor (Medtronic). The iAUC provides a summary measure of the net increase in glucose levels above the fasting level during a 24-hour period and is expressed as mmol/min/L.
Time frame: Change from baseline at week 12 dietary intervention
The frequency and duration of hypo- and hyperglycemia
Optimal versus suboptimal diet. The frequency and duration of hypo- and hyperinsulinemia will be monitored using the iPro2 device and Enlite Glucose Sensor (Medtronic) and is defined as a glucose level of ≥10.0 mmol/l for hyperglycemia, whilst hypoglycemia will be defined as a glucose concentration ≤3.9 mmol/l.
Time frame: Change from baseline at week 12 dietary intervention
Glucose tolerance
Optimal versus suboptimal diet. Determined by 2-hour glucose values (mmol/L) during an oral glucose tolerance test.
Time frame: Change from baseline at week 12 dietary intervention
Muscle insulin sensitivity
Optimal versus suboptimal diet. Determined during a 2-hour, 7-points oral glucose tolerance test. The muscle insulin sensitivity index (MISI) will be calculated as follows: MISI (mmol/l/min/pmol/l) = (dG/dt) / mean plasma insulin concentration (pmol/l) during OGTT. Here, dG/dt is the rate of decay of plasma glucose concentration (mmol/L) during the OGTT, calculated as the slope of the least square fit to the decline in plasma glucose concentration from peak to nadir. Higher values represent higher muscle insulin sensitivity.
Time frame: Change from baseline at week 12 dietary intervention
Hepatic insulin sensitivity
Optimal versus suboptimal diet. Determined during a 2-hour, 7-points oral glucose tolerance test. The hepatic insulin resistance index (HIRI) will be calculated using the square root of the product of the area under curves (AUCs) for glucose and insulin during the first 30 min of the OGTT - i.e., square root (glucose0-30 \[AUC in mmol/l·h\] · insulin 0-30 \[AUC in pmol/l·h). Higher IR values represent lower hepatic insulin sensitivity.
Time frame: Change from baseline at week 12 dietary intervention
Insulin sensitivity
Optimal versus suboptimal diet. Glucose infusion rate (mg/kg/min) during a 2-step hyper-insulinemic euglycemic clamp as golden standard method.
Time frame: Change from baseline at week 12 dietary intervention
Body composition
Optimal versus suboptimal diet. Body composition will be determined by using a dual-energy X-ray absorptiometry scan (DXA).
Time frame: Change from baseline at week 12 dietary intervention
Waist circumference
Optimal versus suboptimal diet. Waist circumferences in centimeters.
Time frame: Change from baseline at week 12 dietary intervention
Hip circumferences
Optimal versus suboptimal diet. Hip circumferences in centimeters.
Time frame: Change from baseline at week 12 dietary intervention
Body fat distribution
Optimal versus suboptimal diet. Magnetic Resonance Imaging (MRI)(UM) and Magnetic resonance spectroscopy (1H-MRS)(WUR) measurements will be included to quantify both subcutaneous and visceral fat depots, and ectopic fat deposition (e.g. in liver and muscle).
Time frame: Change from baseline at week 12 dietary intervention
Blood pressure
Optimal versus suboptimal diet. Systolic and diastolic blood pressure in mmHg.
Time frame: Change from baseline at week 12 dietary intervention
Fasting circulating metabolic markers
Optimal versus suboptimal diet. Fasting circulating metabolic markers include: glucose, insulin, hemoglobin A1c (HbA1c), triacylglycerol, free glycerol, free fatty acids (FFA), lactate, high density lipoprotein (HDL), total cholesterol, short chain fatty acids (SCFA), bile acids, glucagon-like peptide-1 (GLP-1), peptide YY (PYY).
Time frame: Change from baseline at week 12 dietary intervention
Fasting blood lipid spectrum
Optimal versus suboptimal diet. Metabolomics will be used to determine the fasting blood lipid spectrum.
Time frame: Change from baseline at week 12 dietary intervention
Postprandial circulating metabolic markers
Optimal versus suboptimal diet. Postprandial circulating metabolic markers will be determined during a high-fat mixed-meal test and include: glucose, insulin, triacylglycerol, free glycerol, free fatty acids (FFA), lactate, high density lipoprotein (HDL), total cholesterol, short chain fatty acids (SCFA), bile acids, glucagon-like peptide-1 (GLP-1), peptide YY (PYY).
Time frame: Change from baseline at week 12 dietary intervention
Energy expenditure
Optimal versus suboptimal diet. Fasting and insulin-stimulated energy expenditure will be determined by indirect calorimetry during a 2-step hyperinsulinemic-euglycemic clamp.
Time frame: Change from baseline at week 12 dietary intervention
Substrate oxidation
Optimal versus suboptimal diet. Fasting and insulin-stimulated substrate oxidation will be determined by indirect calorimetry during a 2-step hyperinsulinemic-euglycemic clamp.
