Role of the imprinted Igf2 gene in pancreatic development and function

Lead Research Organisation: University of Cambridge
Department Name: Obstetrics and Gynaecology

Abstract

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.

Technical Summary

Physiological conditions such as normal ageing and pregnancy are associated with increased demands for insulin. These needs are also increased in conditions that associate excess nutrient intake such as obesity. In all these circumstances it is essential that the insulin-producing beta-cells can proliferate in response to the increased needs. Recent studies have shown that insulin/IGF signalling regulates beta-cell proliferation and that Insulin-like growth factor 2 (Igf2), a small ligand similar to proinsulin, acts as a mitogen and cell survival factor. However the precise role of Igf2 in pancreas development and function is unknown. This application addresses this deficit in knowledge. This will be achieved using our newly generated conditional Igf2 allele as well as existing mouse models, in combination with exposures that induce beta-cell proliferation (pregnancy, high-fat feeding, partial duct ligation). Our preliminary data suggests that conditional deletion of Igf2 in beta-cells leads to reduced beta-cell mass and that there were high levels of Igf2 expression in the expanded islets of the obese ob/ob mice, suggesting an active role of Igf2 in beta-cell proliferation in response to high metabolic demand. The facultative pancreatic endocrine progenitor cells recently identified in an injury model also express high levels of Igf2 suggesting an involvement of Igf2 in controlling beta-cell neogenesis. The current proposal will capitalise on these findings and will address the following specific questions: Which are the pathways controlled by Igf2 in regulating beta-cell mass during development and in conditions associated with high metabolic demand? Is Igf2 the long-sought and elusive promoter factor of acinar growth during development? Does Igf2 have a regulatory role in beta-cell neogenesis? Answering these questions will lead to new insights into fundamental processes relevant for human physiology and disease.

Publications

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Description We discovered that the Igf2 gene is very important for the growth of the pancreas in fetal and early postnatal life. We developed mice that don't have Igf2 in the different cell types that make up the pancreas. Unexpectedly we found that the most of the Igf2 produced in the pancreas comes from the mesenchyme (or connective tissue). The mesenchyme thus acts as a reservoir of this important growth factor that then acts on other cell types. Accordingly, we found that when Igf2 is not produced by the mesenchyme the whole pancreas is smaller, including the cell types that generate enzymes for food digestion and those cells specialised in making insulin.
Exploitation Route We identified a major mesenchymal factor that is important for pancreatic growth and function. This may have important clinical implications, from cancer to diabetes research.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Igf2 in cardiac function 
Organisation University of Southern California
Country United States 
Sector Academic/University 
PI Contribution Generation of conditional mouse model for Igf2
Collaborator Contribution Analysis of a cardiac-specific Igf2 knockout Advise on planned projects looking at relationship between placenta and cardiac function using IGF related mouse models
Impact One publication so far (in Circulation Research)
Start Year 2011
 
Description Igf2 in cell proliferation/growth 
Organisation University of Oxford
Department Sir William Dunn School of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Biological materials, including mouse models, with manipulations of Igf2 and intronic Igf2 microRNA-483 Intellectual input in experimental design
Collaborator Contribution Analysis of mouse mutations
Impact One publication so far in Embo Molecular Medicine
Start Year 2012
 
Description Igf2 in neurogenesis 
Organisation University of Cambridge
Department Department of Physiology, Development and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided biological materials (e.g. Igf2 conditional mouse model) and intelectual input on experimental design
Collaborator Contribution Conducted experimentation on Igf2 conditional knock-outs
Impact Publication in Nature Communications
Start Year 2014
 
Description Poster presentation by Dr. Ionel Sandovici at conference Metabolism in Action 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Poster presentation titled "Mesenchymal Igf2 is a key regulator of pancreatic growth and function" at the conference "Metabolism in action - lifetime influence of genes and environment", Favrholm Campus, Denmark
Year(s) Of Engagement Activity 2017
URL http://cph-bioscience.com/en/events/metabolism-action-lifetime-influence-genes-environment