Postprandial Metabolism After Bariatric Surgery in Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
Bariatric surgery procedures have now been firmly demonstrated to lead to significant improvement and even, in many cases, complete reversal of abnormal glucose homeostasis in type 2 diabetes (T2D). Various surgery procedures are can be performed to induce weight loss. The most striking anti-diabetic effects are observed with biliopancreatic diversion with duodenal switch (BPD-DS), followed by Roux-in-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). The first two procedures induce both a restriction of energy intake and a low absorption of dietary fatty acids while the latter exclusively targets energy intake restriction. The investigator and others have shown that improvement of T2D occurs within days after BPD-DS or RYGB in the vast majority of patients, prior to any significant weight loss. This very rapid metabolic recovery is explained by a normalization of β-cell function after meal challenges and ameliorated hepatic insulin sensitivity. The investigator and others have shown that these acute anti-diabetic effects are mostly recapitulated by matched caloric restriction, independent of changes in gastrointestinal hormones, showing the importance of gastrointestinal-derived energy fluxes for acute diabetes control. Muscle insulin sensitivity, on the other hand, improves more slowly in association with weight loss, demonstrating the heterogeneous metabolic response of the various organs to BPD-DS. Some preliminary studies also demonstrate a rapid reduction of NEFA levels and production rate upon i.v. administration of lipids during euglycemic hyperinsulinemic clamps. This very rapid improvement in NEFA tolerance strongly suggests that adipose tissue storage of circulating fatty acids also improves very rapidly, prior to any significant weight loss, after BPD-DS. It may also suggest an acceleration of oxidative fatty acid metabolism in organs such as the liver, the heart and/or skeletal muscles. Studies of the rapid metabolic changes after bariatric surgery conducted thus far rapidly improved the understanding of the fundamental pathogenic defects of T2D. However, much remains to be understood about the acute changes in gastrointestinal-derived metabolic fluxes, organ-specific metabolic responses to bariatric surgery and their relationship with the reversal of T2D. Using in vivo methodological approaches, the investigator proposes to investigate the early organ-specific changes in dietary fatty acid metabolism in response to BPD-DS vs. SG and their relation to improved systemic changes in glucose homeostasis, insulin sensitivity and β-cell function in patients with T2D.

Detailed Description
-----------------
Participants will undergo a metabolic study before and 8 to 12 days after bariatric surgery after a 12-hour fast and a three-day food and physical activity diary with accelerometry. The patients recover very rapidly from the surgery and will be able to participate to the proposed investigations the week after their hospitalization on an outpatient basis on the earliest week day between 8 and 12 days after the surgery procedure. The metabolic study is a 6-hour meal test using Positron Emitting Tomography (PET).

Conditions
-----------------
Type 2 Diabetes, Obese

Intervention / Treatment
-----------------
* Procedure: biliopancreatic diversion with duodenal switch
* Procedure: sleeve gastrectomy
* Other: liquid meal
* Radiation: PET/scan
* Other: [7,7,8,8-2H]-palmitate
* Device: indirect calorimetry


