Simmgen, M; (2006) The role of liver insulin signalling pathways in carbohydrate and lipid homeostasis. Doctoral thesis , UCL (University College London).

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Abstract

The prevalence of type 2 diabetes mellitus is rapidly rising worldwide, despite an increasing awareness of the problem. Hepatic insulin resistance is a key factor in the pathogenesis of type 2 diabetes. The liver is central to the maintenance of glucose homeostasis, but the role of intrinsic liver insulin signalling versus indirect effects on the regulation of hepatic metabolism remains under debate. Insulin receptor substrate-2 is a major signalling molecule downstream of the insulin receptor. Global gene targeting in mice and in vitro studies have suggested that Irs2 mediates most metabolic insulin effects in the liver. I hypothesised that the liver-specific deletion of Irs2 would lead to a significant dysregulation of glucose homeostasis, thus further clarifying its role in the development of type 2 diabetes. The work presented in this thesis describes the characterisation of mice with a selective deletion of the Irs2 gene in the liver (Livlrs2KO), generated using the CrelioxP technique. Hepatocyte-specific Irs2 excision was achieved by an albumin promoter-driven recombination event. The animals bred and survived normally into adulthood. Hepatic insulin signalling events were investigated by immunoblotting and found to be normal. Glucose and lipid metabolism was also unaltered in Livlrs2KO mice, except for a mild rise in fasted glucose following a period on a high fat diet. Hyperinsulinaemic-euglycaemic clamp studies revealed a small reduction in glucose utilisation, accounted for by reduced glycogen synthesis. Quantitative gene expression analysis showed elevated G6pc and reduced Gck levels in Livlrs2KO mice after a prolonged fast, but appropriate gene regulation when feeding. Glycogen synthase expression was comparable to controls, as were genes of lipid metabolism. The liver function remained normal in Livlrs2KO animals except for a mild rise in transaminases. In summary, surprisingly, only mild abnormalities resulted from hepatic Irs2 deletion. This suggests that Irs2-associated intrinsic insulin signalling in the liver is not required for long-term glucose and lipid homeostasis and that extra-hepatic Irs2-dependent mechanisms are involved in the regulation of these processes.

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