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Title: Obesity and hypertension in type 2 diabetes : exploring the central and peripheral effects of glucagon-like peptide-1R signalling
Author: Robinson, Louise E.
ISNI:       0000 0004 2749 0599
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2012
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Glucagon-like peptide 1 is a hormone involved in the regulation of glucose. Glucose-dependent activation of brain GLP-1R stimulates GLP-1 secretion from the L-cells of the intestine in response to ingested nutrients and it enters the blood stream to direct insulin secretion and to regulate growth and apoptosis of pancreatic cells, regulate the uptake of glucagon secretion as well as other metabolic processes. GLP-1 agonists are a new class of antidiabetes agent and current research suggests a role in weight and blood pressure reduction. A primary function of GLP-1 is postulated to act as a neuropeptide in the regulation of metabolic and cardiovascular function through gut-brain regulatory feedback. As a secondary effect, GLP-1 may also increase natriuresis by direct action on sodium transport molecules in the kidney and hence play a role in long-term blood pressure homeostasis. The aims of this thesis is to 1) ascertain the effects of GLP-1 agonists on blood pressure, heart rate and body weight in T2DM patients through a systematic review and meta-analysis and 2) to explore the expression of renal GLP-1R during metabolic syndrome (obesity) and diabetes in animals and also hyperglycaemia-like conditions in isolated cells of the human renal proximal tubule and collecting duct. I also investigate for the first time GLP- 1R mediated expression of sodium transport molecules in cells of the human collecting duct. I confirm that GLP-1 agonists produce significant weight reducing effects and also a beneficial reduction in blood pressure in T2DM patients. However, there is a tendency for these agents to increase heart rate which may be related to their effects on the autonomic nervous system and direct activation of sino-atrial node GLP-1R. I show evidence that renal GLP-1R expression is inhibited during obesity and diabetes which might be a consequence of peripheral insulin signalling or regulatory feedback from pancreatic β-cells to the CNS but which needs to be further clarified. GLP-1 was also shown to modestly up-regulate α- ENaC mRNA and protein expression, possibly as a consequence of activation by SGK-1 and PKCdependent ERK activation in HCD cells. The significance of this paradoxical finding in a clinical scenario is unknown because 1) GLP-1(7-36) should theoretically undergo enzymatic degradation in peripheral tissues and further degradation and elimination in the proximal tubule. However, potential for long-acting GLP-1 agonists to remain in the kidney for longer might mean that these agents reach the collecting duct whereby paradoxical sodium reabsorption may occur. This might also be reflected in the meta-analysis findings that exenatideLAR preparations reduce blood pressure less than shorter acting formulations. I conclude that GLP-1 signalling is dysregulated in obesity and diabetes and that treatment with GLP-1 agonists confer favourable effects on body weight and blood pressure. However, due to effects on heart rate further safety studies are required to reassure long term cardiovascular safety and autonomic mechanisms behind the cardiovascular and metabolic effects of GLP-1 needs to be explored further.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; RC Internal medicine