My Type 1 diabetes invades every corner of my life. I hate it. While I am incredibly fortunate to live in a time of tremendous technological advancement, lucky to have quality healthcare, and grateful that I have a manageable disease, I still hate it. I hate that I sleep best when my blood sugar is precariously low but when I wake with precariously low blood sugar I am punished by the feeling that someone is sitting on my chest. I hate that I have grits of scar tissue on my hips from 15 years on an insulin pump. I hate that I can’t exercise unless my blood sugar is high, and if my blood sugar plummets during exercise, I’m forced to drink the calories in orange juice that I just burned on the elliptical. I hate travelling with diabetes—I hate that although I have a letter from my doctor stating that my insulin, insulin pump, and glucose sensor cannot be X-rayed, most TSA agents refuse to believe it. I hate that fluctuations in my blood sugar bring on wildly different sensations: at 172, I may laugh maniacally for minutes; at 263, which is hyperglycemic, I feel like I’m trapped, overdressed, in my own skin; at 37, which is hypoglycemic, I feel floaty but I can hear the tethered voice in the back of my mind telling me to eat something; in the 50s, I worry inexplicably about nothing; a day of rollercoaster changes in my blood sugar brings on bone-crushing fatigue. I want nothing more than a cure, but will I ever be delivered the cure I’ve been promised by clinicians for so many years?
Type I diabetes, or T1D, is a disease driven by the autoimmune destruction of pancreatic β cells, which produce the essential hormone insulin. Insulin and its antagonist glucagon are required to maintain blood glucose levels and chronic high blood sugars due to the loss of insulin lead to kidney failure, neuropathy and impaired circulation. T1D is readily treatable with injectable insulin, but a true cure for diagnosed patients lies in a long-lasting, non-immunogenic, replacement of pancreatic β cells.
The majority of patients receiving a whole pancreas or islet cell transplant may be insulin-independent for at least a year. However, insulin independence decreases over time, most likely due to immune response toward both the transplant itself (allogeneic immune response) and toward insulin-producing cells (autoimmune response) (Robertson, RP. Pancreas and Islet Cell Transplantion in Diabetes Mellitus. In: UptoDate). Moreover, transplants are limited by the numbers of cadaveric donors, and donor tissue can vary dramatically in its functional efficiency. With the recent advent of induced pluripotent stem cell technology (iPSCs), where adult cells may be reverted to stem cells that can generate any cell type, the goal of generating numerous β cells from a patient’s own cells may be attainable. The benefit of these cells is that they do not require cadaveric transplant and may overcome the hurdle of transplant rejection as they derive from a patient’s own cells. In fact, two recent publications demonstrate improved generation of functional human β cells from either human embryonic stem cells or iPS cell lines (termed SC-β) (here and here). While these publications show that such β cells closely resemble primary human β cells in glucose response, calcium influx, and gene expression signature (also reviewed in a recent PhDish article by James Lohner), there are several issues that prevent the rapid transition of these findings to the clinic.
At first glance, the most exciting prospect of both papers is that transplant of SC-β cells into two different diabetic mouse models (one genetic and one chemically induced) reverses diabetes. However, upon closer inspection, we note that both mouse models are immunocompromised, lacking an adaptive immune system and natural killer (NK) cells. In other words, the mice are not capable of mounting an immune response against the insulin or the transplant, and therefore do not recapitulate autoimmune human patients. This detail is critical not only because T1D is a disease mediated by the adaptive immune system (particularly by T cells and, to a lesser extent, B cells), but also because it means that the immunogenicity of the SC-β cells has not been tested. In some instances, the genetic reprogramming of adult cells into stem cells is enough to make these cells immunogenic, i.e. prone to provoking an immune response. For example, the genetic reprogramming used to generate undifferentiated iPS cells resulted in transplant rejection when these cells were transplanted back into the mouse recipient from whom the iPSCs were derived. It will not be useful to generate billions of SC-β cells if their reprogramming alone incites immune response, as their transplant would immediately result in transplant rejection.
The next hurdle to adapting these findings for human patients, as the authors admitted, is that the transplant of SC-β cells will require either long-term immunosuppression or a way of veiling transplanted cells from the immune system. This is requisite because Type 1 diabetics maintain an arsenal of T cells responsive to insulin and islet cells, no matter the origin of the insulin and islet cells. Long-term, broad immunosuppression is not without its complications, however; immunosuppressed patients are prone to infection and kidney toxicity. In contrast, by targeting the immune cells that only respond to insulin-producing cells, side effects could be prevented. Mouse models have shown that targeting T cells specific to insulin-producing β cells can reverse diabetes in these models. Similarly, several Phase 2 and Phase 3 clinical trials have been performed to study the effects of anti-T cell and anti-B cell drugs on recently diagnosed Type I diabetics. While these treatments have yet to reverse diabetes, anti-T cell therapy in Phase 2 trials reduced exogenous insulin required for treating hyperglycemia in recent onset T1D patients over a four-year period. Therefore, if these treatments can be refined to more discretely target human T cells specific to insulin-producing cells, then SC-β cell transplant may yield a long-lasting, non-immunogenic, treatment for T1D.
I read the papers about SC-β cells with excitement and a grain of salt. I saw many other diabetics comment upon the news of these findings; most said that this technology might be what their doctors have been promising them all along. One of the researchers himself has two young children with diabetes and he is eager for their cure. I hope that eventually these fascinating results will work synchronously with targeted immune therapy. However, I fear we all might have to wait at least a few more years.
