Role of cilia in developing hyperinsulinaemia and insulin resistance

Patients with type 2 diabetes and obesity have a higher insulin content in the blood than people without those conditions. It is still not clear whether high insulin content is a cause or a result of these diseases. Currently it is known that there are two key elements driving insulin levels up and thus it is important for us to understand; 1. why pancreatic cells are producing/secreting more insulin and what factors control it? and 2. why do muscle and fat cells (the target cells for insulin) not respond to normal levels of insulin? Recent evidence suggests that defects in cilia, a hair like structure protruding from most cells, might be involved in the development of obesity. Our study is designed to understand whether there may be too many insulin producing cells (in the pancreas), or too little response from muscle and fat cells. Once that is known we will then determine the novel molecular and cellular mechanisms of cilia involvement in hyperinsulinaemia (increased level of insulin). Only through understanding the mechanisms of disease and the factors controlling it, can we begin to design therapy or management regimens to combat these increasingly common diseases.

Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. In spite of their complex aetiology, hyperinsulinaemia and insulin resistance are key factors in causation of these disorders. Investigation of the molecular and cellular mechanisms of hyperinsulinaemia and insulin resistance are, therefore, crucial for understanding the pathogenesis of obesity and diabetes mellitus. Primary cilia are microtubule-based, hair like organelles protruding from the apical cell membrane and contain a high concentration of receptors and other signalling molecules. New evidence suggest that it might act as a signalling organelle. Our data, as well as the research of others suggest that cilia/basal body/IFT proteins are involved in developing obesity, hyperinsulinaemia, insulin and leptin resistance. Our main objective will be to investigate the mechanism of hyperinsulinaemia in knockout mice with cilia defects (Bbs/IFT80/polaris). We will focus on potential underlying defects in insulin secretion and target cellular responses. We propose several ciliary mechanisms, which might be involved in impaired insulin secretion including Wnt and somatostatin signalling - these will also be investigated. Our final goal will be to identify differentially expressed/localised proteins in deciliated MIN6B1 cells using a proteomic approach.