Diabetes, metabolic syndrome in mice treated with a new class of compounds – Washington University School of Medicine in St. Louis

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Improves insulin secretion, lowers blood sugar

Susheel K. Gunasekar (Sah Lab), Pratik R. Chheda (Kerns Lab)

A study in mice – conducted by researchers at Washington University School of Medicine in St. Louis – shows that a new class of compounds developed by scientists can improve multiple aspects of metabolic syndrome. An increasingly common group of conditions that often occur together, metabolic syndrome includes type 2 diabetes, high cholesterol, fatty accumulation in the liver, and excess body fat, especially around the cut. This syndrome often leads to cardiovascular disease, the leading cause of death worldwide.

The study is published in the journal Nature Communications.

By testing one of the compounds called SN-401, researchers found that it treats diabetes by improving the ability of the pancreas to secrete insulin and by stimulating the ability of other tissues to use this insulin to eliminate more blood sugar effectively. In an effort to optimize the treatment, the researchers refined the compound – creating a class of related compounds – based on their studies of a key protein called SWELL1 (also LRRC8a). The progressive decline of this protein may have a central role in the development of diabetes and other aspects of the metabolic syndrome.

“Our goal is to develop better therapies for cardiovascular diseases, including diabetes and metabolic syndrome, which are major risk factors for worsening heart and vascular problems,” said lead author Rajan Sah, MD. , PhD, Associate Professor of Medicine. “We have many treatments for diabetes, but even with these therapies, cardiovascular disease remains a major cause of death in patients with type 2 diabetes. There is a need for new treatments that work differently from current standard therapies. . »

The protein studied by Sah and his colleagues is called SWELL1 because of its role in sensing the size or volume of cells. Their new research reveals that the protein also helps control insulin secretion from the pancreas and improves insulin sensitivity, including in skeletal muscle and adipose tissue, the body’s fat stores.

Surprisingly, the researchers showed that SWELL1 performs these two seemingly independent tasks because the protein has a previously unknown double life. It acts as a signaling molecule, activating cellular tasks that regulate how cells use insulin and also facilitates the secretion of insulin from the pancreas into the bloodstream.

“This protein, SWELL1, has a kind of split personality,” Sah said. “The compound binds to SWELL1 in a manner that stabilizes the protein complex to enhance expression and signaling in multiple tissues, including adipose tissue, skeletal muscle, liver, inner lining of blood vessels and pancreatic islet cells. This restores both insulin sensitivity in all tissue types and insulin secretion in the pancreas.

Sah and colleagues showed that compound SN-401 improved several aspects of metabolic syndrome in two groups of mice that each developed diabetes from different causes, one due to genetic predisposition and the other due to a high-fat diet. In addition to improving insulin sensitivity and secretion, treatment with the compound also improved blood sugar levels and reduced fat accumulation in the liver. Most of these studies were conducted with an injected form of the compound, but researchers have shown that it can also be effective if taken orally.

The researchers further showed that the compound did not have a large impact on blood sugar levels in healthy mice, which is important for its potential as a possible future therapy. Current diabetes medications can cause blood sugar levels to drop too low. Evidence suggests that this compound does not lower blood sugar in situations where it is not needed.

Sah worked with the University of Washington’s Office of Technology Management to patent the class of compounds and co-founded a startup called Senseion Therapeutics Inc., which is developing small molecule drugs that act on SWELL1. The company was first supported by funding from the university’s Leadership Entrepreneurship Acceleration Program (LEAP), and also recently received three Small Business Innovation Research Grants (SBIR ) totaling $4.5 million. SBIR grants are funded by the National Institutes of Health (NIH) Small Business Seed Fund.

This work was supported by the National Institutes of Health (NIH), the number of P30CA086862 subsidies P30DK020579, T32GM008365, GM123496, GM128263, P30 DK056341, UL1 TR000448, T32 HL130357, R01DK115791, R01DK106009, R01DK126068, R01DK127080, R43 DK121598 and R44 DK126600; the John L. & Carol E. Lach Chair in Drug Delivery Technology; grants from the New York Stem Cell Foundation; a McKnight Foundation Scholarly Award; a Rose Hill Innovator Award; a Sloan Fellowship; the Leadership Entrepreneurship Acceleration Program (LEAP) at the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship at Washington University in St. Louis; and the Roy J. Carver Trust, University of Iowa.

Gunasekar SK et al. Induction of the small molecule SWELL1 complex improves glycemic control and non-alcoholic fatty liver disease in murine type 2 diabetes. Communication Nature. February 10, 2022.

The 1,700 doctors at Washington University School of Medicine are also on the medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care, and is currently #4 in National Institutes of Health (NIH) research funding. Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked to BJC HealthCare.

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