The Future Of Curing Type 1 Diabetes

Author: Nazeen Shah

From: New York, USA

“Hold still”, said the doctor.

My breath deepened and time stood still as the terrifying needle paced closer towards my skin. On August 18, 2012, I was diagnosed with type 1 Diabetes (T1D), an alien term to my eight-year-old-self, but I soon learned its nature. I came to realize that an 8mm needle would have to accompany every bit of food I ingested. While living with trypanophobia and in denial for years, I came face-to-face with reality and began to research for potential adaptive and mitigative cures.

Potential Adaptive Cure - Beta Cells

At Harvard University, I studied regenerative medicine and I’ve identified its ability to formulate a cure for type 1 diabetes (T1D). T1D constitutes a consequence of immune-mediated beta cell destruction. Beta cells are specialized cells within a cell cluster called the Islets of Langerhans which also consists of alpha cells, delta cells, and blood vessels (Figure 1 [4]). Non-diabetic patients contain functioning beta cells that produce insulin, whereas diabetic patients do not. Humans need insulin to regulate blood sugar levels and without it, these constant high blood sugar levels will lead to several cardiovascular, neuropathic, and physiological complications.

Figure 1

Researchers now ask, how can we undo beta cell destruction and prevent these health issues? The answer is in finding cellular therapies where reprogrammed human embryonic stem cells or human pluripotent stem cells become insulin-producing beta cells. (Figure 2 [5]) A research study group at the Mayo Clinic reported that human embryonic stem cells after guided differentiation to pancreatic hormone-expressing cells generated up to 12% of insulin-expressing cells [1,2] This shows that embryonic stem cells can produce markers of beta cell functionality. Furthermore, more characteristics of pancreatic beta cells include PDX1, NKX6.1, NEUROD1, ISL-1, and GLUT2. Co-expression of insulin and PDX1 was evident in insulin-producing cells derived from induced pluripotent stem cells as well. Past experiments have shown limited PDX1 expression in embryonic-stem-cell-derived insulin-producing cells and the Mayo Clinic found prevalent insulin/PDX positive cells after stem cell differentiation. Moreover, these islet-like cells secreted C-peptide, another characteristic of insulin production, in response to glucose stimulation. These findings confirm the potential of differentiating stem cells into functional beta-like cells and how T1D may be cured through adaptable scientific approaches.

Figure 2

Potential Mitigative Cure - T Cells

While T1D may be cured adaptively, there’s potential to cure it mitigatively. If we can prevent these destructions, stem cell therapies won’t be necessary. Now we ask, what destroys the beta cells in the first place? The answer is T cells. T cells are ordered to attack antigens (“tags”) that antibodies have marked. When a T-cell receptor fits with its viral antigen on the “foreign” cell, killer T-cell releases cytotoxins and destroys that cell (Figure 3 [6]).

Figure 3

The problem presented is that beta cells are not foreigners. This beta cell misidentification can change someone’s life significantly. While there are “good” T cells known as T regulatory cells, they are not successful in halting this process. Now, how can we stop these T cells from destroying beta cells? That question leaves millions of diabetes researchers in question today. Researcher Honaker from Seattle Children’s Research Institute, along with other researchers, designed a gene-editing approach to expressing FOXP3, the master T regulatory cell transcription factor, in cytotoxic T cells isolated from human peripheral blood. They found that the resulting FOXP3 expression stimulated a preventative phenotype in vitro which models a dysfunctional T cell. Furthermore, the edited cells were also functional in a xenogeneic graft-versus-host disease model and an experimental autoimmune encephalitis model. [3] With this data, genetic engineering of T cells sheds a positive light on a cure for type 1 diabetes.

Conclusion

T1D, a disease that affects almost 10% of the population globally, results from immune-mediated beta cell destruction. Despite major improvements and advancements in insulin therapy and technology, T1D remains a very burdensome disease to manage. Whether we find a cure from fixing destroyed beta cells (adaptive) or destroying the destroyer of beta cells (mitigative), we are one step closer to stimulating insulin production in diabetics. We must spread awareness of different scientific technologies and continue to build our background knowledge on autoimmune diseases. Additionally, teaching and inspiring other type 1 diabetics to research their disease will stimulate extensive reform. By joining and supporting organizations like the American Diabetes Association and the Juvenile Diabetes Research Foundation, we can save lives.

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Author: Nazeen Shah

Nazeen, a high school student in New York plans on revolutionizing type 1 diabetes research. She believes encouraging others to view autoimmune disease with a parallax mindset will lay the foundation for potential cures.

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1. Thatava T, Nelson TJ, Edukulla R, et al. Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Ther. 2011;18(3):283-293. doi:10.1038/gt.2010.145

2. D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006;24:1392–1401.

3. Honaker, Y., Hubbard, N., Xiang, Y., Fisher, L., Hagin, D., Sommer, K., . . . Rawlings, D. J. Gene editing to induce FOXP3 expression in human CD4+ T cells leads to a stable regulatory phenotype and function. Science Translational Medicine. 2020;12(546). doi:10.1126/scitranslmed.aay6422

4. [Pancreatic islets contain beta cells that produce the hormone insulin.]. (2018, October). Retrieved from https://www.niddk.nih.gov/health-information/diabetes/overview/insulin-medicines-treatments/pancreatic-islet-transplantation

5. Harlan, D. M. (n.d.). Reconstructing Type 1 Diabetes [Digital image].

6. [Beta Cell Destruction vs. Normal Tissue]. (n.d.). Retrieved from https://managingdiabetes101.weebly.com