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Type 2 Diabetes Signalling [1]

['This Content Is Not Subject To Review Daily Kos Staff Prior To Publication.']

Date: 2023-12-13

New cause of diabetes discovered, offering potential target for new classes of drugs to treat the disease

Researchers have identified an enzyme that blocks insulin produced in the body -- a discovery that could provide a new target to treat diabetes. The study 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.

On the opposite side, a lack of nitric oxide signalling is fundamental to erectile dysfunction.

"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. 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.

Cell [paywalled]: An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling

SCAN catalyzes protein S-nitrosylation using S-nitroso-CoA as a cofactor

S-nitrosylation of insulin receptor and IRS1 by SCAN regulates insulin signaling

Hypernitrosylation of INSR and IRS1 by SCAN causes diabetes

SCAN expression correlates with human BMI and INSR S-nitrosylation

For those who want to dive deeper into this molecular biology:

Proceedings of the National Academy of Sciences

Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation

We find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6 [in yeasts]. Our studies reveal a novel functional class of enzymes that regulate protein S-nitrosylation from yeast to mammals and suggest that SNO-CoA–mediated S-nitrosylation may subserve metabolic regulation.

There has been talk of doing clinical trials for years, but I don’t see any happening.

"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. 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.

Cell [paywalled]: An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling

SCAN catalyzes protein S-nitrosylation using S-nitroso-CoA as a cofactor

S-nitrosylation of insulin receptor and IRS1 by SCAN regulates insulin signaling

Hypernitrosylation of INSR and IRS1 by SCAN causes diabetes

SCAN expression correlates with human BMI and INSR S-nitrosylation

For those who want to dive deeper into this molecular biology:

Proceedings of the National Academy of Sciences

Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation

We find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6 [in yeasts]. Our studies reveal a novel functional class of enzymes that regulate protein S-nitrosylation from yeast to mammals and suggest that SNO-CoA–mediated S-nitrosylation may subserve metabolic regulation.

There has been talk of doing clinical trials for years, but I don’t see any happening.

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