About one third of individuals with type 1 diabetes will develop kidney complications during their lifetime. Current treatment options for diabetic kidney disease can slow but not stop its progression, highlighting an urgent need for new approaches.
Scientists at Boston’s Joslin Diabetes Center have revealed an unexpected route to slow the progression of diabetic kidney disease, targeting a biological pathway that is the main channel for the metabolism of glucose in the cell.
The finding builds on an earlier surprise from the Joslin Medalist Study program, which looks into how people live with type 1 diabetes for more than 50 years with unusually low levels of complications. Among Medalists with similar blood glucose control, some people developed kidney disease and others did not.
Described in a paper in Nature Medicine, the current study set out to find what biological mechanisms might protect the kidneys of healthy Medalists against damage from high blood glucose levels.
The surprise finding that would begin the researchers’ journey
Using donated kidneys, the Joslin team looked at the levels of thousands of proteins expressed in kidney cells that help to filter blood, and compared the results for Medalists with and without kidney disease.
The investigators expected to see that the unhealthy kidneys demonstrate high levels of a host of enzymes that process blood glucose. Increased glucose processing has long been thought to inflict damage on the mitochondria (the cell’s power generators), which then produce large amounts of reactive oxygen molecules, which leads to kidney disease.
But the Joslin team found just the opposite. Much higher levels of these enzymes were detected instead in the protected kidneys.
A second unexpected discovery
The scientists got another surprise when they followed up on this finding with mouse experiments that exposed specialised kidney cells to high levels of glucose. Instead of damaging the mitochondria while metabolising glucose, the cells somehow stimulated themselves to make new mitochondria, resulting in them working better.
Harnessing this knowledge to test potential treatments
Next, the research team decided to test potential protective treatments by activating a key enzyme in glucose-processing pathways. They picked an enzyme known as PKM2, whose levels almost tripled in healthy Medalists’ kidneys compared to diseased kidneys in the study, and which helps the cell take the final step in supplying fuel by the mitochondria. Another reason to pick PKM2 was that cancer researchers have studied the enzyme intensively (because low activity of PKM2 can boost tumour growth) and created many research tools and drug compounds to probe it.
The team showed that a compound that activates PKM2 could stop abnormalities in mouse models of diabetes.
Joslin scientists plan to explore kidney disease across a much broader sample of people with diabetes to see if the mechanisms can work across both type 1 and type 2 diabetes.
“Anything we could do to delay the progression of diabetic kidney disease would be very helpful, because the need is great and there hasn’t been a new drug in decades,” King says.
“This approach also may prove help defend against eye, nerve or other complications of diabetes.”
JDRF was a lead funder of this work. Sanjoy Dutta, JDRF Assistant Vice President, Translational Development & International Partnerships, noted, “JDRF is proud to have supported this research that will ultimately improve the lives of people with type 1 diabetes. Realising the importance of taking lessons from human biology, JDRF supported the Joslin Medalist Program that studies individuals with long standing T1D to better understand the progression of diabetes and accelerate development of innovative therapies to thwart the complications associated with diabetes, without the necessity of extreme measures like dialysis or a kidney transplant.”
What’s happening in Australia?
Australia is recognised as a world leader in the field of complications. JDRF is currently funding five Australian projects investigating different pathways in the body and their role in kidney disease in type 1 diabetes. Supporting this is the JDRF/NHMRC-funded Centre for Research Excellence in diabetic complications. This Centre aims to translate new experimental findings into strategies for the prevention, treatment and management of type 1 diabetes and its complications, as well as training clinical investigators in the field. The T1DCRN, led by JDRF, is also funding a large clinical trial and a Career Development Award dedicated to reducing kidney disease in T1D.