Rudge, Eleanor J.M.
(2020)
The gut hormone, Glucagon-Like Peptide 2, contributes to the improved glycaemic control observed post-bariatric surgery, as a result of its intestinotrophic effects.
PhD thesis, University of Nottingham.
Abstract
BACKGROUND
Bariatric surgery, specifically Roux-en-Y Gastric Bypass (RYGB), leads to durable weight loss as well as significant improvements in Type 2 Diabetes (T2D). Despite multiple randomised studies showing superiority of RYGB to maximal medical therapy for treatment of T2D, surgery remains grossly underutilised with only 1-2% of patients who qualify for the surgery proceeding with it. The limited acceptance of surgery highlights the need for less invasive interventions that can replicate the metabolic success of RYGB. A better understanding of the anti-diabetic mechanisms of surgery is therefore required in order to allow the development of less invasive T2D therapies (e.g. less invasive surgery, a medical device, or medication) which can then be offered to a wider patient population. RYGB appears to exert its anti-diabetic effects through multiple mechanisms. Work previously carried out within this lab has suggested that, post-RYGB surgery, there is a decrease in intestinal glucose absorption, with an increase in intestinal glucose utilisation. This thesis seeks to gain corroborating data in order to further decipher glucose utilisation and absorption patterns post-RYGB surgery. Additionally, it aims to determine whether these glucose modulations could be linked to the intestinal hypertrophy observed post-RYGB, and whether it could be mediated by Glucagon-Like Peptide 2 (GLP-2), a potent intestinotrophic hormone found at higher concentrations following RYGB.
METHODS
A series of experiments were conducted to look at the effect of administering acute GLP-2 and chronic GLP-2 (in the form of Teduglutide, a degradation-resistant GLP-2 analogue), in both fasted and fed states, and within healthy and pathological rat models, when compared to phosphate buffered saline (PBS) control. Aided by a portal, systemic and small bowel rat catheterisation model (previously developed within this laboratory) which allowed infusion of substances into the venous system and into the intestine, the effect of GLP-2 on blood glucose levels was assessed primarily. Additionally, the effects of GLP-2 on glucose transporter (GLUT-1, GLUT-1, SGLT-1), glucose sensor (SGLT-3) genes, GLP-2 receptors, intestinal proliferation genes (C-MYC and C-FOS), gut hormones (GLP-1, GIP, glucagon and insulin), and intestinal morphology, were studied. Further experiments included: GLP-2 receptor antagonism (GLP-2RA) studies, altered Biliopancreatic (BP) limb length studies, and experiments aiming to replicate RYGB physiology using a non-RYGB model, in order to assess effects on intestinal metabolism, in terms of glucose utilisation and absorption.
RESULTS
GLP-2 had statistically significant effects on glucose handling. Acute GLP-2 infusion resulted in significantly lower post-prandial portal vein glucose levels compared to control, within a healthy rat model. Teduglutide caused significant bowel hypertrophy in experimental animals versus control, and within both healthy and pathological models. Furthermore, increased intestinal hypertrophy was seen within the pathological group compared to the healthy group. Additionally, Teduglutide significantly raised portal and systemic glucose levels at the start of oral glucose tolerance tests (OGTT) but, subsequently, produced a profound hypoglycaemic effect compared to control. This was observed in both healthy and pathological rat models, with the response amplified within the latter of the two models. Despite significant upregulation of SGLT-1, GLUT-1, GLUT-2 and SGLT-3 within the pathological model, no statistically significant difference in glucose utilisation or absorption was observed. GLP-2 antagonism experiments were largely unsuccessful; potential explanations include suboptimal dosing of the GLP-2 receptor antagonist (GLP-2RA), or the possibility of a deleterious effect of GLP-2RA when used within a pathological model. Altered BP limb length studies showed differences in glucose handling, with 40cm BP limb length showing significantly increased levels of glucose absorption. Significantly decreased glucose absorption was demonstrated within the proximal jejunal exclusion studies.
CONCLUSION
This thesis set out to explore mechanisms behind improved glucose handling, observed following RYGB surgery, and to investigate a potential role for GLP-2 in mediating this. Although it would be ambitious to claim that GLP-2 contributes to improvements in glycaemic control, it certainly appears to cause a glucose-related effect in animals treated with it, either acutely or chronically. Additionally, these effects were more dramatic within a pathological animal model. Furthermore, PCR experiments revealed significant upregulation of glucose transporter/sensor genes within the pathological model. Given that pathological animals displayed significantly increased small bowel hypertrophy compared to healthy GLP-2 treated rats, it is possible that Teduglutide may convey a beneficial effect to hyperglycaemic animals. The mechanisms underlying the potential impact of GLP-2 upon glucose metabolism are yet to be established, and further studies are required to delineate these effects and to prove definitive links between GLP-2 mediated bowel hypertrophy and improved modulation of glucose.
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