Personalized Glucose Optimization Through Nutritional Intervention

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Personalized Glucose Optimization Through Nutritional Intervention

Conditions
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Obesity, Pre-diabetic, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Other: Optimal diet
* Other: Suboptimal diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI 25 to <40 kg/m2 Predominantly muscle (MIR) or liver (LIR) insulin resistant Weight stability for at least 3 months (+/- 3 kg) Exclusion Criteria: Diseases Pre-diagnosis of type 1 or type 2 diabetes mellitus Renal or hepatic malfunctioning (pre-diagnosis or determined based on alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and creatinine values) Gastrointestinal diseases or abdominal surgery (allowed i.e.: appendectomy, cholecystectomy) Food allergies, intolerances (including gluten/lactose intolerance) and/or dietary restrictions interfering with the study (including special diets, vegetarians and eating disorders) Cardiovascular diseases (e.g. heart failure) or cancer (e.g. non-invasive skin cancer allowed) High blood pressure (untreated >160/100 mmHg, drug-regulated >140/90 mmHg) Diseases affecting glucose and/or lipid metabolism (e.g. pheochromocytoma, Cushing's syndrome, acromegaly) Anemia defined as hemoglobin (Hb) men <8.5 and women <7.5 mmol/l Diseases with a life expectation shorter than 5 years Major mental disorders Drug treated thyroid diseases (well substituted hypothyroidism is allowed inclusion) Other physical/mental conditions that could interfere with study outcomes Medication Medication known to interfere with study outcomes (e.g. peroxisome proliferator-activated receptor-α (PPAR-α) or PPAR-γ agonists (fibrates), sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, repaglinide, nateglinide and insulin, chronic use of NSAIDs) Use of anticoagulants Use of antidepressants (stable use ≥ 3 months prior to and during the study is allowed) Use of statins (stable use ≥ months prior to and during study allowed) Use of β-blockers (only for the extensive phenotyping participants) Chronic corticosteroids treatment (>7 consecutive days of treatment) Use of antibiotics within 3 months prior to the study Lifestyle Participation in regular sports activities (>4 hours per week) Having a restricted dietary pattern interfering with the study diets (e.g. vegan or Atkins diet) Plans to lose weight Abuse of alcohol (alcohol consumption >14 units/week) and/or drugs (cannabis included) Not willing to limit alcohol consumption to 7 drinks per week Regular smoking (including use of e-cigarettes) Use of strong vitamins or dietary supplements (e.g. pre- or probiotics) expected to interfere with the study outcomes Other Pregnant or lactating women who are planning to become pregnant Inability to comply with the study diet Blood donation within the last 3 months Participation in possibly interfering studies within the last 3 months Inability to understand study information and/or communicate with staff Unwillingness to be randomized or sign informed consent Unwillingness to save data for 15 years

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Optimal diet<br>Participants will follow a diet for a total duration of 12 weeks, optimal for their metabolic phenotype. For participants with muscle insulin resistance (MIR) this will be a diet high in monounsaturated fatty acids, for participants with liver insulin resistance (LIR) this will be a diet high in protein and fiber and low in fat. | Other: Optimal diet<br>* 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.<br>|
| Experimental: Suboptimal diet<br>Participants will follow a diet for a total duration of 12 weeks, suboptimal for their metabolic phenotype. For participants with liver insulin resistance (LIR) this will be a diet high in monounsaturated fatty acids, for participants with muscle insulin resistance (MIR) this will be a diet high in protein and fiber and low in fat. | Other: Suboptimal diet<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from baseline at week 12 dietary intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | Change from baseline at week 12 dietary intervention | 
| Waist circumference | Optimal versus suboptimal diet. Waist circumferences in centimeters. | Change from baseline at week 12 dietary intervention | 
| Hip circumferences | Optimal versus suboptimal diet. Hip circumferences in centimeters. | 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). | Change from baseline at week 12 dietary intervention | 
| Blood pressure | Optimal versus suboptimal diet. Systolic and diastolic blood pressure in mmHg. | 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). | 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. | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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). | 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. | 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. | 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). | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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) | 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 | 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. | 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). | 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. | Change from baseline at week 12 dietary intervention | 
| DNA analysis | Buffy coats will be collected for DNA analysis, pre-intervention only. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin resistance, Personalized nutrition