Adipose Tissue Storage in the Rapid Remission of Hepatic and Cardiac Metabolic Dysfunction After Bariatric Surgery

Study Overview
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Brief Summary
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The present protocol aims to understand and establish whether there is a causal link between adipose tissue metabolic remodeling and Type 2 Diabetes (T2D) remission after bariatric surgery. All participants will have a bariatric surgery, divided in 2 groups: with or without T2D.

Detailed Description
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This clinical assay will include 5 visits: the screening visit and four 9-hour postprandial metabolic sessions (A0, A1, B0 and C0) before and after surgery: initial visit: screening before surgery: 2 metabolic sessions A0 and A1 (without/with niacin) will be performed, in random order, at least one week interval. 12 days post surgery: 1 metabolic session B0 (without niacin) 1 year post surgery: 1 metabolic session C0 (without niacin) Each metabolic visit will last 9 hours with: perfusion of stable tracers, ingestion of a liquid meal Positron-Emitting-Tomography (PET) acquisitions using radiopharmaceuticals such as [18F]-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA) and [11C]-palmitate, MRI acquisitions.[18F]fluoro-6-thia-heptadecanoic acid (FTHA). The niacin will be given during metabolic visits A1 as a regulator of lipids metabolism. During these visits, the subjects will ingest 150mg every half hour for 6 hours. Niacin will be used as a pharmacological suppressor of dietary fatty acid (DFA) spillover in order to determine the role played by this mechanism in the reduction of postprandial endogen glucose production (EGP) in T2D after bariatric surgery.

Official Title
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Improved Adipose Tissue Storage of Dietary Fatty Acids as a New Mechanism for the Rapid Remission of Hepatic and Cardiac Metabolic Dysfunction After Bariatric Surgery

Conditions
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Diabetes Mellitus Type 2

Intervention / Treatment
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* Procedure: Bariatric surgery
* Drug: Nicotinic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 65 BMI 35 kg/m2 Diagnosed T2D - according to Diabetes Canada diagnostics criteria. Diagnosed non-T2D - according to Diabetes Canada diagnostics criteria. Women with a negative serum pregnancy test. Exclusion Criteria: Treatment with an oral contraceptive; Treatment with fibrate, thiazolidinedione, insulin, or beta-blocker, drugs that affect metabolism and cannot be stopped temporarily or which have long-lasting effects; Presence of overt cardiovascular disease, liver or renal failure or other uncontrolled medical conditions; Any other contraindication to surgery or to temporarily suspending current medications for diabetes, lipids or hypertension; Smoking or consumption of more than 2 alcoholic beverages per day; Any contraindication to MRI; A Diabetes Remission (DiaRem) score >8 (low probability of T2D remission); Having participated to a research study with exposure to radiation in the last two years before the start of the study; Pregnant or breastfeeding women; Patients weighing more than 200 kg to respect the weight and gantry limit of our MRI and PET/CT scanners. Being allergic to eggs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: It will be a randomized crossover study prior to bariatric surgery (visits A0 and A1) followed by a longitudinal follow-up study after surgery (visits B0 and C0) in two groups (type 2 diabetes vs. controls). Inside each group, the protocol will be carried out as a within-subject, in which each subject will serve as his/her own control.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>without T2D according to Diabetes Canada diagnostics criteria: | Procedure: Bariatric surgery<br>* Laparoscopic Sleeve Gastrectomy<br>Drug: Nicotinic Acid<br>* Only during A1. 150mg every half hour for 6 hours. A total dose of 1800mg will be ingested.<br>* Other names: Niacin;|
| Experimental: group with Type 2 diabetes<br>with T2D according to Diabetes Canada diagnostics criteria: | Procedure: Bariatric surgery<br>* Laparoscopic Sleeve Gastrectomy<br>Drug: Nicotinic Acid<br>* Only during A1. 150mg every half hour for 6 hours. A total dose of 1800mg will be ingested.<br>* Other names: Niacin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in white adipose tissue dietary fatty acid (DFA) trapping and partitioning | [18F]-FTHA PET | measured after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in lean organ (liver, heart and muscle) DFA uptake and partitioning | [18F]-FTHA PET | measured after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in liver non-esterified fatty acid (NEFA) uptake, oxidation, esterification and secretion into very low-density lipoprotein (VLDL). | calculated from the same multicompartmental equation using liver [11C]-palmitate kinetics | measured before and after liquid meal at Baseline (A0), at Day 12 (B0) and at Week 52 (C0) | 
| Change in Endogenous Glucose production and meal glucose systemic flux | i.v. and oral stable isotope tracer | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in cardiac non-esterified fatty acid (NEFA) uptake, oxidation and esterification | calculated from the same multicompartmental equation using cardiac [11C]-palmitate kinetics | measured before and after liquid meal at Baseline (A0), at Day 12 (B0) and at Week 52 (C0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma NEFA flux | calculated from i.v. stable isotope tracer (mass spectrometry). | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in hepatic Triglyceride (TG) content | magnetic resonance imaging (MRI) | measured at Baseline (A0), at Day 12 (B0) and at Week 52 (C0) | 
| Change in insulin secretion | Determined by measuring C-peptide kinetics following the liquid meal | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in total substrate utilisation | measured by using indirect calorimetry | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in gene and protein expression of white adipose tissue (WAT) | WAT biopsy | measured at Baseline (A0), at Day 12 (B0) and at Week 52 (C0) | 
| Change in hormonal response | Multiplex assay | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in insulin resistance /sensitivity | Determined by measuring circulating glucose, NEFA and insulin following the liquid meal | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in histology of white adipose tissue (WAT) | WAT biopsy | measured at Baseline (A0), at Day 12 (B0) and at Week 52 (C0) | 
| Change in metabolite response | Colorimetric assay | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0 | 
| Change in plasma distribution of DFA metabolites (WAT DFA spillover) | calculated from i.v. and oral stable isotope tracers (mass spectrometry) incorporated into triglyceride-rich lipoproteins and NEFA. | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 
| Change in glycerol turnover | calculated from [1,1,2,3,3-2H]-glycerol i.v. | measured before and after liquid meal at Baseline (A0 +A1), at Day 12 (B0) and at Week 52 (C0) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bariatric surgery, remission from Type 2 diabetes, PET imaging, adipose tissue