obesity-related glycine deficiency: investigating a long-standing metabolic paradox using bedside and bench approaches

Conditions: Glycine Metabolism Disturbances; Insulin Resistance; Morbid Obesity; Oxidative Stress

Summary: 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.

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.

Eligibility criteria:
inclusion criteria: 1. age: 21-65 years 2. bmi \< 25 kg/m2 for non-obese controls or bmi ≥ 32.5 kg/m2 for obese subjects scheduled for bariatric surgery 3. able to provide informed consent exclusion criteria: all subjects: 1. weight \> 150 kg 2. renal impairment (estimated creatinine clearance estimated by cockcroft-gault equation \< 60 ml/min) 3. haemoglobin concentration \< 10 g/l 4. serum alanine aminotransferase or aspartate aminotransferase above 2x upper limit of normal 5. uncontrolled hypertension (bp \> 180/110 mmhg) 6. pregnancy 7. nursing mothers 8. significant cardiovascular disease (e.g. acute myocardial infarction, congestive cardiac failure, ischemic heart disease, atrial fibrillation, sick sinus syndrome, supraventricular tachycardia) 9. previous stroke 10. uncontrolled thyroid disease 11. surgery requiring general anaesthesia within 4-weeks before enrolment 12. psychiatric disorders requiring medication 13. significant alcohol intake (\> 1 unit per day for women and \> 2 units per day for men) 14. subcutaneous insulin injections 15. systemic steroid usage (eg. prednisolone, hydrocortisone, cortisone, dexamethasone) 16. cancer within the last 5-years (except squamous cell and basal cell cancer of the skin) 17. 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%

Keywords: glycine obesity bariatric surgery gluthathione