Curing Diabetes - Article Example

Curing diabetes through Stem Cell Research (Islet transplantation)       In the year 2000, 1500 million people world wide were found to be affected by diabetes mellitus, and this number is considered to double in 2025. The disease progresses from insulin resistance to glucose tolerance and subsequently β cell death by apoptotic mechanisms. Restoration of insulin production by β cells surrogates, either by whole pancreas or isolated islets of Langerhans transplantation, which is a therapeutic alternative to hormone injection for diabetes treatment (Santana, A et al., 2006)       Islet cell transplantation is an effective treatment for diabetes, but its use is limited by shortage of donor material. Allogeneic islet transplantation has been explored as a treatment for type 1 diabetes. Islet cells are extracted from a donor pancreas and injected into the portal vein of the liver. The procedure has to be carried out two or three times and requires as many short term hospitalizations over a period of two to three months. When successful, this treatment has improved patients diabetes. However, the need for intense immunosuppression to prevent graft rejection has limited this approach to patients who are already immunosuppressed either for a previous organ graft or because of simultaneous kidney transplantation. It is also possible that the immunosuppressive regimen itself may have prevented success in some cases, because most protocols use agents that inhibit islet cell function or induce peripheral insulin resistance. As a result, only 10% of the patients on the International Islet Cell Transplantation Registry are recorded as being insulin independent a year after receiving a transplant. Promising results have been reported from transplantation of large amounts of islet cells from cadaveric pancreases that were not HLA matched into seven patients with type 1 diabetes who had multiple hypoglycemic episodes or uncontrolled diabetes despite compliance with the prescribed insulin treatment. All the patients showed normalization of glycated hemoglobin concentration and lasting independence from insulin injections at an average of 11 months follow up. The islet cells were purified in medium free from foreign protein, and this, combined with a glucocorticoid-free immunosuppressive regimen, successfully prevented rejection. Notably, both host versus graft and autoimmune reactions were apparently avoided. This was a small uncontrolled study, however, and its encouraging results need to be confirmed in larger randomized controlled trials.        The shortage of human donor pancreases for islet cell transplantation has led to a search for alternative sources of islet cells. Several sources have been suggested from pigs, induction from human pancreatic duct cells, fetal pancreatic stem cells, and induction of insulin producing β cells by therapeutic cloning and each has its own advantages and disadvantages (Serup et al., 2001).    Standardized mortality rates are higher in children with type 1 diabetes mellitus. Moreover, severe asymptomatic nocturnal hypoglycemia (mean blood glucose 1.9 mmol/l, range 1.6–2.3, duration 30–630 minutes) was detected by overnight venous sampling in 45% of children with type 1 diabetes treated by a split mixed insulin regimen, and in 60% of children on multiple daily injections.    Excluding non-compliance with intensive diabetes management, the above data highlight the need for identification of a small category of compliant high risk children in whom the side effects of a steroid-free immunosuppressive regimen can be justified. Identification of such patients will be extremely difficult and should focus on one of the following criteria: 1. Recurrent unexplained severe hypoglycemia with potentially damaging CNS effects (blood glucose below 2.2 mmol/l, often presenting with seizures, hemi paresis, or coma), despite dietary manipulation and prophylactic insulin adjustment. 2. Presence of incipient progressive vascular complications, especially retinopathy and nephropathy, onset of which in childhood or adolescence carries the potential of severe disability in early or mid-adulthood. 3. Concurrent immunosuppressive medications for a co morbidity which can be safely treated with a steroid-free immunosuppressive regimen. Islet-alone transplants are performed in highly selected adults with type 1 diabetes, with careful consideration to the risk-benefit ratio in every case. Indications for islet transplantation in adults are hypoglycemic unawareness, severe metabolic instability, and the existence of secondary diabetic complications. Concerns about islet transplantation using the Edmonton protocol relate to some known risks of the procedure and medications, as well as unknown elements inherent to any new immunosuppressant modality (Hathout. E. et al., 2003)   Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, but whether intrahepatic islets responded appropriately to hypoglycemia after transplantation was not studied. A study by Rickels et al., (2005) suggested that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.       