Study reveals insights into tacking diabetic kidney disease - with a side order of how anti-obesity drugs work
How a new drug for diabetes gives clues to how anti-obesity drugs work
Data from Australian researchers could partly explain why a trial of a new drug for diabetes, was recently halted because it was found to be so effective. Importantly, the data also reveals how anti-obesity drugs like Ozempic, actually work, which to date have been a mystery.
In early November the FLOW trial of the drug semaglutide on the progression of renal impairment in people with type 2 diabetes and chronic kidney disease was halted ahead of schedule because of the drug’s efficacy.
Part of the rationale for the cessation of the trial could be explained by research led by Monash University’s Associate Professor Melinda Coughlan, and published today in the journal, Kidney International, showing that a drug that targets a particular hormone GLP1, also interacts with a receptor called RAGE, to control the kidney damage that is the hallmark of Type 2 diabetes.
The discovery of the importance of RAGE opens up new therapeutic drug targets for the prevention of kidney disease in people with diabetes. Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes. According to Associate Professor Coughlan, the outlook for DKD has improved over recent decades as a result of improved blood glucose control and blood pressure management through new therapies, “however, a significant proportion of individuals with diabetes will still progress to end stage kidney disease or die prematurely from a cardiovascular event,” she said.
“Our study opens up a way to potentially prevent kidney disease in those people who are, so far, treatment resistant.”
According to another co-author of the study, Professor Mark Cooper, also from Monash University’s Central Clinical School, the discovery of how the RAGE receptor works in diabetes, could also explain how the obesity drug, Ozempic, and similar drugs targeting obesity, work. “To date we know these drugs, which were developed to tackle diabetes, help with weight loss, however their mode of action has not been understood, particularly in reducing diabetic complications including kidney disease” he said.
“We know that the RAGE receptor promotes kidney injury but by blocking interactions between drugs such as Ozempic and this RAGE receptor we now have new information to expand and develop new drugs to protect the kidney.
JOURNAL
Kidney International
ARTICLE TITLE
Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products -induced inflammation
New cause of diabetes discovered, offering potential target for new classes of drugs to treat the disease
Peer-Reviewed PublicationIMAGE:
JONATHAN STAMLER
view moreCREDIT: CASE WESTERN RESERVE UNIVERSITY
Dec. 8, 2023
CLEVELAND—Researchers at Case Western Reserve University and University Hospitals have identified an enzyme that blocks insulin produced in the body—a discovery that could provide a new target to treat diabetes.
Their study, published Dec. 5 in the journal Cell, focuses on nitric oxide, a compound that dilates blood vessels, improves memory, fights infection and stimulates the release of hormones, among other functions. How nitric oxide performs these activities had long been a mystery.
The researchers discovered a novel “carrier” enzyme (called SNO-CoA-assisted nitrosylase, or SCAN) that attaches nitric oxide to proteins, including the receptor for insulin action.
They found that the SCAN enzyme was essential for normal insulin action, but also discovered heightened SCAN activity in diabetic patients and mice with diabetes. Mouse models without the SCAN enzyme appeared to be shielded from diabetes, suggesting that too much nitric oxide on proteins may be a cause of such diseases.
“We show that blocking this enzyme protects from diabetes, but the implications extend to many diseases likely caused by novel enzymes that add nitric oxide,” said the study’s lead researcher Jonathan Stamler, the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation at the Case Western Reserve School of Medicine and president of Harrington Discovery Institute at University Hospitals. “Blocking this enzyme may offer a new treatment.”
Given the discovery, next steps could be to develop medications against the enzyme, he said.
The research team included Hualin Zhou and Richard Premont, both from Case Western Reserve School of Medicine and University Hospitals, and students Zack Grimmett and Nicholas Venetos from the university’s Medical Science Training Program.
Many human diseases, including Alzheimer’s, cancer, heart failure and diabetes, are thought to be caused or accelerated by nitric oxide binding excessively to key proteins. With this discovery, Stamler said, enzymes that attach the nitric oxide become a focus.
With diabetes, the body often stops responding normally to insulin. The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems. Individuals with diabetes, the Centers for Disease Control reports, are more likely to suffer such conditions as heart disease, vision loss and kidney disease.
But the reason that insulin stops working isn’t well understood.
Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can’t be targeted specifically, Stamler said.
“This paper shows that dedicated enzymes mediate the many effects of nitric oxide,” he said. “Here, we discover an enzyme that puts nitric oxide on the insulin receptor to control insulin. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases.”
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About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 21 hospitals (including five joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Northeast Ohio Medical University, Oxford University, the Technion Israel Institute of Technology and National Taiwan University College of Medicine. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.
JOURNAL
Cell
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling
ARTICLE PUBLICATION DATE
5-Dec-2023
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