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Preventing Beta Cell Destruction in T1DM

Surabhi Dangi-Garimella, PhD
While diabetes continues to be a major global health concern, disease management, not cure, remains the steadfast goal. According to the 2014 National Diabetes Statistics Report from the CDC, a steady increase in the number of diabetic patients has been observed since 2010: 29.1 million Americans were estimated to have diabetes in 2012, up from 25.8 million in 2010, including more than 8 million who were undiagnosed. Hyperglycemia, however, is not a health condition managed in isolation; in addition to serious complications associated with disease progression (eg, microvascular disease, blindness, and lack of wound healing), diabetes also increases one’s susceptibility to cardiovascular disease, dyslipidemia, stroke, and kidney disease. A tremendous influence on the overall health of an individual, diabetes associated healthcare costs amount in the billions. The cost in the United States alone was estimated at $245 billion in 2012, and 30% of the expenses were calculated as being indirect, such as those due to loss of productivity.1
 
Type 1 diabetes mellitus (T1DM), previously known as juvenile diabetes, is diagnosed in only 5% of people with hyperglycemia.2 An autoimmune disorder that results in the immune-mediated destruction of the pancreatic β cells that produce insulin, T1DM can affect both children and young adults, resulting in a lifetime of insulin therapy.
 
ALTERNATIVES TO INSULIN
 
Several out-of-the-box approaches are being evaluated in T1DM patients to save them the misery of everyday insulin treatment. One such approach is transplanting these patients with functional insulinproducing β cells that have been differentiated from human pluripotent stem cells (hPSCs). A collaborative study between the Harvard Stem Cell Institute and the Diabetes Center of Excellence at the University of Massachusetts generated functional human β cells from hPSCs in vitro without any genetic alterations of the cells. The β cells, which were generated following sequential differentiation resulting from high-glucose challenges, were structurally and functionally similar to pancreatic β cells. Mice transplanted with these cells could secrete insulin and reduce hyperglycemia.3
 
Another approach has been to regulate a person’s immune system to suppress the autoimmune response generated in individuals with T1DM, the hypothesis being that a personalized approach to modulating the immune system could cure patients. While generalized immune suppression is not a feasible option—considering the associated adverse effects—procedures such as autologous hematopoietic stem cell therapy could prove useful. Clinical immune interventions have been conducted, but immune-modulators such as rituximab and otelixizumab showed functional variability based on age and ethnicity.4
 
Vaccination with HLA-binding peptide epitopes is another option, though several challenges remain, including a person’s HLA haplotype, defining the route of administration, and the dose and frequency of administration. Trials examining the efficacy of cell therapy with FOXP3+ TREG cells to halt T1DM progression are presenting encouraging results in preliminary studies. However, the specificity of the FOXP3+ TREG cells to selectively suppress islet autoimmunity, as well as stability of their cells, remains questionable.4
 
REPURPOSING THE CALCIUM CHANNEL BLOCKER VERAPAMIL
 
In their attempt to find a cure for T1DM and to help rid patients of their daily insulin dose, investigators at the University of Alabama at Birmingham (UAB) have designed a clinical trial to evaluate the blood pressure medication verapamil for use in T1DM.5 To be initiated early this year, the trial, funded by a multi-million dollar grant from the Juvenile Diabetes Research Foundation, is based on preliminary evidence from a mouse model, which showed that the commonly used blood pressure medication could completely reverse diabetes in mice.6
 
Research conducted in the laboratory of Anath Shalev, MD, director of UAB’s Comprehensive Diabetes Center, found that administering oral verapamil could prevent β-cell death in mice with T1DM. How? The authors found that verapamil repressed the expression of thioredoxin-interacting protein (TXNIP), a gene whose glucose-regulated expression is induced in the islets of diabetic individuals, resulting in β-cell death.6 TXNIP also induces the expression of IL-1β, a cytokine that promotes T1DM. Following their discovery that verapamil can inhibit the expression of TXNIP,7 Shalev’s research team evaluated the drug in vitro in pancreatic β cells, and in vivo in mice, and found that verapamil-mediated downregulation of TXNIP prevented β-cell apoptosis, improved β-cell survival and function, and rescued mice from diabetes. Importantly, verapamil could regulate TXNIP expression only in the presence of elevated glucose levels, which offsets any unwanted side effects due to excessive reduction of TXNIP below physiological levels.6
 
THE VERAPAMIL TRIAL
 
The trial aims to enroll 52 people, 19 to 45 years of age, within 3 months of being diagnosed with T1DM. These patients will be initiated on a placebo or verapamil while on their insulin pump therapy, and blood glucose will be monitored using a continuous glucose monitoring system.5 In an e-mail, Shalev informed Evidence-Based Diabetes Management that the trial, which has already been initiated will continue to enroll adults within 3 months of being newly diagnosed with T1DM, until spring 2016. 
 
The current trial will follow patients for a period of 1 year after initiating verapamil. However, Shalev informed EBDM that funding permitted, encouraging results from the current trial would be followed-up with a longer-term trial to observe more sustained effects of verapamil. “We definitely would like to conduct a longer-term trial, as 1-year may indeed be rather short to see the full extent of the effects in humans. At that point, we would also like to expand our inclusion criteria to allow patients with slightly longer disease duration to participate,” wrote Shalev.
 
Although it’s early to predict verapamil adoption in practice, Shalev hopes it will be, considering that the molecule has already been used in clinic for other indications for 30 years. “So, adaptation into clinical practice would only require official repurposing. At least until more specific strategies are being developed and tested down the road, it would provide a unique approach trying to enhance the patient’s own beta cell mass and insulin production,” Shalev anticipates. Additional information on the project can be found at http://www.uab.edu/medicine/diabetes/new-clinical-trial.
References
 
1. National diabetes statistics report, 2014. CDC website. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed December 15, 2014.
 
2. General diabetes facts. JDRF website. http://jdrf.org/about-jdrf/fact-sheets/general-diabetes-facts/. Accessed December 16, 2014.
 
3. Pagliuca FW, Millman JR, Gürtler M, et al. Generation of functional human pancreatic cells in vitro. Cell. 2014;159(2):428-439.
 
4. Roep BO and Tree TIM. Immune modulation in humans: implications for type 1 diabetes mellitus. Nat Rev Endocrinol. 2014;10:229-242.

5. Greer T. In human clinical trial, UAB to test drug shown to completely reverse diabetes in human islets, mice. University of Alabama at Birmingham website. http://www.uab.edu/news/innovation/item/5508-in-human-clinical-trial-uab-to-test-drug-shown-to-completely-reverse-diabetes-in-humanislets-mice. Published November 6, 2014. Accessed December 5, 2014.
 
6. Xu G, Chen J, Jing G, Shalev A. Preventing cell loss and diabetes with calcium channel blockers. Diabetes. 2012;61:848-856.
 
7. Chen J, Cha-Molstad H, Szabo A, Shalev A. Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxininteracting protein. Am J Physiol Endocrinol Metab. 2009;296:E1133-E1139.
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