Islet transplantation has become an option for the treatment of insulin-dependent diabetes mellitus and is usually performed using brain-dead heart beating donors. However, there are a limited number of such donors in Japan; therefore, it was not allowed to perform islet transplantation with brain-dead donors. In order to perform islet transplantation in Japan, there was a need to seek new donor resources. Matsumoto et al., (2006) performed the first successful living-donor islet transplantation. The authors concluded that in their first case of living donor islet transplantation, both the donor and the recipient had been maintaining excellent glycemic control with no untreatable complications for more than one year.       Shapiro et al (2006) conducted an international, multicentre trial to explore the feasibility and reproducibility of islet transplantation with the use of common protocol (The Edmonton) protocol. They concluded that the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and control, but insulin independence is not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin       Tight glycemic control can reduce progression of diabetic nephropathy (DN) while the histological changes may regress after pancreas transplantation. Clinical islet transplantation (CIT) can restore euglycemia but the effects of CIT and concomitant immunosuppression on renal function were not known. Senior et al,(2007) reported that the risk of progressive nephrotoxicity with decline in eGFR should be discussed with prospective CIT candidates and the risk: benefit ratio carefully considered in individuals with pre-existing renal impairment.       Islet transplantation to become widely applicable in the treatment of diabetes, better strategies for tolerance induction to the transplanted insulin-producing cells, which will be clinically relevant and will not introduce significant risks for the recipients need to be developed..       In this direction, a very promising and safe approach to increase the level of chimerism and induce tolerance without the risks of harsh radiation conditioning has been introduced. This consists in a novel targeted bone marrow minimal conditioning strategy, based on the delivery of minimal doses of radiation, specifically targeting the bone marrow, through a bone-seeking compound, Lexidronam, coupled to a radioisotope, Samarium. This very promising strategy has already been successfully tested in experimental skin transplantation and is now under evaluation in islet transplantation.       There is a need to develop new sources of insulin-producing tissue to treat a majority of patients. An effort should be made to minimize islet loss before and after isolation so that a single donors and maybe even one donor for multiple recipients could be used.       Major efforts are under way studying stem cells and pancreatic cell development. Efforts are being made to define the very complex up regulation and down regulation pathways that characterize normal ß-cell development, as well as to develop unlimited sources of human ß-cells, starting from ß-cell precursors.         New tools for defining and monitoring metabolic pathways within islets and ß-cells. Cell biology and signal transduction studies will allow not only to better characterize human islet preparations before transplantation but also to follow and characterize the generation of mature islet cells from ß-cell precursors need to be developed (Ricordi 2003)                 References Santana, A., R. Enseñat – Waser, María Isabel Arribas , J. A. Reig and E. Roche . “Insulin - producing cells derived from stem cells: recent progress and future directions”. J. Cell. Mol. Med 10, No 4 (2006): 866-883. Serup, Palle., Ole D. Madsen, and Thomas Mandrup-Poulsen. “Islet and stem cell treatment for treating diabetes.”BMJ. 322 (2001): 12-18. Senior , PA., Zeman M, Paty BW,  Ryan EA and Shapiro AM. “Changes in renal function after clinical islet transplantation: four-year observational study.” Am. J. Transplant 7 no. 1(2007): 91-8. Matsumoto, S., Okitsu T, Iwanaqa Y, Noguchi H, Nagata H, Yonekawa Y, Liu X, kamiya H, Ueda M, hatanaka N, Kobayashi N, Yamada Y, Miyakawa S, Seino Y, Shapira AM and Tanaka K.  “Follow-up study of the first successful living donor islet transplantation.” Transplantation 82 no. 12 (2006): 1629-33. Rickels, MR., Schutta MH, Mueller R, Markman JF, Barker CF, Naji A and Teff, KL. “Islet , cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes” Diabetes. 54 11 (2005): 3205-11.    Ricordi. C. “Islet transplantation : A Brave new world”. Diabetes. 52(2003): 1595-1603.   Shapiro, James, AM., Hugh A, Antonio S, Daniel CB, Edmond AR, Kenneth SP, Fererico B, David ERs, Miriam S, Franca BB, and  Jeffrey B.  “International Trial of the Edmonton Protocol for Islet Transplantation”. N Eng J Med. 355 (2006): 1318-30.    Hathout, E., J Lakey, and J Shapiro. “Islet transplant: an option for childhood diabetes?”. Archives of Disease in Childhood 88 (2003): 591-594.            Read More