Diabetes is a debilitating lifestyle disease that leads to a variety of severe complications and an overall shortened life expectancy.
The current treatment of insulin does not represent a cure because insulin dosage is difficult to adjust. Exogenous insulin frequently fails to achieve optimal glucose control even when intensive regimens are used. In addition, intensive therapy, which uses multiple daily insulin injections or insulin pump infusion with frequent monitoring of blood glucose, often leads to an increased incidence and severity of hypoglycaemic episodes.
Thus, according to Dr. Vikas Ahluwalia, President of the New Delhi-based Diabetes Care Foundation of India, diabetes represents an attractive candidate for cell therapy.
Dr. Ahluwalia is of the view that reversal of diabetes along with total independence from insulin injections, can be achieved through pancreas and islet transplantation, but shortage of donor organs has prompted an intensive search for alternative sources of cells.
Stem cells are defined as cells that have clonegenic and self-renewing capabilities and differentiate into multiple cell lineages. Embryonic stem cells (ESCs) are derived from mammalian embryos in the blastocyst stage and have the ability to generate any differentiated cell in the body.
Adult stem cells are part of tissue-specific cells of the postnatal organism into which they are committed to differentiate. Another advantage is that they behave as an autologous model whereby a patient's own cells can be used, thereby preventing an immune rejection.
The benefits of the ESCs include the possibility of propagating an unlimited number of cells that possess the ability to become fully functioning endocrine tissue.
Dwelling on the advantages and disadvantages of islet transplantation, Dr. Ahluwalia says that the main advantage includes the achievement of physiologic insulin secretion in those patients who are able to achieve insulin independence. "Islet transplantation is a much less invasive procedure and is considered safer than whole pancreas transplantation. Isolated islets carry a lower antigenic property than the whole organ, which may thus require reduced immunosuppression with fewer side effects. Islets can also be manipulated in vitro before transplantation to reduce graft rejection," he adds. A major disadvantage is the commitment of a patient to lifelong immuno-suppression that is not only costly, but also has potential side effects.
According to Dr. Ahluwalia, the use of high dose calcineurin inhibitor therapy has raised concerns because of the possibility of worsening nephropathy in long-standing diabetic patients. Moreover islet transplantation requires at least two donor organs for each recipient and therefore its broad application remains limited due to lack of sufficient cadaveric donors.
In his view, while cadaveric islets are currently the mainstay of endocrine cell replacement, alternative cell sources, such as stem cells hold great promise to provide a ready source of transplantable, insulin-secreting tissues that would not be limited by the supply of donor organs.
Those going in for stem cell transplantation need to follow certain criteria to ensure the effectiveness of diabetes therapy, Dr. Ahluwalia opines.
"It is not clear whether it will be desirable to produce only islet b-cells that manufacture insulin or whether other types of pancreatic islet cells are also necessary. Studies by Soria et al. indicate that isolated b-cells, those cultured in the absence of the other types of islet cells, are less responsive to changes in glucose concentration than intact islet clusters made up of all islet cell types. Islet cell clusters typically respond to higher than normal concentration of glucose by releasing insulin in two phases: a quick release of high concentrations of insulin and a slower release of lower concentrations of insulin," he says. I
"solated b-cells, as well as islet clusters with lower than normal amount of non b-cells, do not release insulin in this biphasic manner, with no fine-tuning for intermediate concentrations of glucose in the blood. Therefore, it is important to develop a system in which stem or precursor cell types can be cultured to produce all the cells of the islet cluster in order to generate a population of cells that will be able to coordinate the release of appropriate amount of insulin to physiologically relevant concentrations of glucose in the blood. The main goal is not only induction of insulin biosynthesis, but also its correct processing, storage and regulated secretion in response to physiologic signals, without which such cell-therapy approaches would not be significantly advantageous over insulin administration," he adds.
Type 1 diabetes appears to be especially difficult to cure, because the cells are destroyed when the body's own immune system attacks and destroys them. This autoimmunity must be overcome if researchers hope to use transplanted cells to replace damaged ones.
While stem cells may have the potential to regenerate a variety of tissues, as indicated by a number of groundbreaking but preliminary reports, ethical issues and safety considerations seem to preclude the use of human stem cells in the clinical setting.
A major consideration is whether any precursor or stem-like cell transplantation into the body might revert to a more pluripotent state and induce the formation of tumors.
Clinical evidence indicates that there is an inverse association between beta-cell (a type of cell in the pancreas that secretes insulin) preservation and function and chronic complications of type 1 diabetes mellitus (DM), and the higher the C-peptide levels (a byproduct of insulin production, made up of amino acids), the lower the incidence of some types of complications of type 1 DM.
A previous study found that autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in 15 patients with newly diagnosed type 1 DM resulted in the majority of patients becoming insulin free during the follow-up, which averaged about 19 months.
In the continuously insulin-free group, average area under the curve (AUC; a type of measurement) of C-peptide levels before transplantation (225.0 ng/mL per 2 hours) showed a significant increase at 24 months after transplantation (785.4 ng/mL per 2 hours) and at 36 months after transplantation (728.1 ng/mL per 2 hours). In the transient insulin-independent group, average AUC of C-peptide levels also increased from 148.9 ng/mL per 2 hours pretransplantation to 546.8 ng/mL per 2 hours at 36 months, which was sustained at 48 months.
In this group, 2 patients regained insulin independence after treatment with the antihyperglycemic drug sitagliptin, which was associated with an increase in C-peptide levels. Two patients developed pneumonia in the hospital, 3 patients developed late endocrine dysfunction, and 9 patients developed oligospermia (sperm deficiency). There were no deaths.
According to Dr. Ahluwalia, embryonic and adult stem cells are potential sources for beta-cell replacement and merit further scientific investigation.
" Discrepancies between different results need to be reconciled. Fundamental processes in determining the differentiation pathways of stem cells remain to be elucidated, so that rigorous and reliable differentiation protocols can be established. Encouraging studies in rodent models may ultimately set the stage for large-animal studies and translational investigation," he says.
He concludes by saying that diabetes is a chronic disease with significant morbidity and mortality. Pancreas or islet cell transplantation is limited by a shortage of donors and chronic immune suppression to prevent allograft rejection. Consequently, interest exists in islet cell neogenesis from embryonic or mesenchymal stem cell as a possible cure for diabetes. However, unless tolerance to islet cells is re-established, diabetes treated by islet cell transplantation would remain a chronic disease secondary to immune suppression related morbidity.
Dr. Vikas Ahluwalia can be reached by e-mail - firstname.lastname@example.org, email@example.com. For appointments, he may be contacted on Mobile No. 9910328390 or landline no. 91-11-26167893. The Diabetes Institute is located at B-4/234, Safdarjang Enclave, New Delhi-110029. By Dr. Vikas Ahluwalia