Promising new drug target to treat diabetes and other metabolic diseases

A new preclinical study has demonstrated how an experimental drug can treat type 2 diabetes by increasing the expression of a recently discovered protein found to influence insulin signaling in cells. Across several mouse studies, the research shows the novel compound improved aspects of metabolic syndrome associated with diabetes.

In the early 2000s, a protein dubbed SWELL1 was identified and it was initially thought to solely play a role in lymphocyte function. Around a decade later, researchers discovered SWELL1 also influences insulin signaling in many tissues across the body. Subsequent study revealed SWELL1 activity is vital for normal insulin secretion from pancreatic cells. And, SWELL1 activity seems to be significantly disrupted in type 2 diabetic patients.

“Since T2D [type 2 diabetes] is characterized by both a loss of insulin sensitivity of target tissues (fat, skeletal muscle, liver) and ultimately, impaired insulin secretion from the pancreatic β-cell, these data raised the question: could impaired SWELL1-mediated signaling contribute to T2D pathogenesis, and if so, could this be corrected pharmacologically to improve systemic glycemia?” the researchers wrote in the new study.

Rajan Sah, senior author on the study, says SWELL1 has a double life, affecting insulin sensitivity in a number of cells across the body, while at the same time influencing insulin secretion from the pancreas. So his team developed a molecule called SN-401 to augment SWELL1 expression in the hopes it could normalize metabolic function in diabetic animals.

“This protein, SWELL1, has a sort of dual personality,” explained Sah. “The compound binds to SWELL1 in a manner that stabilizes the protein complex so as 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.”

Across several mouse experiments the new study showed SN-401 improved metabolic markers of diabetes, from increasing insulin sensitivity and secretion to normalizing glycemia in diabetic animals. Most significantly, the researchers found the novel drug did not impact blood sugar levels in healthy animals. Instead, it normalized glucose tolerance, meaning it didn’t seem to lower blood sugar levels when those levels were healthy.

Promisingly, the new study indicates targeting SWELL1 signaling could broadly treat a number of metabolic diseases beyond just type 2 diabetes. This includes certain types of cardiovascular disease and a condition called NASH, a severe form of nonalcoholic fatty liver disease. Sah has recently formed a startup to investigate commercial drug outcomes from his SN-401 research, so it may be several years before human clinical work beings to validate these findings.

“The current study provides an initial proof-of-concept for pharmacological induction of SWELL1 signaling using SWELL1 modulators (SN-40X) to treat metabolic diseases at multiple homeostatic nodes, including adipose, skeletal muscle, liver, and pancreatic β-cell, whereby SN-40X compounds function to restore both insulin sensitivity and insulin secretion,” the researchers conclude in the new study. “Hence, SN-401 may represent a tool compound from which a novel drug class may be derived to treat T2D, NASH, and other metabolic diseases.”

The new study was published in the journal Nature Communications.

Source: Washington University School of Medicine in St. Louis

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