Author: Two Moons

Hopes are growing that West Australian researchers may be on the brink of discovering a new way to treat obesity and type 2 diabetes – and the development may also give rise to a new way to tackle type 1 diabetes.

Supported by funding from Diabetes Research WA, the latest findings on work into TNFSF14 confirms that in mice fed a high-fat diet, the protein plays a role in helping to stop the body developing obesity and type 2 diabetes.

“Our work uncovers for the first time that when these mice start to show signs of metabolic syndrome – which includes high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels – TNFSF14 levels are elevated as a response to these conditions,” said lead researcher Vance Matthews.

“TNFSF14 is trying to fight the first flames of the fire so to speak and we know this because mice on a high fat diet who are deficient in the protein develop increased obesity, glucose intolerance and impaired insulin sensitivity which can lead to type 2 diabetes.

“Excitingly, we also showed that TNFSF14 treatment can directly promote insulin secretion from pancreatic beta cells so it may also give rise to new ways to tackle type 1 diabetes in cases where the patient still has beta cells left.”

The group’s work, which has already been published online in Nature Publishing Group journal Immunology and Cell Biology and which was recently presented at the Australian Diabetes Society Meeting in Perth, shows that adipose tissue and the liver are key sources of TNFSF14, as are hematopoietic cells (cells within the bone marrow that produce cells that circulate in the blood).

“We’ve also discovered that a lack of TNFSF14 can exacerbate chronic liver injury, inflammation and dysregulation of mitochondrial function in the liver,” Assistant Professor Matthews, from The University of WA’s School of Biomedical Sciences, explained.

“We suspect that elevated levels of the protein IL-6 and FGF-21 in the liver could be helping TNFSF14 in its fire-fighting role in this organ.”

The next step for the team is to design compounds that can activate TNFS14 receptors and test them in select human cells.

“The ultimate hope is that TNFSF14 could give rise to an alternative to anti-obesity drugs which have not resulted in consistent and effective weight loss,” said Assistant Professor Matthews.

“This is a very promising line of research that we are proud to have supported with a $75,000 grant and the critical next stage of this work can be funded with the help of the corporate sector and the community,” said Diabetes Research WA executive director Sherl Westlund.

“It could be where the next major breakthrough in treating type 2 diabetes and type 1 diabetes comes from.”

West Australian researchers racing to create a new treatment to prevent and protect people from the potentially life-threatening complications of type 2 diabetes have been awarded new funding to fast-track their quest.

WA’s peak diabetes research funding group, Diabetes Research WA, has revealed that Associate Professor Kevin Pfleger and his Perth-based team will receive $60,000 to progress their work into a molecule called RAGE (the Receptor for Advanced Glycation End-products).

Professor Pfleger said RAGE was a molecule that sat in the membrane surrounding cells that were injured or stressed.

“As RAGE is only present when cells are in this injured or stressed mode – which happens in type 2 diabetes – it’s a key target that we believe we can home in on to possibly prevent and definitely use to help fight the health effects of this condition,” he explained.

“With our collaborators, we’ve discovered a new way in which this molecule is activated, triggering a cascade of signalling in cells that leads to inflammation and cell injury, and we’ve found a way to inhibit this process which should, in turn, limit the complications of type 2 developing, so it’s incredibly exciting.”

Diabetes Research WA executive director Sherl Westlund congratulated A/Professor Pfleger.

“This project could be a significant game-changer in the treatment of type 2 diabetes as there remains an unmet need for innovative treatment strategies to manage this condition, and shows how Western Australia is at the forefront of advances in this field,” she said.

The work will also harness powerful bioluminescence resonance energy transfer (BRET) technology, developed at the University of Western Australia, that A/Professor Pfleger is well-known for using in his cutting-edge research.

The project is being done in collaboration with leading diabetes researcher Professor Merlin Thomas from Australia’s Monash University.

Diabetes Australia states that every day, 280 Australians develop diabetes – or one every 5 minutes.

Including an estimated half a million undiagnosed type 2 diabetes cases, 1.7 million Australians have diabetes and this number is growing at a rate faster than other chronic diseases such as heart disease and cancer.

Type 2 diabetes accounts for 85% of all diabetes and is increasing.

West Australian researchers have been awarded funding for a world-first project that could ultimately help prevent type 1 diabetes developing in very young children who are at high-risk of the condition.

WA’s peak diabetes research funding group, Diabetes Research WA, has provided a $60,000 grant to research fellow Dr Aveni Haynes from the Children’s Diabetes Centre at Telethon Kids Institute, and her team, to investigate continuous glucose monitoring (CGM) for measuring blood sugar levels in children at high-risk of developing type 1 diabetes but who are not yet showing clinical signs of the condition.

