Emmanuel, JJ; (2015) Metabolic Hormones in bariatric surgery and reward behaviour. Doctoral thesis , UCL (University College London).

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Abstract

The World Health Organization (WHO) defines obesity as a condition in which body fat is increased to the extent that health and well-being are impaired. Obesity and type-2 diabetes are two of the leading healthcare challenges facing this generation. Bariatric surgery is the most effective therapeutic option for morbid obesity. A systematic review has concluded that surgery is superior to conventional treatment in reducing weight. However, the review failed to show the superiority of one surgical method over others. It is thought that the re-routing of food through an anatomically altered and/or shorter gastrointestinal tract leads to an increased delivery of incompletely digested nutrients to the ileum and colon. This leads to over-stimulation of the specialized entero-endocrine L cells. Others argue that the exclusion of an inhibitory factor from the foregut may mediate the rapid improvement in diabetes. Several studies have shown a blunted hind gut hormone (PYY and GLP-1) response in the morbidly obese patients that is reversed by Roux-en-Y gastric bypass (RYGBP) and sleeve gastrectomy (SG). Recent studies on patients undergoing bariatric surgery have revealed a key role for PYY, GLP-1 and acyl-ghrelin in regulating appetite, bodyweight and glucose homeostasis. A correlation between changes in gut hormone secretion and weight loss has not yet been shown in humans, but has been shown in rats after RYGBP. This discrepancy may be related to study design and sample processing, as not all studies have measured the active forms of the circulating hormone, and standardized for collection of blood samples. Some have compared post-surgical changes in gut hormones against control groups, not their pre-operative state, making it difficult to draw conclusions on individual physiological changes and corresponding correlations to anthropometry. Further, no study to date has found correlation between change in active gut hormones and change in perception of hunger and satiety. In my study, RYGBP and SG led to a differential change in hunger, prospective food consumption and satiety. RYGBP had a more pronounced influence on prospective food consumption and hunger, despite non-significant changes in acyl-ghrelin. As RYGBP led to a more pronounced PYY3-36, GLP-1 and amylin response, it would be expected to alter satiety more. SG by contrast led to a more pronounced and significant decline in acyl-ghrelin, but only mediated a lesser change in hunger in comparison to RYGBP. However, my study does provide a link between the change in gut hormones and measures of appetite and satiety. My study also confirms gut hormone changes that occur after RYGBP and SG correlate to a decline in appetite and an increase in satiety, and therefore mediate weight loss. I also compared the change in hunger, prospective food consumption and satiety from baseline, and confirm a significant decrease in Δ hunger and Δ prospective food consumption, and a significant increase in Δ satiety after RYGBP and SG. There is equivalent excess weight loss (%EWL) after both RYGBP and SG at 6 weeks and 12 weeks after surgery. Despite starting with a lower BMI, the SG group lost similar BMI points to the RYGBP group at 6 weeks and at 12 weeks after surgery. This is in keeping with other recent short term and long term human studies. RYGBP and SG led to equivalent fat mass loss and decline in plasma leptin. RYGBP led to a pronounced hind gut hormone response, and SG led to a similar but less pronounced hind gut response. SG alone led to a significant decline in acyl-ghrelin. The amylin response after RYGBP and SG are divergent. In our study patients continued to lose weight from the first post-operative study point at 6 weeks to the second study point at 12 weeks, however there was no significant change in the fasting or meal stimulated insulin, PYY3-36, acyl-ghrelin, GLP-1 and amylin response from 6 to 12 weeks, apart from acyl-ghrelin in the RYGBP group, where acyl-ghrelin did increase between these time points. I also explored the role of insulin/ amylin ratio in appetite and weight loss. It is thought that an increased ratio of amylin/ insulin expression may act as a marker for beta cell dysfunction. Hyperglycaemia is thought to lead to the hypersecretion of amylin relative to insulin, and increase the amylin /insulin ratio in insulin-resistance. In the RYGBP group changes in PYY3-36 and insulin: amylin ratio correlates to weight loss. In the SG group change in PYY3-36, acyl-ghrelin, GLP-1 and amylin correlate to weight loss after surgery. RYGBP and SG seem to utilize different mechanisms to engender weight loss. The outcome after SG is dependent on the hormonal changes that ensue, whereas RYGBP may mediate its effects through neuro-anatomical changes associated with surgery. My findings, like those of others recently, lend support to the hind gut mediating the effects of weight loss after RYGBP and SG surgery. The resolution of type 2 diabetes occurs immediately after RYGBP and SG. RYGBP and SG markedly improved glucose homeostasis by improving insulin secretion through the augmented GLP-1 response, weight loss and the decrease in acyl-ghrelin secretion seen after SG, leading to improved insulin sensitivity. These changes in insulin secretion and insulin resistance are seen early after surgery before any substantial weight loss has occurred. My study confirms RYGBP and SG to be equally efficacious as metabolic surgical options. The disparity in GLP-1 response after RYGBP and SG is further complicated by the GLP-1 stimulated insulin release displaying a threshold phenomenon. Thus the GLP-1 response after RYGBP and SG did not lead to equivalent glucose-dependent insulin secretion. The GLP-1 stimulated amylin response also showed a threshold phenomenon. However, there did not seem to be any difference between the two groups. In our study there was a decline in HOMA IR after RYGBP and SG. The decline after SG showed a trend towards statistical significance. This discrepancy can partly be explained by the significant decline in acyl-ghrelin seen only after SG but not RYGBP. The duodenal exclusion hypothesis is unlikely to be a viable explanation given our results on sleeve gastrectomy, which occur in spite of a functional duodenum. The differential insulin/ amylin ratio after RYGBP and SG is noteworthy. In our study, there was a significant decrease in insulin: amylin ratio after RYGBP. Insulin secretion was not significantly altered after RYGBP. However there was an increase in amylin secretion after RYGBP leading to a decrease in insulin: amylin ratio at 6 and 12 weeks after surgery. There was a significant increase in meal stimulated insulin secretion after SG. This led to lower insulin: amylin ratio after SG. The lower amylin seen after SG may also contribute to the improved glucose homeostasis after SG, and further compensate for the relatively lower GLP-1. However, relative increase in amylin secretion did not adversely influence glucose homeostasis after RYGBP. The contrasting alteration in ratio did not correlate to satiety, prospective food consumption or weight loss. In our study GLP-1 secretion did show a positive correlation to amylin secretion in both groups, before and after surgical intervention. It is known that some patients fail to lose weight after RYGBP and SG, but the mechanisms behind this failure have yet to be explored. One patient in our SG group was noted to have lost no further weight between 3 and 12 months following surgery. This patient had a three month meal stimulated amylin, Δ PYY3-36 and Δ acyl-ghrelin curve below the baseline curve for the respective hormones. This was in sharp contrast to all the other patients in the SG group. In other words a poor hormone response after surgery predicts failure to respond after SG. This altered meal stimulated response could be utilized to fast-track patients predicted to fail to a second stage procedure. My second study suggests that an individual’s metabolic state influences their monetary decisions. The risk-sensitive monetary decisions were influenced by both long-term metabolic signals indexing energy stores and short-term metabolic signals that index energy gains. At the neurobiological level, my results suggest an overlap between food and monetary reward. This has significant implications for all decisions that incorporate risk and monetary reward. In other words an individual’s body mass index and his nutritional intake could alter risky behaviour.

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