Monash researchers win large slice of Diabetes Australia research program funding

Each recipient with the Lieutenant-Governor The Hon. Marilyn Warren AC, Chief Justice of Victoria.

Five of Monash University's researchers, four from the newly establishedMonash Biomedicine Discovery Institute(BDI) and one from theMonash Institute of Pharmaceutical Sciences(MIPS) have been announced as winners of the 2016 Diabetes Australia Research Program (DARP) funding pool, announced in November. The DARP $3.9 m fund provides money for basic, clinical, psycho-social and translational research into all types of diabetes.

Grants were awarded after a peer-reviewed and competitive process, overseen by a Research Advisory Panel involving 34 expert reviewers and 13 specialist sub-committees. This year, according to Diabetes Victoria which contributed $1.3 million to the funding pool, there were more than 340 applications with a success rate of 16 per cent.

DARP award winner Professor John Bertram, Head of the Department of Anatomy and Developmental Biology said that it was an honour to receive funding from "such a respected organisation that has done so much to promote research into diabetes."

At the ceremony, Diabetes Victoria CEO Craig Bennett congratulated Monash on its success.

"The grant awardees will undertake timely and important research in Australia, given that diabetes is on track to become the single greatest burden of disease in this country within the next few years. I congratulate the Monash University awardees and wish them well with their research," he said.

The Monash researchers awarded DARP funding are Professor John Bertram, Dr Garron Dodd, Associate Professor Ian Smyth and Dr Bo Wang from the Monash BDI, and Professor Raymond Norton from MIPS.

Details of their research projects are as follows:

Professor John Bertram: Monash BDI, 2016 DARP funding: $58,020

Research project summary:  Kidney disease is a common complication of diabetes, with approximately a third of patients with diabetes being diagnosed with diabetic nephropathy. Diabetic nephropathy originates from damage to glomeruli – the filtration units of the kidney. Podocytes are highly specialised epithelial cells that form a critical part of the glomerular filtration barrier that prevents protein leakage into the urine (proteinuria). Podocyte depletion has emerged in recent years as a unifying concept in kidney disease. In short, if podocytes are lost, or their density (number per volume) decreases beyond a threshold, pathology ensues. Fortunately, if podocyte depletion is mild, remaining podocytes can adapt and thereby maintain glomerular function. This project examines for the first time how podocyte adaptation is affected by diabetes. We hypothesize that a diabetic environment impairs podocyte adaptation, rendering glomeruli more susceptible to pathological change, resulting in diabetic kidney disease. If our hypothesis is true, our future studies will determine if and how standard and new-age diabetic drugs influence podocyte adaptation, with the aim of identifying optimal therapies for preserving podocytes and promoting podocyte adaptation, and thereby preventing or slowing the progression of diabetic nephropathy.

Dr Garron Dodd, Monash BDI, 2016 DARP funding: $60,000

Research project summary: Over one third of the western population is either overweight or obese. Roughly 80 per cent of overweight/obese individuals are 'insulin resistant' and/or have type 2 diabetes. With these figures set to rise by another third by 2020, the current obesity and type 2 diabetes epidemics will place an unsustainable burden on world health agencies. A key hallmark of type 2 diabetes is insulin resistance. Insulin is secreted from pancreatic beta cells in response to elevated blood glucose levels. Insulin targets several tissues including the liver, muscle, fat and the hypothalamus in the brain to regulate metabolic processes. Amongst other things insulin promotes glucose uptake in muscle and fat and inhibits further glucose production by the liver. During pre-diabetes defects in insulin signalling occur downstream of the insulin receptor rendering insulin's peripheral target tissues (liver muscle, fat) insensitive to insulin. What is becoming apparent is that neurons in the brain, particularly those in the hypothalamus, also become resistant to insulin, just like peripheral tissues. Our recent studies published in Cell have shown that one of the key molecules responsible for the attenuation of insulin receptor signalling in the hypothalamus is the protein tyrosine phosphatase TCPTP. Our preliminary data shows that TCPTP levels rise in the hypothalamus of obese mice, indicating that the increased TCPTP levels in obesity may be serving to de-sensitise the insulin receptor and make these neurons insulin resistant. Furthermore, we found that deleting TCPTP in key neuronal populations of the hypothalamus has profound effects promoting whole-body insulin sensitivity. Despite an emerging role of hypothalamic insulin signalling in glucose metabolism, the relative contribution of central insulin resistance to the development of type 2 diabetes in obesity is poorly understood. In this proposal we aim to assess the contribution of elevated hypothalamic TCPTP in obesity to the development of whole-body insulin resistance and glucose intolerance. Our studies will provide fundamental insight into the molecular causes of whole-body insulin resistance and define novel opportunities/approaches for alleviating type 2 diabetes in obesity.

Associate Professor Ian Smyth Monash BDI, 2016 DARP funding: $59,278

Research project summary: Pancreatic beta cells are exquisitely sensitive to lipid levels, which affects the viability of these cells and their ability to secrete insulin in response to glucose. Loss of beta cells and defective insulin secretion are typical of type 2 diabetes and our preliminary findings suggest that the ABCA12 protein is a novel mediator of both of these conditions' features. We have further evidence suggesting that changes in ABCA12 sequence are associated with diabetes in patients and this study will provide important mechanistic insights into how ABCA12 functions in pancreatic beta cells and how it might influence the development of disease.

Dr Bo Wang: Monash BDI, 2016 DARP funding: $60,000

Research project summary: This proposal will identify a novel therapeutic target, namely microRNA-378 (miR-378), to improve diabetic nephropathy caused by type I diabetes. Long-term severe kidney damage results in end-stage renal failure, requiring dialysis or organ transplantation. However, there is no effective treatment to delay the occurrence of kidney injury. Current pre-clinical studies have demonstrated therapeutic potential of microRNA in the treatment of diabetic complications. Here, we identify a novel target, miR-378, which has the potential to reduce glomerular damage as reported in our preliminary studies. This new-found therapeutic target will alleviate diabetic nephropathy through regulation of the MAPK pathway. Furthermore, experimental models of diabetic nephropathy will be used to study the reno-protective effect of miR-378.

Professor Raymond Norton,MIPS, 2016 DARP funding: $60,000

Research project summary: There is an ongoing need to develop new drugs for the treatment of type 2 diabetes. Most of the current therapeutics are associated with weight gain, which exacerbates the condition, and each has specific side effects. For example, the widely used sulphonylureas stimulate uncontrolled insulin secretion, promoting the incidence of hypoglycaemic episodes and eventually causing pancreatic beta-cell exhaustion. In fact, additional medications are almost always required over time, owing to the lack of a durable effect of most of the agents used. Protein kinase C epsilon (PKCe), exhibits increased levels and activity in patients with type 2 diabetes. Our collaborators in the diabetes program at the Garvan Institute have shown that deletion or inhibition of PKCe in fat-fed mice improves insulin action and enhances insulin secretion acutely in response to elevations in blood glucose, but, importantly, not chronically in an uncontrolled manner. This avoids hypoglycaemia and beta-cell exhaustion. The aim of this project is to screen for molecules that will form the basis of a drug development program for PKCe inhibitors. These would represent a new class of drugs with potentially significant benefits over existing treatments.