Dr Haynes said the project will involve children enrolled in the Australia-wide Environmental Determinants of Islet Autoimmunity (ENDIA) study who have either a parent or sibling with type 1 diabetes and who have developed type 1 diabetes specific autoantibodies that indicate they are on the path towards developing the autoimmune condition.

“There’s evidence that blood sugar levels in these high-risk children could be abnormal some months to years before they develop type 1 diabetes symptoms. Previously these children have been monitored using blood tests which only reflect a snapshot in time,” explained Dr Haynes.

“Our work is looking to find early changes in the pattern of blood glucose levels in very young children in more detail and the CGM will show us what’s happening to those levels 24 hours a day.”

Dr Haynes said given these children had a much higher risk of being diagnosed with clinical type 1 diabetes, their parents may experience anxiety related to this. This project could help alleviate some of that anxiety by giving parents more information about whether or not there were any signs of changes in their child’s day-to-day blood glucose levels.

“The information could also be used in future research aimed to reverse, delay or slow the progression of these children developing symptomatic or clinical type 1 diabetes; perhaps by helping to preserve insulin-producing cells that are lost in type 1 diabetes, or using other possible treatments earlier than is standard practice now,” she said.

“And we want to reduce the chances these at-risk children will first present to hospital with diabetic ketoacidosis which can be life-threatening and is caused by blood sugar levels being too high for too long.”

Diabetes Research WA executive director Sherl Westlund said the project held enormous potential to impact future treatment and prevention of type 1 diabetes.

“Type 1 diabetes – for which there is no cure and which can pose many health complications – is becoming more common, so any research that can help reduce its impact is very important,” she said.

WA researchers have been awarded fresh funds to investigate if a so-called wonder drug may be able to be used to prevent a diabetes-related eye condition that can lead to blindness.

SGLT2 inhibitors – a relatively new class of oral medications that lower blood sugar levels by stopping the reabsorption of glucose in the kidney – have been shown to benefit cardiovascular and kidney health in those with type 2 diabetes.

Led by Dr Lakshini Herat and funded by a grant from Diabetes Research WA, the WA team will investigate if the SGLT2 inhibitor known as Canagliflozin may also halt the development and progression of diabetes related eye disease.

“Diabetic retinopathy, which occurs when the tiny blood vessels inside the retina at the back of the eye are damaged as a result of either type 1 or type 2 diabetes, is a leading cause of irreversible blindness worldwide, so there’s a great need to advance our treatment of it,” said Dr Herat.

“Our recent investigations demonstrate elevated expression of SGLT2 in the whole eye and retina of a diabetic retinopathy mouse model and this new funding will allow us to understand the protein’s role in the development and progression of diabetic retinopathy and its potential as a therapeutic target.

“If successful, this research may pave the way for a clinical trial in humans with the ultimate hope that Canagliflozin may be able to be used in people with early signs of eye damage to stop them losing their sight.”

A 2013 report Out of Sight: A Report Into Diabetic Eye Disease In Australia stated that almost all those with type 1 diabetes and more than 6 out of 10 people with type 2 diabetes will develop diabetic eye disease within 20 years of diagnosis*.

It’s now estimated that there are 422 million adults with diabetes worldwide and that’s projected to rise to 629 million by 2045**.

Diabetes Research WA executive director Sherl Westlund said the research could have a significant positive impact.

“The impact of diabetes on the eyes can be debilitating and with rates of diabetes rising quickly in Australia, this research has huge potential to reduce the burden on human health and our health system,” said Ms Westlund.

Other UWA researchers involved in the study include Assistant Professor Vance Matthews, Professor Markus Schlaich, and the Lions Eye Institute’s Professor Elizabeth Rakoczy.

The research is due to get underway early next year.

*Source: ‘Out of Sight: a report into diabetic eye disease in Australia’

**Source: Global prevalence of diabetic retinopathy: protocol for a systematic review and meta-analysis

West Australian researchers have won funding to progress work that could lead to simplified screening for gestational diabetes, and improved screening across regional WA. Current screening for gestational diabetes mellitus (GDM) – which only appears in pregnancy – is known as Oral Glucose Tolerance Testing (OGTT) and is done between 24 and 28 weeks of pregnancy. Women have to fast and undergo blood tests before and after drinking a glucose-loaded mixture, meaning the test takes over two hours.

