Cantley, J.M.; (2007) The molecular control of beta cell function by insulin and hypoxia cellular signalling pathways. Doctoral thesis , University of London.

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Abstract

This thesis reports the investigation of the role of the insulin receptor substrate 2 (Irs2) and von Hippel-Lindau (Vhl) genes in B-cell function, using the cre-loxP system to delete these genes in the pancreas of mice. Pancreatic 8-cells sense and respond to the metabolic status of the body via cellular signalling networks. The genes studied represent critical nodes in the insulin (Irs2) and hypoxia response (Vhl) cellular signalling pathways. IRS2 mediated insulin and insulin like growth factor 1 receptor signalling (IIS) has previously been demonstrated to be critical in maintaining a functional B-cell mass in the presence of peripheral insulin resistance. However, in these previous studies, the study of Irs2 null B-cell function was complicated by the insulin resistance. Therefore, this thesis reports the generation and characterisation of the pancreatic Irs2 knock out (Plrs2KO) mouse, which has enabled the clarification of the role of Irs2 in the pancreas without the complication of increased body mass or insulin resistance. This has demonstrated the importance of IRS2 mediated IIS in maintaining correct B-cell function, by positively regulating B-cell mass and insulin secretion, thereby controlling whole body glucose homeostasis. The transcription factor hypoxia inducible factor (HIF) initiates the transcription of hypoxia response genes. HIF is earmarked for destruction by the VHL protein in the presence of oxygen, but HIF is stabilised and active during hypoxia. To investigate the role of HIF in the B-cell, B-cell and pancreas specific Vhl knock out mice were generated (BVhlKO and PVhlKO) and characterised. These models exhibited B-cell HIF1a activation and glucose intolerance due to altered gene transcription, defective glucose sensing and insulin secretion, despite having a normal B-cell mass. This has established that HIF can regulate insulin secretion and B-cell function. Importantly, these data have implications for human islet transplantation whereby HIF activation may impair glucose sensing and therefore insulin secretion in islet grafts.

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