Oral drug shows benefits for treating type 1 diabetes for at least two years after diagnosis – News
The benefits of verapamil, a blood pressure medication, include delaying disease progression, reducing insulin requirements, and preserving certain beta cell functions.
Using the drug verapamil to treat type 1 diabetes continues to show benefit for at least two years, researchers report in the journal Nature Communications. Patients taking the oral high blood pressure medication not only needed less daily insulin two years after the disease was first diagnosed, but also showed evidence of surprising immunomodulatory benefits.
Continuous medication was necessary. In the two-year study, subjects who stopped daily doses of verapamil at one year saw their disease worsen at two years at rates similar to those in the control group of diabetic patients who did not use the drug at all. of verapamil.
Type 1 diabetes is an autoimmune disease that causes the loss of pancreatic beta cells, which produce endogenous insulin. To replace this, patients must take exogenous insulin by injection or pump and are exposed to dangerous events of hypoglycemia. There is currently no oral treatment for this disease.
The suggestion that verapamil could serve as a potential drug for type 1 diabetes was the serendipitous discovery of study leader Anath Shalev, MD, director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham. This discovery stems from more than two decades of his fundamental research on a pancreatic islet gene called TXNIP. In 2014, Shalev’s UAB Research Lab reported that verapamil completely reversed diabetes in animal models, and she announced plans to test the drug’s effects in a human clinical trial. The United States Food and Drug Administration approved verapamil for the treatment of high blood pressure in 1981.
In 2018, Shalev and colleagues reported the benefits of verapamil in a year-long clinical study of type 1 diabetic patients, finding that regular oral administration of verapamil allowed patients to produce higher levels of their own insulin, thus limiting their need for injected insulin to regulate blood sugar levels.
The current study builds on this finding and provides crucial mechanistic and clinical insights into the beneficial effects of verapamil in type 1 diabetes, using proteomic analysis and RNA sequencing.
To examine changes in circulating proteins in response to verapamil treatment, the researchers used tandem liquid chromatography mass spectrometry of blood serum samples from subjects diagnosed with type 1 diabetes within three months of diagnosis. and at one year follow-up. Fifty-three proteins showed significantly altered relative abundance over time in response to verapamil. These included proteins known to be involved in immune modulation and autoimmunity in type 1 diabetes.
The major serum protein altered by verapamil treatment was chromogranin A, or CHGA, which was down-regulated with treatment. CHGA is localized to secretory granules, including those of pancreatic beta cells, suggesting that altered levels of CHGA may reflect alterations in beta cell integrity. In contrast, elevated CHGA levels at the onset of type 1 diabetes did not change in control subjects who did not take verapamil.
CHGA levels were also easily measured directly in serum using a simple ELISA test after a blood draw, and lower levels in verapamil-treated subjects correlated with better endogenous insulin production. , measured by C-peptide boosted by mixed meals, a standard test for type 1 diabetes development. In addition, serum CHGA levels in healthy volunteers without diabetes were approximately two-fold lower than those in subjects with type 1 diabetes, and after one year of treatment with verapamil, subjects with type 1 diabetes treated with verapamil showed CHGA levels similar to healthy people. During the second year, CHGA levels continued to decline in subjects treated with verapamil, but increased in subjects with type 1 diabetes who discontinued verapamil during the second year.
“Thus, serum CHGA appears to reflect changes in beta-cell function in response to verapamil treatment or progression of type 1 diabetes and may therefore provide a longitudinal marker of treatment success or disease worsening. “, Shalev said. “This would fill a critical need, as the lack of a simple longitudinal marker has been a major challenge in the field of type 1 diabetes.”
Other labs have identified CHGA as an autoantigen in type 1 diabetes that causes immune T cells involved in autoimmune disease. Thus, Shalev and colleagues asked whether verapamil affected T cells. They found that several follicular helper T cell pro-inflammatory markers, including CXCR5 and interleukin 21, were significantly elevated in monocytes from subjects with type 1 diabetes, compared to healthy controls, and they found that these changes were reversed by treatment with verapamil.
“Now our results reveal for the first time that verapamil treatment can also affect the immune system and reverse these type 1 diabetes-induced changes,” Shalev said. “This suggests that verapamil, and/or the type 1 diabetes improvements achieved by it, may modulate certain circulating pro-inflammatory cytokines and helper T cell subsets, which in turn may contribute to the overall beneficial effects clinically observed.
To assess changes in gene expression, RNA sequencing of human pancreatic islet samples exposed to glucose, with or without verapamil, was performed and revealed a large number of genes that were either down-regulated up or down. Analysis of these genes showed that verapamil regulates the thioredoxin system, including TXNIP, and promotes an antioxidant, anti-apoptotic, and immunomodulatory gene expression profile in human islets. Such protective changes in pancreatic islets could further explain the sustained improvements in pancreatic beta-cell function observed with continued use of verapamil.
Shalev and his colleagues caution that their study, with its small number of subjects, needs to be confirmed by larger clinical studies, such as a current type 1 diabetes study of verapamil underway in Europe.
But the preservation of some beta cell functions is promising. “In humans with type 1 diabetes, even a small amount of preserved endogenous insulin production – as opposed to higher exogenous insulin requirements – has been shown to be associated with better outcomes and may contribute to improved quality of life and reduce the high costs associated with insulin use,” Shalev said. lends further support to its potential usefulness for long-term treatment.”
At UAB, Shalev is a professor in the Division of Endocrinology, Diabetes, and Metabolism Medicine, and holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.
Co-authors with Shalev, in the Nature Communications report “Exploratory study reveals wide-ranging systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes”, are Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen, Lance A. Thielen, and Fernando Ovalle, UAB Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism; Hubert M. Tse, UAB Microbiology Department; Peng Li, UAB School of Nursing; Matt Kanke and Praveen Sethupathy, College of Veterinary Medicine, Cornell University, Ithaca, New York; and Tai-Tu Lin, Athena A. Schepmoes, Adam C. Swensen, Vladislav A. Petyuk, and Wei-Jun Qian, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
Support came from National Institutes of Health grants DK078752, Human Islet Research Network DK120379, DK110844, and DK122160; and the American Diabetes Association Pathway Award 1-16-ACE-47.
UAB’s Departments of Medicine and Microbiology and the UAB Comprehensive Diabetes Center are part of the Marnix E. Heersink School of Medicine.