Elevated blood glucose in pregnancy has been linked to an increased risk of adverse birth outcomes and research shows babies born to women with GDM are more likely to develop obesity and type 2 diabetes. The condition and risks can usually be managed with diet and lifestyle changes, and sometimes medication. Researcher Julia Marley from the Rural Clinical School of Western Australia said many women in regional and remote WA don’t complete the test. “The current screening process for gestational diabetes is time-consuming and difficult. Many women, in particular Aboriginal women, opt not to – or can’t – do it, which potentially puts their health and that of their unborn child at risk, so our aim is to simplify the testing in a bid to ensure more women have it done,” she said.

Associate Professor Marley and her team will use their $60,000 grant to investigate using one blood test to screen for GDM. This could lead to more pregnant women being tested by using two alternate markers of blood glucose, glycated haemoglobin (HbA1c) and glycated albumin (GA), which can be done by taking two tubes of blood in one sitting, with no fasting or glucose drink required. It may be that this test is used as an initial screen so only certain women would need to be referred on to have an OGTT.

Pregnant women in the Kimberley, South West and Osborne Park presenting for an OGTT will be invited to take part in the study. The hope is to use this new model to categorise women as having a low, medium or high risk of experiencing birth complications due to their blood glucose levels, rather than simply diagnosing them as having or not having GDM. This new model may also address, as found in a previous study, the high number of women being mistakenly classified as not having gestational diabetes due to unavoidable delays in blood samples getting to the lab for testing in regional areas of WA.

For more information, view our video presentation for National Diabetes Week 2020

West Australian researchers have won funding to carry out a world-leading trial that could reduce the chances of people with type 2 diabetes who’ve had a heart attack suffering further heart failure.

Fiona Stanley Hospital cardiologist Dr Girish Dwivedi has been awarded charity Diabetes Research WA’s $60,0000 Jamie Cripps 2021 Research Grant for the project, which focuses on a new class of medications known as sodiumglucose co-transporter-2 inhibitors (SGLT2Is), and could also ultimately benefit those with type 1 diabetes.

Heart attacks and strokes are up to four times more likely in people with diabetes, despite treatment advances, and in those who’ve recently experienced cardiac arrest, the risk of recurrent heart attack or death is increased substantially.

“In a small non-randomised study, we found that in patients with type 2 diabetes and heart attack, starting treatment with the SGLT2i medication empagliflozin just before hospital discharge was linked to a reduction in heart chamber thickening and favourable changes in pumping function that reduced the risk of heart failure,” said Dr Dwivedi.

The new funding will be used to launch a larger randomised study in a bid to confirm the group’s early findings and pave the way for a nationwide trial.

“We’re also hopeful this trial can address doctors’ concerns about rare side effects of SGLT2i therapy, which appears to have been stopping them using it in hospital patients in the aftermath of heart attack, despite well-established blood glucose-lowering benefits and recommendations for its use,” Dr Dwivedi explained.

“It’s well known that initiation of therapies prior to hospital discharge improves long-term health outcomes for patients and encourages them to stick to their medication regime, so if we can prove this class of drug is safe and effective, it could become one of the mainstays of treatment of heart attack patients with type 2 diabetes.

“There is also increasing interest in using these drugs for type 1 diabetes for managing blood glucose and reducing insulin dosage and we hope our work will also contribute to understanding how that may be best done.”

Diabetes Research WA executive director Sherl Westlund said the organisation was thrilled to be supporting this powerful research.

“As those with diabetes are up to four times more likely to die from heart disease than people who don’t have diabetes, it’s critical we make advances in tackling this, and this project has the potential to do just that,” said Ms Westlund.

“We’re also particularly proud to be supporting this research as it may have benefits for type 1 and type 2 diabetes, both of which are becoming increasing common worldwide.”

Dr Dwivedi is also the Wesfarmers Professor of Cardiology at The University of Western Australia and the head of the Harry Perkins Institute of Medical Research’s Advanced Clinical and Translational Cardiovascular Imaging laboratory.

Other researchers involved in the project include Professor Bu Yeap and Dr Gerry Fegan, endocrinologists at Fiona Stanley Hospital, Assoc Prof Frank Sanfilippo, a cardiovascular epidemiologist at University of WA and Royal Perth Hospital senior pharmacist, and Dr Nick Lan, trainee cardiologist at Fiona Stanley Hospital.

The new study is expected to begin in April 2021.

The Jamie Cripps 2021 Research Grant is named in honour of West Coast Eagle Jamie Cripps.

Jamie, who has type 1 diabetes, is a Diabetes Research WA Ambassador and helped raise the $60,000 awarded to Dr Dwivedi through the ‘Help Crippa Kick Diabetes Research Goals’ crowdfunding campaign.

West Australian researchers will use fresh funding to investigate how a single gene change causes insulin resistance and type 2 diabetes.

