In a study published in the journal Nature Communications, researchers from Washington University School of Medicine in St. Louis highlight the importance of their work in developing a new class of compounds based on a protein that they assert plays a vital role in the modulation of metabolism. When this protein declines, there is an increased risk of metabolic diseases, including diabetes.

Senior author Rajan Sah, MD, PhD, associate professor of medicine, and colleagues, embarked on their study to provide evidence that SWELL1-mediated currents and SWELL1 protein are reduced in both mouse and human adipocytes and pancreatic beta-cells in the setting of type 2 diabetes (T2D) and hyperglycemia. SWELL1 (also LRRC8a) is a key protein that gradually declines with age and illness.
 
The authors wrote, "The gradual decline of this protein may have a central role in the development of diabetes and other aspects of metabolic syndrome." The team suggested that dysfunction in the signaling cascade likely contributes to impaired insulin secretion and sensitivity and increasing the risk of developing T2D, suggesting that dysfunctional SWELL1-mediated signaling could contribute to T2D pathogenesis by impairing insulin sensitivity and insulin secretion.

Dr. Sah stated, "This protein, SWELL1, has a sort of dual personality," and elaborated further, saying, "The compound binds to SWELL1 in a manner that stabilizes the protein complex to enhance expression and signaling across multiple tissues, including adipose, skeletal muscle, liver, the inner lining of blood vessels, and pancreatic islet cells. This restores both insulin sensitivity across tissue types and insulin secretion in the pancreas."

One of the compounds they developed was referred to as SN-401, which they tested and found enhances the ability of peripheral tissues to utilize insulin more effectively, removing glucose from the bloodstream, and increases the ability of the pancreas to secrete even more insulin. The authors wrote that in vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion in insulin-resistant T2D mouse models, while augmenting tissue glucose uptake, suppressing hepatic glucose production, inducing serum FGF21 levels, and reducing hepatic steatosis and hepatocyte damage in obese T2D mice. They refer to this new compound as a "chemical chaperone" that augments SWELL1 expression and plasma membrane concentrations.

"Our goal is to develop better therapies for cardiovascular disease, including diabetes and metabolic syndrome, which are major risk factors for worsening heart and vascular problems," stated Dr. Sah. "We have many treatments for diabetes, but even with those therapies, cardiovascular disease remains a leading cause of death among patients with type 2 diabetes. There is a need for new treatments that work differently from the current standard-of-care therapies."

The research was conducted on pancreatic beta cells freshly isolated from mice with induced T2D and compared with healthy mice. This allowed the researchers to further demonstrate that the new compound did not significantly impact blood glucose in the healthy subjects, which would be a novel departure from current medication that can cause hypoglycemia.

The authors concluded that SWELL1 channel modulators improve SWELL1-dependent, systemic metabolism in T2D, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

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