Funded Research

Diabetes is the most common cause of end stage renal failure (ESRF) in the developed world. Although the link between diabetes and kidney failure is not understood, the progression of diabetic nephropathy follows a predictable clinical course. Initially, in early diabetic nephropathy the kidneys leak small amounts of protein (microalbuminuria), and as the kidneys deteriorate further (progressive nephropathy) this amount increases (overt albuminuria). The kidney's filters consist of two cell types called podocytes and endothelial cells which interact together to form the filter. We can grow both cell types within our laboratory and the major aim of our laboratory is to understand how these cells interact and communicate with each other to form the filter in a healthy individual, and how this healthy state is disrupted during diabetes. In collaboration with Desmond Mascarenhas, (Mayflower Organization for Research & Education, Sunnyvale, CA, USA) we have become interested in the possible beneficial actions of the neuroprotective peptide humanin on the kidney. Dr. Mascarenhas has shown that this compound can markedly reduce protein loss (albuminuria) in an animal model of diabetes. This proposed work focuses on understanding the actions of humanin and other related bioactive peptides (being developed by Dr. Mascharenas) in treating the disturbances in the filtration function of the kidney seen in diabetes.

Type 2 diabetes is due to defects in production and action of insulin. Diabetes develops when pancreatic beta cells do not work properly. We still do not know precisely what goes wrong and why pancreatic beta cells release less insulin. Our work so far has suggested that pancreatic beta cells from people with type 2 diabetes possess a reduced amount of a specific protein belonging to a family of enzymes called "phosphoinositide 3-kinases" (PI3K). Furthermore our studies have revealed that when cells cultured in laboratory have reduced amount of this particular enzyme they secrete less insulin. This project wants to understand how this PI3K controls insulin secretion and the consequences of its reduction observed in diabetic individuals. This can reveal whether defects in insulin secretion observed in type 2 diabetes can be at least in part due to defect in this enzyme. This will add brand new information on how beta cells work and will help identify at least some of the steps that go wrong in type 2 diabetes, potentially leading to new treatments. It must be noted that this is the first time that a role for this enzyme in insulin secretion has been observed therefore its potential contribution to diabetes has not been investigated so far.