key: cord-0252533-8tj3qai6 authors: Fanaropoulou, Nina Maria title: Hope Injections: The Promises of Regenerative Medicine in Curing Type 1 Diabetes Mellitus date: 2021-10-18 journal: EJIFCC DOI: nan sha: 0fd91770ee1fa67302fd641a83b9437e7eae12b3 doc_id: 252533 cord_uid: 8tj3qai6 nan This is a Platinum Open Access Journal distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. One evening of 2006, my mother announced that scientists had made a groundbreaking discovery. By 2012, we would be having the first "vaccine" against type 1 diabetes mellitus (T1D), and so my chronic disease would finally come to an end. It was the most fascinating news I had heard as a 9-year-old. T1D is a chronic autoimmune endocrine condition, caused by a faulty recognition of self and foreign antigens by the immune system 1 . It attacks the insulinproducing beta cells of the islets of Langerhans in the pancreas; insulin is a vital hormone for blood glucose control. Without it, patients must turn to insulin injections multiple times daily, adjusting doses to fluctuations in food, activity and numerous other 2012 came and went. Today, more than 1.25 million Americans are affected 4 , a reality that seems odd, considering the massive accomplishments in Regenerative Medicine. Upon the recent outbreak of the COVID-19 pandemic, individuals with T1D have been reported to be at higher risk for severe illness 5 and in-hospital death 6 due to COVID-19. On top of that, the endocrine tropism of SARS-CoV2, the virus causing COVID-19, offers a potential explanation for the observed link between the infection and increased incidence of T1D 7 . Beyond health complications, for many low or middle-income countries (LMICs), and even for patients in high income countries with private healthcare systems, T1D constitutes a heavy financial burden, with essential insulin and technology often being unaffordable 8 . More often than not, physicians are faced with diagnostic challenges regarding the pathophysiological mechanism of diabetes mellitus. For example, some patients are erroneously diagnosed with T1D and treated with insulin, while having a different, rare form of monogenic diabetes: Maturity onset diabetes of the young (MODY), which often manifests with comparable clinical characteristics to T1D, but without an autoimmune origin. Genetic testing is required and treatment usually involves diet, sulfonylureas or metformin 9 . Evidently, MODY should be included in the differential diagnosis of every case of atypical manifestation of T1D. Even though my medical background has now enabled me to grasp why unimagined roadblocks would not have allowed for a cure of T1D in 2012, the cumulative global progress seems poised to ultimately take the disease to meet smallpox in history books. Planning to specialize in diabetes research and management, I wish to contribute to finding a cure for the disease that has been my life's greatest challenge. The leading strategy today is beta cell replacement, though only therapeutically available for a small fraction of patients [10] [11] [12] . It can be achieved by transplanting self or allogeneic stem cells, differentiated into specialized insulin-producers. Replenishing pancreatic islets will theoretically reverse the deficiency, but certainly, that is easier said than done. Difficulties appear from in vitro stages. The engineered beta cells often exhibit immature metabolism and insulin kinetics which deviate from the normal glucosedependent secretion pattern. A key point, yet to be clarified, is whether the artificial islets should include beta cells only, or other endocrine islet cells, too. Embracing the idea that all these types of cells were phylogenetically preserved in adjacent sites advantageously, most protocols include integral islet-like clusters, but the optimal ratio remains an open question 13 . However, even if we inject the best, functional islets, there are further setbacks ahead. One risk is the development of malignancy, if incompletely differentiated cells are accidentally co-transplanted 14 . Moreover, transplants can be Nina Maria Fanaropoulou Hope injections: the promises of regenerative medicine in curing type 1 diabetes mellitus immunogenic, meaning that, the immune system will lurk on two sides. The new cells might be different enough from the host's to provoke an allogeneic rejection response, or similar enough to trigger the autoimmunity roller-coaster again 15 . So far, the only option has been immunosuppression, with the well-known severe risk of susceptibility to infections and malignancy 16 . An elegant alternative is wrapping transplants in immune-proof devices (macro-encapsulation) or hydrogel-based biomaterials serving as molecular coats (micro-encapsulation) [17] [18] [19] . Yet, it remains a bioengineering challenge, as the desirable composition must be impermeable to attack, but permissive to the secretion of insulin and the exchange of oxygen and nutrients. Over time, capsule architecture has been debated. Previously, microcapsules were larger than islets, allowing poor contact. Improved designs have now hit the labs, able to wrap around islets and conform to their shape and size 19, 20 . Even without coats, transplants can be processed with the help of gene-editing tools such as CRISPR-Cas9 to "ninja cells", which are devoid of surface proteins and evade immune recognition and attack 21 . These might have another advantage: They could constitute universal cell donors, with minimal immunogenicity, taking us closer to industrial islet production. However, escaping immune surveillance must not be taken too far: If cell division aberrations occur, the immune system would not be able to prevent malignancy stemming from the transplants. Subsequently, scientists are attempting to add a suicide protein, activated upon administration of a certain drug, to serve as a safety valve 22 . Moving from disguise to adaptation, immunomodulation trials have been in place 23 , and may reduce the need for immunosuppression more promptly than encapsulation. Such an agent, Teplizumab, has reached final stages in multinational clinical trials 24 , both to reverse overt T1D, and to prevent clinical manifestation in individuals at-risk of developing it, meaning siblings of T1D patients with a considerable titer of isletspecific autoantibodies but so far preserved islet function 25 . But where to plant our little