February 24, 2021

Identification of an anti-diabetic, orally available small molecule that regulates TXNIP expression and glucagon action

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Shalev articleAnath Shalev, M.D., professor in the Department of Medicine and director of the UAB Comprehensive Diabetes Center, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members.

Shalev’s study, “Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action,” published in Cell Metabolism, researched new therapies for diabetes.

Shalev and her team explored root causes of diabetes, like pancreatic islet dysfunction and imbalance of glucose-lowering insulin and glucose-raising glucagon, as well as new therapeutics that would target these underlying causes.

Shalev says, “No oral medications are currently available for type 1 diabetes and none of the approved therapies target the additional problems associated with diabetes, namely the elevation in glucagon (a hormone that leads to even higher blood sugar) and the increase in TXNIP (a detrimental protein that leads to death of insulin-producing pancreatic islet cells).”

“Our studies now show that a newly designed, orally available small molecule, lowered TXNIP and glucagon and showed strong anti-diabetic effects in mouse models of type 1 and type 2 diabetes. In addition, this small molecule performed even better than some of the top anti-diabetic drugs currently available and its pharmacological and safety profiles were also very favorable making it an attractive novel diabetes drug candidate.”

This small molecule is called SRI-37330, and its success in animal models presents new hope to future research and treatment options for patients with diabetes. The burden of diabetes in Alabama is heavy, and Shalev’s work provides new opportunities to help remedy the epidemic across our state.

Read the full publication here.

The School of Medicine communications staff sat down with Dr. Shalev to gain insights about the research of this study, UAB, and the science community.

Q: What compelled you to pursue this research?

We discovered TXNIP almost 20 years ago as the top gene upregulated by glucose in human islets, and subsequently, as a major factor contributing to islet cell death and dysfunction. We then found that genetic deletion or non-specific pharmacological inhibition of TXNIP (with the blood pressure drug, verapamil) protected mice from type 1 and type 2 diabetes. More recently, our placebo controlled randomized clinical trial demonstrated that verapamil also had beneficial effects in subjects with recent onset type 1 diabetes and a number of epidemiological studies showed protective effects in terms of type 2 diabetes. Together, this suggested that a specific TXNIP inhibitor could provide a novel and effective therapeutic approach for type 1 and type 2 diabetes.

Q: How do you feel your research will impact the science community?

The results revive and underline the importance of glucagon as another hormone besides insulin having a major impact on blood sugar control in the context of diabetes.

Q: What is your research’s relevance to human disease?

Based on the promising effects in human islets and the increasing evidence of beneficial metabolic effects associated with inhibiting TXNIP signaling in humans, we believe that the chances of this particular work being translatable to humans is high. Also, currently no oral medications are available for type 1 diabetes and none of the current therapies target the elevated glucagon or the increased TXNIP associated with diabetes. The novel small molecule drug is therefore clearly addressing an unmet need.

Because of this, we are committed to move this work into a phase 1 trial and hopefully ultimately into humans affected by diabetes. At the moment, we are exploring potential partnerships to do so as safely and quickly as possible.

Q: How has being at UAB and living in Birmingham affected your research?

The south of the U.S. is often referred to as the ‘diabetes belt’ and Alabama is the ‘buckle’ of this belt. In fact, our state consistently ranks in the top three in terms of diabetes prevalence and over 15% of adults have diabetes (over 20% in some counties). In addition, over 30,000 Alabamians are newly diagnosed with diabetes every year. This obviously represents a great challenge, but also a mandate and an opportunity. It serves as a reminder that by focusing on diabetes research at UAB, we can make a big difference locally and in our community. Indeed, the community leadership in Birmingham has been extremely supportive of our work, and continues to champion our research efforts and many of the advances to date would not have been possible without this commitment.

Q: What do you find makes the science community here (at UAB) unique?

The science community at UAB is extremely collaborative. In addition, with the growth of our Comprehensive Diabetes Center as a University-Wide Interdisciplinary Research Center (UWIRC), we have built a strong, highly successful and unique team capable of dealing with a complex disease such as diabetes. In fact, now the 250 faculty members of the UAB Comprehensive Diabetes Center come from all 10 schools on campus, and the ongoing work spans the full spectrum of basic, translational, clinical and outcomes research.