Monash researchers win large slice of Diabetes Australia research program funding

Five of Monash University’s researchers, four  from the newly established Monash  Biomedicine Discovery Institute (BDI) and one from the Monash  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.