Time frame: Change from baseline at week 12 dietary intervention
Fecal microbiota composition
Optimal versus suboptimal diet. Fecal samples to be used for analysing microbiota composition will be collected.
Time frame: Change from baseline at week 12 dietary intervention
Oral microbiota composition
Optimal versus suboptimal diet. Saliva samples to be used for analysing microbiota composition will be collected.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported perceived stress
Optimal versus suboptimal diet. Perceived stress will be assessed using a 10-item perceived stress scale (PSS-10). Items will be scored based on a 5-point Likert scale, with higher scores representing higher perceived stress levels.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported self efficacy in physical activity
Optimal versus suboptimal diet. Self efficacy in physical activity will be assessed using Likert scales, determining an individual's ability to achieve performing physical activity.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported sleep behaviour
Optimal versus suboptimal diet. Sleep behaviour will be assessed using the Munich Chronotype Questionnaire (MCTQ).
Time frame: Change from baseline at week 12 dietary intervention
Self-reported sleep quality over a 1 month period
Optimal versus suboptimal diet. Sleeping quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI).
Time frame: Change from baseline at week 12 dietary intervention
Self-reported daytime sleepiness
Optimal versus suboptimal diet. Daytime sleepiness is assessed using the 8-item Epworth Sleepiness Scale (ESS). Items will be scored on a scale of 0-3, with a higher score representing a higher probability of falling asleep.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported fatigue
Optimal versus suboptimal diet. Self-reported fatigue will be assessed using the Chalder Fatigue Scale.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported sedentary behaviour
Optimal versus suboptimal diet. Sedentary behaviour will be assessed using the sedentary behaviour questionnaire (AQUAA).
Time frame: Change from baseline at week 12 dietary intervention
Self-reported physical activity
Optimal versus suboptimal diet. Self-reported physical activity will be assessed using the physical activity questionnaire (Baecke).
Time frame: Change from baseline at week 12 dietary intervention
Self-reported eating rate
Optimal versus suboptimal diet. Self-reported eating rate will be assessed using the eating rate index.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported intestinal health
Optimal versus suboptimal diet. Self-reported intestinal health will be assessed using an intestinal health questionnaire and the Bristol Stool Chart.
Time frame: Change from baseline at week 12 dietary intervention
Self-reported quality of life
Optimal versus suboptimal diet. Self-reported quality of life will be assessed using the 36-Item Short Form Health Survey (SF-36). Higher scores represent less disability.
Time frame: Change from baseline at week 12 dietary intervention
Physical activity patterns
Optimal versus suboptimal diet. Physical activity patterns will be monitored continuously with the ActivPAL3 device.
Time frame: Change from baseline at week 12 dietary intervention
Cognitive performance
Optimal versus suboptimal diet. Cognitive function will be assessed using the Cambridge Neuropsychological Test Automated Battery.
Time frame: Change from baseline at week 12 dietary intervention
Subcutaneous adipose tissue biopsy
Optimal versus suboptimal diet. Subcutaneous adipose tissue biopsies will be taken for histology and gene and protein expression analysis.
Time frame: Change from baseline at week 12 dietary intervention
Skeletal muscle biopsy
Optimal versus suboptimal diet. Skeletal muscle biopsies will be taken for histology and gene and protein expression analysis.
Time frame: Change from baseline at week 12 dietary intervention
Advanced glycation end-product (AGE) accumulation
Optimal versus suboptimal diet. AGE accumulation will be measured by skin autofluorescence using an AGE reader (Diagnoptics)
Time frame: Change from baseline at week 12 dietary intervention
Fasting immune metabolism (PBMCs)
Optimal versus suboptimal diet. Assessment of PBMCs as measure of fasting immune metabolism
Time frame: Change from baseline at week 12 dietary intervention
Carotid artery reactivity
Optimal versus suboptimal diet. Assessment of (peripheral) vascular function by carotid artery reactivity (CAR) in response to a cold pressor test.
Time frame: Change from baseline at week 12 dietary intervention
Food preferences
Optimal versus suboptimal diet. Food preferences will be assessed by using the computer-based Macronutrient and Taste Preference Ranking Task (MTPRT).
Time frame: Change from baseline at week 12 dietary intervention
Intervention effects on all above outcomes within the LIR and MIR group.
In contrast to the other outcomes, the intervention effect within the MIR and LIR group will be analysed for all above mentioned outcomes (as compared to an analysis of optimal versus the suboptimal diet). MIR and LIR are two measures of insulin resistance, in primarily the muscle and liver, respectively. MIR and LIR can be modelled from an OGTT, as described above. Thus, for each of the outcomes described above, their change following 12 weeks of dietary intervention will be compared between the two metabolic phenotypes, MIR and LIR.
Time frame: Change from baseline at week 12 dietary intervention
DNA analysis
Buffy coats will be collected for DNA analysis, pre-intervention only.
Time frame: Baseline
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