The research by University of WA Professor Aleksandra Filipovska, supported by a newly-announced $60,000 grant from Diabetes Research WA, will also look at how diet and exercise may be able to target a gene change to reveal ways to prevent and manage the onset of type 2 diabetes.

Also the head of the Mitochondrial Medicine and Biology laboratory at the Harry Perkins Institute of Medical Research, Professor Filipovska said the gene change was known to be a significant contributor to metabolic disease.

“This common variation of a gene inside mitochondria, which are microscopic energy producing machines within our cells, can change energy production and breakdown of fats and sugars to cause insulin resistance and type 2 diabetes, and is commonly found in the population,” she explained.

“Using a new model we’ve created using the latest genome editing technology, we hope this project will build on findings from our pilot study to show how this gene is linked to the predisposition to and cause of insulin resistance and its contribution to the development of type 2 diabetes,” said Professor Filipovska.

“We will also test how this single gene change may be impacted by different diets and exercise to understand how we can prevent the onset of type 2 diabetes by altering our nutrition and energy usage.

“Pinpointing the molecular mechanisms linked to this gene change will also help uncover important drug targets for new medicines, test available drugs and antioxidants that may be able to delay insulin resistance, and provide new avenues for tests to diagnose the conditions.”

Diabetes Research WA executive director Sherl Westlund said the charity was pleased to be supporting such vital research.

“Insulin resistance is one of the main features of type 2 diabetes, which is the seventh leading cause of death nationally, so the potential positive impact of this project on the health of Australians is immense,” she said.

“Being able to identify how energy levels fail as type 2 diabetes develops is an important piece of the puzzle in tackling the condition.”

More than 100,000 Australians have developed diabetes in the past year and the total cost impact of diabetes in Australia is estimated at ~$14 billion.

Professor Oliver Rackham from Curtin University, Dr Stefan Siira and Judith Ermer, both from The University of WA are also part of the research team.

Diabetes Research WA, based at Royal Perth Hospital, was established in 1976 to stimulate research into diabetes in Western Australia.

$60,000 has been awarded for a project investigating a new way to tackle disease-inducing chronic inflammation linked to type 2 diabetes.

Professor Pfleger and Dr Elizabeth Johnstone (pictured above) and the Molecular Endocrinology and Pharmacology Laboratory team at the Harry Perkins Institute of Medical Research, in collaboration with colleagues at Monash University, hope to reduce health complications of type 2 diabetes by blocking a newly-discovered pathway.

Inflammation is increased in type 2 diabetes and we’ve found this pathway effectively stokes the fires of inflammation in the body, making it burn more fiercely, increasing the risk of it getting out of control and causing collateral health damage.

The group has found that key proteins on the surface of cells involved in chronic inflammation – known as Immunoglobulin-like Cell Adhesion Molecules – are turned on by a process called transactivation when other G protein-coupled receptor molecules on the cell surface are themselves turned on. They aim is to develop smart inhibitors of this pathway in order to keep inflammation under control and, in doing so, treat and prevent type 2 diabetes complications, such as atherosclerosis – which is the formation of fatty deposits in arteries – and kidney disease.

This new funding will support research into the underlying molecular mechanisms driving this transactivation process and test peptides that modulate the pathway, to expand the number of potential type 2 diabetes drug targets.

Additionally, the work will involve use of BRET – bioluminescence resonance energy transfer – technology, which Professor Pfleger’s laboratory is a world-leader in using to study protein-protein interactions.

Dr Mary Abraham from the Telethon Kids Institute and Perth Children’s Hospital has secured $60,000 from our 2022 Diabetes Research Grants program to launch a pilot study into the use of oral insulin in type 1 diabetes – a medication intervention that could be a game-changer for those with the chronic condition.

Oral insulin had so far predominantly been tested in those with type 2 diabetes while insulin injections or insulin pump therapy are the cornerstone of type 1 diabetes treatment but still, most people remain unable to achieve optimal blood glucose levels, so there’s a very real need to improve on treatment.

Oral insulin has enormous benefits of being a non-invasive form of insulin and offers the hope of reducing the risk of blood sugar levels falling dangerously low in people with diabetes, and it may also help to minimise weight gain that can be an issue with subcutaneous insulin because it causes high insulin levels in the body. It is also believed oral insulin may reduce the long-term risk of diabetes-related vascular complications, as well as possibly restore beta cell function.

This 12-week study aimed to see if oral insulin could be used alongside injected insulin. The success of oral insulin has so far been limited due to absorption issues. This trial of an improved oral drug delivery system has been designed to overcome this challenge. If it can be used to reduce the amount of insulin that needs to be injected by people with type 1 diabetes or mean they require less total insulin, this would be a very welcome breakthrough.