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Title: Mechanisms underlying diabetes remission after weight loss surgery for morbid obesity : energy restriction, weight loss, gut hormones or adipokines?
Author: Aditya, B.
ISNI:       0000 0004 6059 6475
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Background: Obesity and type 2 diabetes are closely linked both epidemiologically and pathophysiologically. Calorie restriction and weight loss improve diabetes and insulin resistance. Weight loss surgery, in particular malabsorptive procedures, causes durable weight loss and leads to early diabetes remission. The exact mechanisms by which diabetes undergoes remission even before weight loss occurs is not fully understood. Objectives: Firstly I aimed to study diabetes remission rates after various weight loss procedures and to compare outcomes between diabetes and non-diabetes subjects. I then aimed to study the mechanisms which lead to diabetes remission after RYGB with particular focus on the effects of energy restriction, appetite regulating gut hormones, incretins, changes in weight and body composition, adipokines and eating behaviour. Methods: 986 patients who had undergone a weight loss procedure in Aintree were identified from the database and their weight outcomes were studied. The results were compared between 216 patients who had type 2 diabetes and 770 patients who did not have type 2 diabetes. Diabetes remission rates following the four procedures were studied. In the prospective study, 8 obese patients who were given a calorie restricted diet of 1200 kcal/day and 22 patients who underwent RYGB were studied. In the RYGB group changes to glucose, insulin and GLP1 in response to a 330 kcal liquid meal was studied at baseline, 2 weeks post-surgery, at 4 and 12 months. Calorie restriction group were studied at baseline and after 4 weeks. Longitudinal changes to weight, body composition, eating behaviour, PYY and adipokines were studied. Results: Patients with type 2 diabetes had comparable weight loss to non-diabetes subjects 3 years after LAGB (EWL 44.8% vs 55%, p = 0.33) and 2 years after RYGB (71.4% vs 77.6%, p = 0.08). Diabetes remission rates using the ADA consensus criteria were: LAGB (15%), RYGB (42.2%), LDS (62%) and SG (33.3%). In the prospective study there was no difference in the weight loss achieved between them at 2 weeks, 4 or 12 months. Weight loss after RYGB was significant at 4 and 12 months but not 2 weeks. Fasting glucose and AUC glucose fell significantly in the surgery (RYGB) group at all the time points. Fasting insulin was also reduced significantly but there was no change in the AUC for insulin. Early insulin response rose significantly within 2 weeks mirroring the changes seen in post-prandial GLP1 response. Fasting PYY did not change significantly. Hunger and disinhibition reduced and restraint improved immediately after RYGB. Adiponectin rose and Leptin, IL6. sTNF RII and hs-CRP fell after RYGB in keeping with the degree of weight loss. Insulin sensitivity improved significantly as shown by the fall in HOMA2 IR and rise in Matsuda index. None of the markers for insulin secretion from OGTT (HOMA %B, AUC insulin/glucose, Insulinogenic index or Disposition index) except the early insulin response (?Ins 30 – ?Ins 0) reflected the improved insulin response seen after RYGB. Conclusion: Patients with type 2 diabetes achieved similar weight loss to non-diabetes subjects in the long term. Improvements in glycaemia were seen soon after RYGB before weight loss had occurred. Glycaemic improvements were due to improved insulin sensitivity caused by calorie restriction and improved insulin production driven by incretins in the early phase. Later this was maintained by better appetite regulation, weight loss and reduced fat mass which led to favourable changes in adipokines.
Supervisor: Wilding, J. P. H. Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral