Scott, Mary Thomson; (1998) Enhancement of insulin signalling in adipose tissue by malarial extracts. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Malarial extracts (MEs) derived from the erythrocytic stages of Plasmodium infection in mice have been shown to synergise with insulin in both stimulating lipogenesis and inhibiting lipolysis in rat adipocytes in vitro. In this study, rat adipocytes were used as a test system in an attempt to determine where in the insulin signalling network these malarial extracts were exerting their effects. Initial studies demonstrated that the MEs had no effect on insulin receptor binding or internalisation, nor did they enhance insulin stimulated 3-O-methylglucose uptake. Investigation of their effects on the activity of the downstream enzymes involved in lipogenesis showed that they had no effect on the stimulation of pyruvate dehydrogenase by insulin. They did however potentiate insulin's stimulation of the committal enzyme in fatty acid synthesis, acetyl-CoA carboxylase (ACC), without changing its total activity. The MEs were also shown to synergise with insulin in the activation of glycogen synthesis. They appeared to exert this effect by enhancing the insulin stimulation of glycogen synthase, having no effect on the inactivation of glycogen phosphorylase activity by insulin. Neither epidermal growth factor nor isoproterenol had any effect on the ability of the MEs to synergise with insulin and enhance glycogen synthesis and the MEs did not induce EGF to stimulate glycogen synthesis. Isoproterenol did however block any insulin-mimetic effect of the MEs. The MEs synergistically enhanced the effect of insulin to increase anti- phosphotyrosine immunoprecipitatable phosphatidylinositol 3-kinase (PI3-kinase) activity. Since both ACC and glycogen synthase have been shown to be stimulated by insulin through a PI3-kinase dependent pathway, these results suggest that the ME's effects on PI3-kinase may be a key step in their synergistic enhancement of insulin signalling. As well as synergising with insulin, some of the ME preparations were also able to stimulate the production of tumour necrosis factor (TNF) by isolated macrophages. However there was no correlation between these two properties of the MEs. There was also no correlation between the synergistic effects of the MEs and their ability to mimic insulin. While these results were very interesting it should be noted that the malarial extracts used in this project were specifically chosen for their ability to synergise with insulin. Of the total number of malarial extracts prepared only approximately 40% actually demonstrated this ability.

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