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

Not Applicable

• Conditions: Insulin Sensitivity; Bariatric Surgery Candidate; Type2 Diabetes; Metabolism and Nutrition Disorder; Weight Loss; Metabolism Disorder, Glucose
• Interventions: Procedure: Gastric by-pass surgery; Dietary Supplement: Low-caloric diet

• Registration Number: NCT02988011
• Lead Sponsor: Uppsala University

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).

Study Timeline

• Study Start: 2016-02-28
• Study First Submitted: 2016-12-01
• Study First Submitted QC: 2016-12-06
• Study First Posted: 2016-12-09
• Status Verified: 2017-10
• Last Update Submitted: 2017-10-25
• Last Update Posted: 2017-10-27
• Primary Completion: 2020-06
• Study Completion: 2020-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 50

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low-caloric diet	Low-caloric diet	Low-caloric diet followed by gastric by-pass surgery
Gastric by-pass surgery	Gastric by-pass surgery	Gastric by-pass surgery without prior low-caloric diet
Low-caloric diet	Gastric by-pass surgery	Low-caloric diet followed by gastric by-pass surgery

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Uppsala univeristy hospital; 🇸🇪 Uppsala, Sweden