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Title: The roles of AMPK and LKB1 in hormone secreting cells
Author: Sayers, Sophie
ISNI:       0000 0004 5920 8228
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Regulation of insulin secretion from the pancreatic β-cell and glucagon secretion from the α-cell is vital for the control of normal glucose homeostasis. Dysfunction may lead to some forms of Diabetes. Liver kinase B1 (LKB1) is a tumour suppressor that is mutated in the premalignant disorder Peutz-Jeghers Syndrome (PJS). PJS is characterised by the formation of polyps in the gastrointestinal tract. LKB1 exerts its biological effect via direct phosphorylation of AMP-activated protein kinase (AMPK) and related kinases. The incretin hormones glucagon-like-peptide 1 (GLP-1), secreted from proglucagon-expressing enteroendocrine L-cells, is involved in the regulation of appetite and glucose homeostasis. Therefore, GLP-1 is considered of therapeutic value in the treatment of Type 2 Diabetes. Both LKB1 and AMPK have been shown to play some role in insulin secretion. However, the role of LKB1 and AMPK in proglucagon-expressing cells in regulating GLP-1 secretion and glucose homeostasis has yet to be studied in vivo. In this study, we investigate how LKB1 contributes to insulin secretion in pancreatic β-cells by deleting LKB1 using a β-cell selective Ins1Cre promoter in mice. I also explore the roles of LKB1 and AMPKα1α2 in proglucagon-expressing cells including enteroendocrine L-cells of the gut and pancreatic α-cells using a proglucagon specific iGluCre promoter. Deletion of LKB1 in β-cells resulted in two opposing effects. (1) Glucose tolerance and β-cell mass were increased and (2) the cytosolic ATP/ADP and Ca2+ response to glucose was impaired. Despite these effects, insulin secretion in vitro remained unaffected. Moreover, deletion of LKB1 resulted in amplification of a glutamate-induced signalling pathway. Therefore, ablation of LKB1 amplifies other pathways which compensates for impairments in cytosolic and mitochondrial function. Deletion of LKB1 in proglucagon-expressing cells has no effect on GLP-1 secretion or glucose homeostasis but result in the development of large gastro-duodenal polyps. On the other hand, deletion of AMPK from these cells improves glucose tolerance as well as L-cell mass and GLP-1 secretion. Therefore, both LKB1 and AMPK play roles in normal insulin secretion. Targeting inhibition of these kinases in β- and L-cells may thus provide a new therapeutic strategy in some forms of Type 2 Diabetes.
Supervisor: Rutter, Guy Sponsor: European Foundation for the Study of Diabetes ; Biotechnology and Biological Sciences Research Council ; Royal Society ; Wellcome Trust ; Diabetes UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available