The metabolic effects and therapeutic utility of novel GLP-1/Glucagon receptor co-agonists in type 2 diabetes
File(s)
Author(s)
Farooq, Gala
Type
Thesis
Abstract
Type 2 Diabetes Mellitus is a metabolic disorder characterised by persistent hyperglycaemia. The global rise in obesity has fuelled an increase in the prevalence of diabetes and necessitates more
effective treatments. Glucagon-like peptide-1 (GLP-1) analogues are one of the most efficacious therapeutics currently available, and simultaneously stimulate insulin secretion and increase insulin
sensitivity through weight loss. Consequently, GLP-1 analogues are particularly useful for diabetic patients who are overweight or obese.
It has been hypothesised that the tolerability and therapeutic efficacy of GLP-1 analogues could be enhanced by combining GLP-1 with a second insulinotropic hormone. Based on the well-established beneficial metabolic effects of oxyntomodulin, a naturally occurring GLP-1 and glucagon receptor co-agonist, glucagon has been proposed as a co-adjunct for GLP-1. While multiple groups have demonstrated the superior weight loss efficacy of GLP-1 and glucagon receptor co-agonists versus GLP-1 analogues, the insulinotropic effects of co-agonists remain undetermined.
This project involved the development of novel GLP-1 and glucagon receptor co-agonists based on the sequence of oxyntomodulin, with targeted sequence modifications to confer longer plasma half
lives and greater potency. To determine the direct beta cell effects of co-agonists, insulin secretion assays were performed in vitro using INS-1 832/3, MIN6B1 and EndoC-βH1 beta cells. In comparison to GLP-1 analogues, my co-agonists augmented insulin release in vitro. These insulinotropic effects were preserved in vivo in a high-fat, high-sucrose fed mouse model of type 2 diabetes, where the co-agonists led to greater insulinotropic responses than GLP-1 analogues acutely. On chronic administration, co-agonists did not impair glycaemic control despite their considerable glucagon receptor activity. In addition, co-agonists induced profound weight loss chronically, which was attributed to both food intake reduction through the GLP-1 receptor and energy expenditure effects through glucagon receptor activation. Paradoxically, the weight loss did not lead to improvements in glucose tolerance.
The in vitro insulinotropic effects were associated with a signalling bias against β arrestin recruitment at the GLP-1R and could be due to reduced receptor trafficking and internalisation. However, the in vivo characteristics show no correlation to bias, and weight loss was instead found to be positively associated with relative glucagon receptor activity of the co-agonists.
These findings highlight the potential of co-agonists as a safe therapy for weight loss in patients with diabetes and could inform the design of more potent insulinotropic compounds for therapeutic use in type 2 diabetes.
effective treatments. Glucagon-like peptide-1 (GLP-1) analogues are one of the most efficacious therapeutics currently available, and simultaneously stimulate insulin secretion and increase insulin
sensitivity through weight loss. Consequently, GLP-1 analogues are particularly useful for diabetic patients who are overweight or obese.
It has been hypothesised that the tolerability and therapeutic efficacy of GLP-1 analogues could be enhanced by combining GLP-1 with a second insulinotropic hormone. Based on the well-established beneficial metabolic effects of oxyntomodulin, a naturally occurring GLP-1 and glucagon receptor co-agonist, glucagon has been proposed as a co-adjunct for GLP-1. While multiple groups have demonstrated the superior weight loss efficacy of GLP-1 and glucagon receptor co-agonists versus GLP-1 analogues, the insulinotropic effects of co-agonists remain undetermined.
This project involved the development of novel GLP-1 and glucagon receptor co-agonists based on the sequence of oxyntomodulin, with targeted sequence modifications to confer longer plasma half
lives and greater potency. To determine the direct beta cell effects of co-agonists, insulin secretion assays were performed in vitro using INS-1 832/3, MIN6B1 and EndoC-βH1 beta cells. In comparison to GLP-1 analogues, my co-agonists augmented insulin release in vitro. These insulinotropic effects were preserved in vivo in a high-fat, high-sucrose fed mouse model of type 2 diabetes, where the co-agonists led to greater insulinotropic responses than GLP-1 analogues acutely. On chronic administration, co-agonists did not impair glycaemic control despite their considerable glucagon receptor activity. In addition, co-agonists induced profound weight loss chronically, which was attributed to both food intake reduction through the GLP-1 receptor and energy expenditure effects through glucagon receptor activation. Paradoxically, the weight loss did not lead to improvements in glucose tolerance.
The in vitro insulinotropic effects were associated with a signalling bias against β arrestin recruitment at the GLP-1R and could be due to reduced receptor trafficking and internalisation. However, the in vivo characteristics show no correlation to bias, and weight loss was instead found to be positively associated with relative glucagon receptor activity of the co-agonists.
These findings highlight the potential of co-agonists as a safe therapy for weight loss in patients with diabetes and could inform the design of more potent insulinotropic compounds for therapeutic use in type 2 diabetes.
Version
Open Access
Date Issued
2018-09
Date Awarded
2019-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Bloom, Professor Steve
Minnion, Dr. James
Jones, Dr. Ben
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)