Bariatric Surgery Candidate, Insulin Sensitivity, Metabolism and Nutrition Disorder, Metabolism Disorder, Glucose, Type2 Diabetes, Weight Loss
Conditions
Keywords
type 2 diabetes, gastric by-pass surgery, low calorie diet, glucose metabolism
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).
Interventions
PROCEDUREGastric by-pass surgery
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.
DIETARY_SUPPLEMENTLow-caloric diet
Energy restricted diet with a total energy intake of 800-1200kcal/day
Sponsors
AstraZeneca
Uppsala University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| Changes in plasma protein profile (proteomics) assessed by immunohistochemistry | 4 weeks |
| Lipoprotein changes in plasma assessed by routine clinical chemistry | 4 weeks |
| Epigenetic changes assessed as DNA methylation | 4 weeks |
| Plasma adipokines (e.g. adiponectin) assessed by elisa | 4 weeks |
| Fatty acid composition in plasma assessed by gas chromatography | 4 weeks |
Countries
Sweden
Contacts
Primary ContactMagnus Sundbom, MD, PhD
Backup ContactUlf Riserus, PhD
Outcome results
None listed