Tested on isolated human and mouse pancreatic subjects, mouse and rat cell cultures and animal models of Type 1 and Type 2 diabetes, the experimental drug significantly improved four detrimental characteristics of diabetes: high blood sugar; elevation in the hormone glucagon that counteracts the effects of insulin, promotes glucose production and increases blood glucose; excessive production of glucose by the liver; and fatty liver.
The drug candidate SRI-37330 is a nontoxic small molecule that effectively rescued mice from streptozotocin- and obesity-induced diabetes and improved glucose homeostasis.
A study published in the journal Cell Metabolism describes the strong anti-diabetic properties of this newly designed chemical compound. The researchers, led by Dr. Anath Shalev, director of UAB’s Comprehensive Diabetes Center, said that “compared to currently available diabetes therapies, the compound may provide a distinct, effective and highly beneficial approach to treat diabetes.”
“While the safety and efficacy of SRI-37330 in humans still remains to be determined,” Shalev said, “it is highly effective in human islets, is orally bioavailable and is well-tolerated in mice.”
SRI-37330 was discovered through two decades of research by Shalev, followed by high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization at Southern Research, headquartered in Birmingham.
Diabetes is a disease affecting two hormones – insulin and glucagon. In healthy people, insulin helps cells take glucose from the blood when glucose levels are high. Glucagon helps the liver release glucose into the bloodstream when glucose levels are low. In diabetes, insulin release is diminished, cell sensitivity to insulin can decrease and glucagon release is excessive. This can cause a vicious cycle of escalating blood glucose levels.
SRI-37330 appears to act beneficially on pancreatic areas that produce the two hormones, and also at the liver.
Diabetes affects 425 million people worldwide and more than 30 million in the United States. It is a growing epidemic, with 1.5 million Americans newly diagnosed each year. The preclinical studies led by Shalev suggest that the drug could be beneficial in both Type 1 and Type 2 diabetes in lean and obese individuals. Diabetes appears to be a significant factor in the COVID-19 pandemic.
The 80 million people in the United States who have prediabetes might also benefit from the potential drug. The effectiveness of SRI-37330 in reducing fatty liver in mice suggests it might have potential to treat nonalcoholic fatty liver disease, which affects about 100 million people in the U.S. and 1 billion worldwide.
The path to discovery of SRI-37330 began 18 years ago when Shalev and colleagues identified the protein TXNIP – pronounced “tix-nip” – as the top glucose-induced gene in human islets, which are the cell groups in the pancreas that produce insulin and glucagon. This was followed by the researchers’ work showing that TXNIP negatively affected islet function and survival, suggesting that TXNIP might play an important role in treating diabetes.
In previous research, Shalev and colleagues showed that TXNIP was increased in different mouse models of diabetes and in diabetic human islets, and that deletion of the TXNIP gene protected mice from diabetes and had beneficial effects on pancreatic islet biology. Altogether, these data suggested that a search for a TXNIP inhibitor could provide a novel approach to diabetes treatment.
Some of the details of the current study – which covers 10 years of work – involve the inhibitory effect of SRI-37330 on the TXNIP gene. SRI-37330 inhibited activity of the TXNIP promoter by 70%.
RNA sequencing of isolated human pancreatic islets treated with SRI-37330 showed that TXNIP signaling was inhibited.
SRI-37330 is effective in reducing TXNIP and shows no toxicity in mice, even at doses about tenfold above its therapeutic dose.
Adding SRI-37330 to the drinking water of obese diabetic mice, that modeled severe Type 2 diabetes, led within days to normalization of their blood glucose. SRI-37330 also protected mice from a model of Type 1 diabetes. Of note, SRI-37330 achieved better blood glucose control than two of the leading oral anti-diabetic drugs: metformin and empagliflozin.
“Together with the fact that SRI-37330 was also effective after the onset of overt diabetes, as well as when just dosed twice a day by oral gavage, is particularly promising and raises the possibility that SRI-37330 may ultimately lead to a much-needed oral drug that could also be used for Type 1 diabetes,” Shalev said.
SRI-37330 decreased blood glucose levels primarily by lowering serum glucagon levels and inhibiting basal glucose production from the liver. This mode of action is very different from that of currently used anti-diabetic drugs, Shalev said.
In another surprising result – and in contrast to previous attempts to inhibit glucagon function for the treatment of diabetes – the inhibitor dramatically improved the severe fatty liver in obese diabetic mice. “This now raises the intriguing possibility,” Shalev said, “that SRI-37330 might also be beneficial in the context of nonalcoholic fatty liver disease, a complication frequently associated with diabetes and/or obesity.”
Co-authors with Shalev on the study, “Identification of an anti-diabetic, orally available, small molecule that regulates TXNIP expression and glucagon action,” are Lance Thielen, Junqin Chen, Gu Jing, Guanlan Xu, SeongHo Jo, Truman B. Grayson and Brian Lu, UAB Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism; Omar Moukha-Chafiq, Corinne Augelli-Szafran and Mark Suto, Drug Discovery Division, Southern Research; Peng Li, UAB School of Nursing; Matt Kanke and Praveen Sethupathy, College of Veterinary Medicine, Cornell University, Ithaca, New York; and Jason Kim, University of Massachusetts Medical School, Worcester, Massachusetts.
Support came from National Institutes of Medicine grants and from the Alabama Drug Discovery Alliance.
At UAB, Shalev is a professor in the Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.
This story originally appeared on the University of Alabama at Birmingham’s UAB News website.