insulin factory? So far, experiments have involved the omentum (a large membrane covering the intestines), subcutaneous tissue and the portal vein, as locations differ in their ability to generate vasculature 22 . Especially the portal vein, although a convenient choice for transplantation, entails exposure of the islets in maximum concentrations of nutrients and drugs, as per human physiology, and that can be harmful to cells used to surviving protected in the pancreas. Another interesting approach involves the interaction of islets with the host microbiome 26 . Among other institutions, the Joslin Diabetes Center is testing this, after their striking Medalist Study revealed a percentage of patients, who were somehow protected against complications, after 50 years with the disease 27 . This leads to the hypothesis that Precision Medicine may have an important role in creating effective cures. As exciting as it may sound, it introduces a new level of challenge, with growing evidence that T1D immunopathology varies among patients 9 . Table 1 shows a summary of the main therapeutic targets and approaches to restore or preserve beta cell function in T1D currently under laboratory development or in clinical trials, discussed in this article. Nevertheless, while we wait for definitive therapies, we luckily have the technologies of continuous glucose monitoring (CGM) and insulin pumps making life with T1D easier 28 . Still, as exquisite as they are, they entail a heap of information for the patient. The dual-hormone iLet Bionic Pancreas pump seems like an "external electronic version" of our previously described mixed-cell islet: Along with insulin, the pump delivers glucagon -the insulin counteracting hormone, micro-adjusting their balance every Nina Maria Fanaropoulou Hope injections: the promises of regenerative medicine in curing type 1 diabetes mellitus few minutes, just like a real pancreas. Its goal is to automate glucose control and it may soon enter the market, now that the stability of glucagon in room temperature is finally optimized 29 . Overcoming all these diverse obstacles may be frustrating, but the concepts we are now handling seemed like science fiction twenty years ago. I speculate that the cure, once perfected, will seem to future generations like Oedipus' solution to the riddle of the Sphinx: a solution so sensical, which however, only he was able to conceptualize. A prominent scientist devoted his career to T1D research after his two children were inflicted 30 . My life motto will be his answer when asked whether he thinks we will find a cure: "I am not going to give up until we do". In fact, I already feel as part of the efforts of the T1D scientific community. When reading original research and hitting the key message, a little internal voice shouts "Eureka!", as if it were my own discovery to celebrate. These are hope injections, and thankfully they don't hurt. Eventually, my disease came with an appreciation that healthy individuals own a miraculous pancreas. Still, while life-threatening 31 , T1D is manageable. Interning in hospitals, I often see fatally ill patients, inflicted with ailments that can be destroyers. But me? I have the precious chance to fight. My gift was the inexhaustible desire for a cure, combined with the physical and mental ability to search for one. My fervent hope is that someday, I will be privileged to know life without diabetes 32 . It is also that my patients will, too. I view my challenge as to continuously evolve from a chronic worrier to a chronic warrior, as one of my mentors put it. Can a system with such complexity be modified to work harmoniously, with no component falling short? The tools are all on our hands, and we are only facing an "assembly" puzzle. Personally, I can see myself tightening some screws, as we make this dream reality. Table 1 Main therapeutic targets and approaches to restore or preserve beta cell function in T1D currently under laboratory development or in clinical trials Nina Maria Fanaropoulou Hope injections: the promises of regenerative medicine in curing type 1 diabetes mellitus Type 1 diabetes mellitus Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications American Diabetes Association -Statistics about Diabetes Type 1 Diabetes and COVID-19: Preliminary Findings From a Multicenter Surveillance Study in the U Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study New-Onset Diabetes in Covid-19 Type 1 diabetes research: poised for progress. The Lancet Diabetes & Endocrinology Monogenic Forms of Diabetes Mellitus Islet transplantation Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia Defining outcomes for β-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop A Stem Cell Approach to Cure Type 1 Diabetes Report of the key opinion leaders meeting on stem cell-derived beta cells Overcoming immunological barriers in regenerative medicine A historical view from thirty eventful years of immunotherapy in autoimmune diabetes Encapsulated islet transplantation: where do we stand? Islet and stem cell encapsulation for clinical transplantation Immunoisolation of murine islet allografts in vascularized sites through conformal coating with polyethylene glycol Device design and materials optimization of conformal coating for islets of Langerhans Generation of hypoimmunogenic human pluripotent stem cells How stem cells could fix type 1 diabetes. Nature Immune therapy in type 1 diabetes mellitus Treatment of type 1 diabetes with teplizumab: clinical and Nina Maria Fanaropoulou Hope injections: the promises of regenerative medicine in curing type 1 diabetes mellitus immunological follow-up after 7 years from diagnosis An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes Microbiota regulates type 1 diabetes through Tolllike receptors Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-year Medalist study Sensor-Augmented Insulin Pumps and Hypoglycemia Prevention in Type 1 Diabetes Home use of a bi hormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial Diabetes cure-is the glass half full? The author acknowledges Professor Eleftherios P. Diamandis and Markos Markakis, for their valuable feedback and review of this article.Research funding: None declared. Author has accepted responsibility for the entire content of this manuscript and approved its submission. Author states no conflict of interest. Ethical approval: Not applicable.