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Four groups of 11 subjects each: obese subjects with T2D or with normal glucose tolerance undergoing either BPD-DS or SG for treatment of obesity. T2D and control subjects will be matched for age (± 3 years), BMI (± 2 kg/m2) and gender across both BPD-DS and SG. Exclusion Criteria: presence of overt cardiovascular disease, as assessed by history, physical exam, and abnormal EKG; treatment with a fibrate, a thiazolidinedione, a beta-blocker or other drugs known to affect lipid or carbohydrate metabolism (except statins, sulfonylurea, metformin, and other antihypertensive agents that can be temporarily stopped prior to the protocols); presence of liver or renal disease, uncontrolled thyroid disorder or other major illnesses; smoking (>1 cigarette/day) and/or consumption of more than 2 alcoholic beverages per day; prior history or current fasting plasma cholesterol level > 7 mmol/l or fasting TG > 6 mmol/l; any other contraindication to temporarily stop current medications for hyperglycemia, lipids, or hypertension.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Before DBP-DS surgery<br> | Other: liquid meal<br>* will be consumed over 30 minutes with [U-13C]-palmitate (0.2 g mixed in the liquid meal) and H2-glucose<br>Radiation: PET/scan<br>* a dynamic and whole body PET acquisition will be performed on a thoraco-abdominal segment, 150 minutes after an oral administration of 18FTHA<br>Other: [7,7,8,8-2H]-palmitate<br>* i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to 360 min.<br>Device: indirect calorimetry<br>* will be performed every hour throughout the protocol along with exhaled breath collection<br>|
| Experimental: After DBP-DS surgery<br>It is a bariatric surgery. BPD consists in the exclusion of the duodenum from the alimentary tract with re-anastomosis of the blind loop 100 to 150 cm proximal to the ileo-coecal valve. This leads to bypass of the biliopancreatic secretions towards the distal small intestine, resulting in fat malabsorption. BPD also entails a distal gastrectomy to avoid the occurrence of peptic ulceration of the gastrointestinal anastomosis. | Procedure: biliopancreatic diversion with duodenal switch<br> <br> Other: liquid meal<br>* will be consumed over 30 minutes with [U-13C]-palmitate (0.2 g mixed in the liquid meal) and H2-glucose<br>Radiation: PET/scan<br>* a dynamic and whole body PET acquisition will be performed on a thoraco-abdominal segment, 150 minutes after an oral administration of 18FTHA<br>Other: [7,7,8,8-2H]-palmitate<br>* i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to 360 min.<br>Device: indirect calorimetry<br>* will be performed every hour throughout the protocol along with exhaled breath collection<br>|
| Other: Before SG surgery<br> | Other: liquid meal<br>* will be consumed over 30 minutes with [U-13C]-palmitate (0.2 g mixed in the liquid meal) and H2-glucose<br>Radiation: PET/scan<br>* a dynamic and whole body PET acquisition will be performed on a thoraco-abdominal segment, 150 minutes after an oral administration of 18FTHA<br>Other: [7,7,8,8-2H]-palmitate<br>* i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to 360 min.<br>Device: indirect calorimetry<br>* will be performed every hour throughout the protocol along with exhaled breath collection<br>|
| Experimental: After SG surgery<br>It is a bariatric surgery where the stomach is reduced to about 15% of its original size, by surgical removal of a large portion of the stomach along the greater curvature. | Procedure: sleeve gastrectomy<br> <br> Other: liquid meal<br>* will be consumed over 30 minutes with [U-13C]-palmitate (0.2 g mixed in the liquid meal) and H2-glucose<br>Radiation: PET/scan<br>* a dynamic and whole body PET acquisition will be performed on a thoraco-abdominal segment, 150 minutes after an oral administration of 18FTHA<br>Other: [7,7,8,8-2H]-palmitate<br>* i.v. administration of [7,7,8,8-2H]-palmitate (in 25% human albumin) from time -60 to 360 min.<br>Device: indirect calorimetry<br>* will be performed every hour throughout the protocol along with exhaled breath collection<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| glucose metabolism | will be determined using tracers of glucose | 2 years | 
| dietary fatty acid uptake | assessed using PET/CT method with oral administration of 18FTHA | 2 years | 
| whole body inter-organ partitioning | assessed using PET/CT method with oral administration of 18FTHA | 2 years | 
| lipid metabolism | will be determined using tracers of fatty acids | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dietary fatty acid oxidation rate | will be measured using breath 13CO2 enrichment | 2 years | 
| Total oxidation rate | will be determined by indirect calorimetry | 2 years | 
| Hormonal responses | will be determined using a multiplex assay system. | 2 years | 
| Insulin sensitivity | will be determined using different standard methods, including the HOMA-IR | 2 years | 
| Insulin secretion index (ISI) | will be assessed using deconvolution of plasma C-peptide with standard C-peptide kinetic parameters | 2 years | 
| habitual food intake | with a 3-day food record, | 2 years | 
| physical activity | with portable arm band accelerometry for 3 days prior to each metabolic study | 2 years |