Pancreatic beta-cell dysfunction in diabetes [ 2005 - 2007 ]

Research Grant

Researchers: A/Pr David Laybutt (Principal investigator)

Brief description In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes. This project will investigate the mechanisms responsible for beta-cell failure in a mouse model with a similar time-dependent progression to obesity and type 2 diabetes as that seen in humans. C57BL-KsJ db-db mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity. With age, there are also a reduced number of beta-cells because of increased cell death. db-db mice will be studied at different stages in their natural progression to diabetes to fully characterise the secretory dysfunction and the changes in beta-cell phenotype over the time-course of diabetes development. The use of laser capture microdissection will allow us to study selectively the actual beta-cells without contamination from the other cells of the pancreas. The mice will also be treated with an agent that lowers blood glucose levels without affecting lipids to test the influence of hyperglycaemia itself in the development of beta-cell dysfunction. We will also test if the changes observed in the mice are regulated independently by high glucose levels in cell culture systems. The role of one candidate protein called ID-1 will be investigated as a potential link between hyperglycaemia and the development of beta-cell dysfunction.

Funding Amount $AUD 389,250.00

Funding Scheme NHMRC Project Grants

Notes New Investigator Grant