Role of the imprinted Igf2 gene in pancreatic development and function

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The pancreas is a large gland in the body with two very important functions: it makes insulin and digestive enzymes. The part of the pancreas which produces insulin and other hormones is called the endocrine pancreas. The part of the pancreas that produces the digestive enzymes is called the exocrine pancreas. Digestive enzymes break down food into small components allowing it to be easily absorbed from the intestine. Insulin is produced by specialized cells of the endocrine pancreas called beta cells. Insulin controls your sugar levels in the blood and makes sure that the body cells get enough energy and can store it for later use. The pancreas is able to 'sense' the level of sugar in the blood - if too high the beta cells make and secrete more insulin. If the level is too low, it secretes less. There are conditions when not only more insulin is needed but the number of beta cells needs to increase in order to cope with the increased demand for insulin. These circumstances include normal ageing, pregnancy and obesity to mention a few. Failure to increase the number of beta cells in the above conditions can lead to increased levels of sugar in the blood and diabetes. We know little about how the pancreas is able to increase the number of beta cells when needed. Consequently, to determine the factors that control this adaptive process is very important. The aim of this study is to determine precisely how a gene, that we think is a master regulator of pancreatic growth and function, actually works. This gene encodes for a protein that is similar to insulin - it is suggestively called insulin-like growth factor 2 (Igf2). We have preliminary evidence suggesting that Igf2 is an important factor that controls the normal development of the pancreas and makes beta cells multiply when needed. Many of our attempts to decipher mechanisms which are important for human health and disease both rely and benefit from studying animal models. In this study we will use mice because their pancreas is similar to the human one and because we can remove the Igf2 gene in their beta cells or in the entire pancreas, allowing us to understand how this gene works. We can also increase the amount of Igf2 produced by the beta cells or in the entire pancreas. We will study the development and the structure of the pancreas that can not make Igf2 or makes more Igf2 than normal mice. We will pay particular attention to the effect of the lack or excess of Igf2 on development of the pancreas and the number of beta cells during ageing. We will also study how changing the amount of Igf2 affects the way pancreas makes new beta cells during normal pregnancy, during exposure of mice to high-fat diet (to mimic human obesity) or when the pancreas is injured. We will use these experiments to find which other genes are under the control of Igf2. The results of this study will help to understand better how the pancreas develops, how it works during normal circumstances and how it adapts to conditions which increase the demand for insulin.