Obesity-Related Glycine Deficiency: Investigating a Long-standing Metabolic Paradox Using Bedside and Bench Approaches

Study Overview
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Brief Summary
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Obesity, in addition to causing abnormal glucose and lipid metabolism, is also associated with altered plasma concentrations of multiple amino acids, including increased levels of branched-chain amino acids and decreased levels of glycine. The mechanisms and consequences of obesity- related glycine deficiency are unknown. The overall aim of this project is to comprehensively study glycine metabolic pathways in morbid obesity using stable-isotope tracer techniques in human subjects and validating kinetic findings using a cell model of oxidative stress. This will be a single-centre, observational study. 21 individuals with morbid obesity scheduled for bariatric surgery and 21 non-obese controls will be recruit. They will undergo different study visits and procedures and the human biological materials collected will be analysed for as per aims of the studies. We believe that the glycine metabolic pathways, possibly through the optimization of gluthathione (GSH) synthesis, may provide targets to develop novel therapeutic agents.

Detailed Description
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Metabolic tracers: 1,2-[13C2]-Glycine, 1,2-[13C2]-Glycine, 2,3,3,-[2H3]-Serine and [2H5]-Phenylalanine will be infused for quantification of various pathways associated with glycine metabolism.

Official Title
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Obesity-Related Glycine Deficiency: Investigating a Long-standing Metabolic Paradox Using Bedside and Bench Approaches

Conditions
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Morbid Obesity, Glycine Metabolism Disturbances, Insulin Resistance, Oxidative Stress

Intervention / Treatment
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* Procedure: Bariatric surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 21-65 years BMI < 25 kg/m2 for non-obese controls or BMI ≥ 32.5 kg/m2 for obese subjects scheduled for bariatric surgery Able to provide informed consent Exclusion Criteria: All subjects: Weight > 150 kg Renal impairment (estimated creatinine clearance estimated by Cockcroft-Gault Equation < 60 ml/min) Haemoglobin concentration < 10 g/L Serum alanine aminotransferase or aspartate aminotransferase above 2x upper limit of normal Uncontrolled hypertension (BP > 180/110 mmHg) Pregnancy Nursing mothers Significant cardiovascular disease (e.g. acute myocardial infarction, congestive cardiac failure, ischemic heart disease, atrial fibrillation, sick sinus syndrome, supraventricular tachycardia) Previous stroke Uncontrolled thyroid disease Surgery requiring general anaesthesia within 4-weeks before enrolment Psychiatric disorders requiring medication Significant alcohol intake (> 1 unit per day for women and > 2 units per day for men) Subcutaneous insulin injections Systemic steroid usage (eg. prednisolone, hydrocortisone, cortisone, dexamethasone) Cancer within the last 5-years (except squamous cell and basal cell cancer of the skin) Any factors likely to limit adherence to study protocol (e.g. dementia; alcohol or substance abuse; history of unreliability in medication taking or appointment keeping; significant concerns about participation in the study from spouse, significant other or family members) Non-obese controls 1. Known Diabetes Mellitus (diagnosed according to 2014 Ministry of Health Clinical Practice Guidelines for Diabetes Mellitus) Obese subjects 1. HbA1C < 9%

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Morbid obesity<br>BMI 32.5 kg/m2 and above | Procedure: Bariatric surgery<br>* Subjects with morbid obesity underwent bariatric surgery<br>|
| Non-obese healthy controls<br>BMI below 25 kg/m2 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycine kinetic | Differences in glycine kinetic measurements between obese subjects and controls, and within obese subjects after bariatric surgery | Baseline for all subjects and 5-12 months after bariatric surgery for morbid obesity group | 
| Insulin sensitivity | Differences in insulin sensitivity between obese subjects and controls, and within obese subjects after bariatric surgery | Baseline for all subjects and 5-12 months after bariatric surgery for morbid obesity group | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glycine, obesity, bariatric surgery, gluthathione