Improving Glucose and Lipid Metabolism Through Caloric Restriction Using Diet or Surgery (CRUDOS)

Study Overview
=================
Brief Summary
-----------------
In this explorative randomized clinical study, the investigators aim to study metabolic, cellular, and molecular changes that occur during weight loss in obese subjects with and without type 2 diabetes. Using novel imiomics (imaging technique using PET/MR bioinformatics) analyses to examine possible metabolic differences between energy restricted diet and gastric by-pass surgery on whole-body and tissue specific insulin sensitivity, glucose tolerance, metabolite and protein profiles, fatty acid metabolism, ectopic fat content, and gene expression in adipose tissue. This study aims to identify novel biomarkers and drug targets for type 2 diabetes as well as validate promising and established biomarkers in an interventional model for improved glucose metabolism.

Detailed Description
-----------------
By using omics platforms such as genomics, proteomics and metabolomics we can have large amount of information about metabolic changes at both tissue and whole body level. In parallel to this, clinical imaging modalities such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) have developed rapidly, allowing for whole-body studies of how different tissues are involved in systemic diseases. Furthermore, new hybrid systems such as integrated PET-MRI provide combined information of human morphology and function. The integration of PET with MRI reduces the radiation dose compared with PET-CT to acceptable levels for metabolic studies. To handle the large amounts of data from these examinations we are currently developing an image analysis concept, Imiomics, that allows holistic analysis of whole-body imaging data with integration of non-imaging data. In the current study, we plan to use PET-MRI as well as imiomics methodology, together with gold standard methodology to assess insulin sensitivity and glucose tolerance in vivo. We aim to conduct a randomized study (CRUDOS study; Caloric Restriction Using Diet Or Surgery) to study glycometabolic effects before and after gastric bypass surgery and low-calorie diet in subjects at different stages of glucose tolerance (i.e. obese subjects with and without T2D).

Official Title
-----------------
Influence of Weight Loss by Diet and Surgery on Metabolomic Profile, Body Composition, and Tissue Specific Glucose Uptake: Insights in Type 2 Diabetes Regression (CRUDOS Study)

Conditions
-----------------
Type2 Diabetes, Weight Loss, Insulin Sensitivity, Metabolism and Nutrition Disorder, Metabolism Disorder, Glucose, Bariatric Surgery Candidate

Intervention / Treatment
-----------------
* Procedure: Gastric by-pass surgery
* Dietary Supplement: Low-caloric diet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: 18-60 years BMI 35-45 Sagittal abdominal diameter ≤38.5cm For participants with type 2 Diabetes Mellitus, a disease duration of no more than 10 years, treated with 0-3 oral antidiabetic drugs and/or with diet. HbA1C 48-80mmol/mol at baseline visit. Exclusion Criteria: Diabetes complications: proliferative retinopathy, maculopathy, chronic renal failure stadium 3 with an eGFR<60, foot ulcers, symptomatic neuropathy Medications within 3 months: Insulin, Thiazolidinediones Any other condition with in the opinion of the investigator would render the participant unsuitable for inclusion in the study and /or for the patients safety Judgment by the investigator that the subject should not participate in the study if considers subject unlikely to comply with study procedures, restrictions and requirements Pregnant or planning to be pregnant during the study. Known or suspected history of significant drug abuse. History of alcohol abuse or excessive intake of alcohol as judged by investigator. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator Sleep apnoea Any previous serious cardiovascular event, stroke, acute myocardial infarction. Any condition when MRI-PET is contraindicated such as, but not limited to, having a pacemaker or claustrophobia

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gastric by-pass surgery<br>Gastric by-pass surgery without prior low-caloric diet | Procedure: Gastric by-pass surgery<br>* Gastric by-pass surgery is expected to achieve a mean weight loss of 7-8kg in 4 weeks, which is similar weight-loss achieved in the other arm (low-caloric diet) during this time period.<br>|
| Active Comparator: Low-caloric diet<br>Low-caloric diet followed by gastric by-pass surgery | Procedure: Gastric by-pass surgery<br>* Gastric by-pass surgery is expected to achieve a mean weight loss of 7-8kg in 4 weeks, which is similar weight-loss achieved in the other arm (low-caloric diet) during this time period.<br>Dietary Supplement: Low-caloric diet<br>* Energy restricted diet with a total energy intake of 800-1200kcal/day<br>* Other names: Energy restricted diet;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tissue specific glucose uptake measured by euglycemic clamp in PET/MR scanner | Tissue specific assessment of glucose metabolism (18FDG uptake) using in-scanner (integrated PET-MR) insulin clamps. | 4 weeks | 
| Metabolite concentrations in plasma | Plasma metabolite concentrations (metabolomics) are assessed by liquid chromatography-mass spectrometry | 4 weeks | 
| Gene expression in adipose tissue | Change in gene expression is assessed by microarray (untargeted) messenger ribonucleic acid (mRNA) analyses | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lipoprotein changes in plasma assessed by routine clinical chemistry |  | 4 weeks | 
| Plasma adipokines (e.g. adiponectin) assessed by elisa |  | 4 weeks | 
| Fatty acid composition in plasma assessed by gas chromatography |  | 4 weeks | 
| Changes in plasma protein profile (proteomics) assessed by immunohistochemistry |  | 4 weeks | 
| Epigenetic changes assessed as DNA methylation |  | 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
type 2 diabetes, gastric by-pass surgery, low calorie diet, glucose metabolism