Mechanisms of remission in type 2 diabetes mellitus using Roux-en-Y gastric bypass

Abstract

Introduction
Defects in fat processing, in particular non-esterified fatty acids (NEFA), may hold the link between obesity, hyperlipidaemia, insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The secretion of insulin, more effective at inhibiting lipolysis than glucose production, is inhibited by high NEFA levels. I hypothesised that postprandial hormone alterations following Roux-en-Y gastric bypass (RYGB) improve adipocyte insulin sensitivity through the peripheral effects of incretins.

Methods
Participants with T2DM (n=9) and without T2DM [NDM] (n=10) underwent RYGB for morbid obesity. Fasting and postprandial blood was analysed for glycaemic, lipidaemic and gut hormones changes around surgery. Intra-operatively, adipose tissue biopsies were taken and lipolysis assessed during a 2hr incubation with pre- and post-RYGB plasma and relevant hormonal concentrations.

Results
By post-operative day 4, there were improvements in IR (p<0.0001) and reduced fasting insulin levels (p=0.0017) despite no reduction in postprandial insulin (p=0.6714). Fasting NEFA levels were reduced in NDM (p<0.05) but not in the T2DM group (p=0.0816), whilst postprandial NEFA (∆AUC [360min]) reduced in the T2DM group (p<0.0001) but not in the NDM group (p=0.4111), ANOVA p<0.05.

Significant changes in gut hormone levels around RYGB were noted, in fasting: reduced GIP (p=0.0079), PYY (p=0.0066) and ghrelin levels (p=0.0005); post-prandial: increased GLP-1 (p=0.0018) and PYY levels (p<0.0001); reduced GIP (p=0.0318) and ghrelin levels (p=0.0004).

Incubation of adipocytes in both fasting and postprandial plasma post-RYGB resulted in increased lipolysis versus pre-RYGB plasma (peripheral p=0.0235
and p=0.0205, respectively [n=8]). Insulin and PYY inhibited lipolysis but no effect of GLP-1, GIP and ghrelin on lipolysis was detected.

Conclusions
Although likely that postprandial hormonal alterations improve adipocyte lipolysis through their peripheral effects, it is most likely the global reduction in insulin levels, thereby reducing the anti-lipolytic effect, combined with overall improvements in IR, responsible for these findings and not the peripheral effects of incretins.

Date of Award	1 Dec 2017
Original language	English
Awarding Institution	King's College London
Supervisor	Stephanie Amiel (Supervisor) & Ameet Patel (Supervisor)