AlRasheid, Noora; (2018) Effect of different surgical weight-loss interventions and ethnicity on GLP-1 secretion. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BACKGROUND: Roux–en-Y gastric bypass (RYGB) is the most successful treatment for obesity that results in sustained, long-term weight loss and improved insulin sensitivity. Generally, these benefits are mediated by gut peptides such as glucagon-like peptide-1 (GLP-1). However, their role(s) in some scenarios is yet to be investigated, for example in some patients who, following weight-reducing surgery, develop chronic intolerable nausea and vomiting (N&V) symptoms, in those undergoing a primary obesity surgery endoluminal (POSE) procedure, a new less invasive, incisionless weight-loss technique that seems to be effective for losing weight, or in ethnicities that have a high prevalence of obesity. Therefore, the aim(s) were to investigate systemic GLP-1 concentrations in three separate groups: 1) patients with prolonged N&V after metabolic surgery (Study I), 2) patients who had POSE for weight loss, compared to RYGB (Study II), and 3) an obesityprone, Arab population (Study III). METHODS: Study I: female non-diabetic subjects were studied in five groups. Group 1: patients with N&V after RYGB surgery. Group 2: patients with no symptoms after RYGB surgery. Group 3: morbidly obese patients. Group 4: obese/overweight subjects. Group 5: lean healthy subjects. Study II: female subjects were studied before surgery (POSE and RYGB), and 1 week, 2 months and 6 months after surgery, in the fasting and postprandial states. Study III: Arab non-diabetic female subjects were studied before and after a 388.6-kcal liquid mixed-meal challenge. Blood was collected in the fasting and postprandial states after a defined meal challenge (182.7-kcal meal used in Study I and 388.6-kcal meal used in Studies II and III). Systemic concentrations of glucose, lipids, insulin, GLP-1 and adipokines were determined using a routine chemistry analyser (Roche) or commercial ELISA. Subcutaneous (SC) adipose tissue organ cultures were incubated with recombinant GLP-1, and leptin concentrations were detected from the conditioned medium. RESULTS: Study (I): subjects with N&V post-RYGB had significantly elevated fasting GLP-1 levels compared to those without N&V (p = 0.035) and compared to morbidly obese, obese/overweight and lean subjects. Weight loss and glucose, insulin and GLP-1 response to a 180-kcal meal challenge were similar in subjects with and without N&V. Fasting plasma leptin was significantly lower in subjects with N&V compared to those without N&V (p = 0.04). In vitro, leptin secretion was inhibited by GLP-1. Study (II): both POSE and RYGB patients lost a significant amount of weight early after surgery, with a concomitant decrease in leptin. However, only RYGB patients continued to lose weight at 6 months. Adiponectin increased at 2 and 6 months, and serum lipid levels were unchanged. First-phase responses (30 minutes) of insulin and GLP-1 were dramatically increased 1 week after RYGB only. Study (III): in the non-diabetic Arab subjects, the mixed meal provoked a similar GLP-1 response to that reported in Caucasians. However, even in this apparently healthy population, postprandial hyperinsulinemia was evident. CONCLUSIONS: Subjects with persistent N&V post-RYGB surgery had elevated fasting GLP-1 levels related to their symptoms. Inhibiting GLP-1 with antagonists might help to ameliorate these symptoms. However, potential detrimental effects on weight maintenance and insulin sensitivity need to be considered. GLP-1 directly inhibits leptin secretion, so a decreased leptin level early after RYGB might be explained by an elevated GLP-1 level, and this could at least partially be explained by the alteration in GLP-1. POSE provides reasonable short-term weight loss without having an effect on GLP-1 in the morbidly obese but it is not as effective as RYGB. Finally, no significant lesion in systemic GLP-1 levels was seen in a cohort that could explain the obesity phenomenon in this population.

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