Modulation of Rab7 in [beta] cells to treat diabetes

Lhaf, Fadel (2017) Modulation of Rab7 in [beta] cells to treat diabetes. (PhD thesis), Kingston University, .

Abstract

According to the World Health Organisation, 422 million adults worldwide are currently suffering from either type 1 diabetes or type 2 diabetes and this number is continuously on the rise. Sufferers of type 1 diabetes have a near complete deficiency in islet [beta] cells, while patients with type 2 diabetes have an insufficient number of functioning islet [beta] cells. The apparent solution to treat diabetes would be to replace the damaged and non-viable [beta]-cells, with healthy and functioning ones by either endogenous regeneration of [beta] cells or exogenous transplantation of [beta]-cells. Even though transplantation is a viable option, the number of available donors is insufficient to meet the demands. Expanding a patient's own [beta]-cells could theoretically provide an unlimited supply of [beta] cells and restor glycaemic control, but current protocols have been unable to generate insulin producing [beta] cells with high mitotic index. Rab7 is a smal GTPase regulatory protein responsible for membrane trafficing. Recent research has found that Rab proteins are crucial for the regulation of signalling receptors. Following internalisation of cell membrane components, cell surface receptors either become degraded or recycled back to the cell surface. Some cell surface receptors are responsible for activation of cellular proliferation, differentiation and inhibition of apoptosis. The aim of this study was to determine the effect of Rab7 knockdown on [beta] cell survival, growth and signalling. We hypothesise that attenuation of Rab7 will increase the number of growht factors and as a result increase ERK1/2 signalling, which will lead to enhanced survival. Here, we show that attenuation of Rab7 in [beta]-cells increases levels of insulin growth factor receptor by 60% (p= 4.2 x 10[to the power of]-8) and the c-Met receptor by 70% (p = 0.03) in INs-1 cells. This indicates a role of Rab7 in the trafficking of both receptors. In addition, ERK1/2 phosphorylation in response to growth factors was greatly enhanced in the Rab7 knockdown group of both INS-1 cells and islets. [Beta] cells of type 2 diabetes patients typically have increased autophagy due to high levels of circulating free fatty acids that are cytoxic to [beta] cells. Furthermore, Rab7 is also known to be involved in the regulation of autophagy, and there is growing evidence that the autophagy pathway is important for [beta] cell survival in type 2 diabetes patients and therefore inhibiting autophagy could have a detrimental role. Our data shows that free fatty acids activate both autophagy and caspase pathways in [beta] cells, and inhibit [beta] cell growth. Our data indicates that Rab7 knockdown does not alter autophagy and reduces [beta] cell death and caspase-3 activation under conditions of free fatty acid exposure, such as are found in type 2 diabetes patients. These results suggest that Rab7 inhibition has a beneficial role against cell death and increased proliferation of [beta] cell mass.

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