This article highlights the indications,procedure and outcome of islet transplant .It discusses the pros and cons of the procedure to evaluate how it fares as a treatment modality in type 1 Diabetes in the current era, with a brief insight into its outcome in pediatric patients.

Type 1 diabetes mellitus (T1DM) is an emerging noncommunicable disease, both in India and abroad. It occurs due to the autoimmune destruction of insulin secreting beta cells of the pancreas [1]. It is associated with both short-term problems of hypoglycemia, hyperglycemia, ketoacidosis, and long-term complications such as nephropathy and retinopathy, among others. The best available medical strategy for achieving normoglycemia is subcutaneous insulin. A basal bolus regimen is currently the most favored approach to keep blood sugar levels in control. Glycemic control is assessed on the basis of glycosylated hemoglobin (HbA1c) levels. Transplant, either whole pancreas or islet cell, is a known therapeutic option for treatment of type 1 diabetes in adults. Initiated as an experimental therapy in the 1980s, pancreatic transplant has been reinvented with timely advances in adult care and is now a commonly performed procedure [2].

For a child with T1DM, multiple daily injections of insulin and repeated pricks to check blood sugar as a part of self-monitoring of blood glucose makes life difficult for the patient and the family. The not-so-rigid meal timings of children, their resistance to pricks, parental anxiety, and the risk of hypoglycemia have all indicated the need for a treatment modality that is independent of insulin. Besides, the recommended target HbA1c of <7% is difficult to achieve and the need for stringent blood sugar control poses the risk of hypoglycemia, which is detrimental to the growing brain of the child [3]. Thus, there is increasing interest in the role of pancreatic and islet transplant in T1DM.

Broadly, pancreas transplant consists of three types [4].

The Collaborative Islet Transplant Registry report of 2014 has shown notably improved outcomes, both short- and long-term, with achievement of insulin independence in up to 80% of patients with favorable factors such as autoantibody negative for islet antigen, islet mass >5,000 islet equivalents (IEQ)/kg, among others [23,26,27]. The minimal beta cell mass for a significant effect after transplant is greater than 5,000 IEQ per kg of the recipient body weight [28]. Some centers claim to have insulin independence rates of 50%–70% by five years after the transplantation approaching those of patients of type 1 diabetes with whole pancreas transplant [29-31].

Studies have revealed that endogenous insulin secretion from transplanted islets led to near normalization of blood glucose. It also resulted in decreased basal hepatic glucose output and normal plasma amino acid levels. Transplant restores glucagon secretion, normalization of hepatic glucose production, and improvement in lipid profile and insulin mediated protein kinetics. Clinical benefits seen are numerous and significant (Table 4). Well controlled HbA1c levels were seen after transplant in patients off insulin, although insulin independence seemed to decrease over a period of time. Even with intensive blood glucose monitoring, no other insulin regimen can achieve such goals [32]. The success of pancreas and islet transplant in treating severe hypoglycemia led to its being recommended as a therapeutic option in cases of problematic hypoglycemia [33]. Reduced frequency of blood glucose monitoring and freedom from insulin injection is a huge benefit in the pediatric population, as frequent pricks can be frightening for them.

Pancreas and islet transplant is uncommon in children with diabetes due to the reasons enumerated above. Hence the experience in pediatrics is limited. Islet cell transplant was tried and considered better than whole pancreas transplant, which poses major operative risks. Other disadvantages of the latter include chronic immunosuppression and its related side effects and posttransplant complications. Islet transplant in the pediatric age group has been conducted mostly for chronic pancreatitis after total pancreatectomy where improvement in pain resolution and quality-of-life were comparable to adults, with >80% of recipients being able to attend school or work [34]. Rates of insulin independence were seen up to 40% at two years post islet transplant in these children. More than 50% of the youngest recipients between five and 12 years of age were insulin-independent at 1 year post islet transplant. During three years of follow-up in pediatric patients, HbA1c <7.0% was maintained in 100% who received >5,000 IE/kg [11,35]. So younger age and shorter duration of pancreatitis have been associated with higher islet yields, as in adults [36].

Avoiding a major operative procedure and opting for a less invasive islet cell transfer therapy is quite alluring but it needs to be poised against the scarcity of donors and difficulties faced in processing the islet cells. Besides, there is a lack of equipment and expertise in successful performance of such complex procedures. In pediatric ages, especially when development of complications due to diabetes is not imminent in the near future, the balance between the efficacy and toxicity of the procedure needs to be evaluated. As there is little experience of islet cell transplant in the pediatric age group, long-term studies are needed to evaluate the outcome of transplant in cases in chronic pancreatitis in children. Even more experience is needed for such procedures in children with T1DM, and their outcome on follow-up needs to be studied. Only then can better insight be available about the future of such a procedure in the pediatric age group.

Newer developments in transplant procedures have made it possible, to some extent, to overcome existing barriers such as scarcity of donors and immune reactions leading to rejection. Porcine islet cells have been used to form xenoislets for transplantation, but immune rejection was a drawback. Extensive studies are being carried out to investigate the ability of human embryonic stem cells and induced pleuripotent stem cells to differentiate into functional insulin producing cells. This may lead to successful use of such cells for transplant [37].

To protect against immune reactions, islet encapsulation is another advanced method of islet transplantation. Isolated islets of human origin or porcine xenoislets are encapsulated in a semipermeable membrane that allows the passage of nutrients and hormones but prevents cell contact with immune cells and hence, protects against immune reactions. This can be particularly beneficial for xenotransplantation [38]. When multiple islets are encapsulated within a device >1 mm in diameter, it is called macroencapsulation. It is usually placed in an extravascular space. Microencapsulation means coating of islets in an immunoprotective cover.

Several innovative drugs are being tried to limit reduction of transplanted islet cell mass in the posttransplant period. Efforts are being made to improve the efficacy of islet graft with the minimal toxicity of immunosuppressive therapy. Several methods to reverse diabetes with cellular replacement of insulin secreting cells, along with ways to prevent recurrent autoimmune destruction of the newly transplanted cells, are under study.

Diabetes mellitus is a chronic debilitating disease associated with macrovascular and microvascular complications. Maintaining euglycemia is crucial to preventing complications and also reversing their progression. Currently, intensive insulin regimes have contributed to maintenance of normal blood glucose levels, which is an uphill task, and more so in the pediatric population. Emergence of islet transplant as an experimental procedure and its evolution over the last 2 to 3 decades has opened new avenues in the treatment of T1DM. A great deal of research and experiments in islet transplant are evolving to provide a novel strategy for providing successful normalization of HbA1c with insulin independence. Its lower surgical risk, and the reduced toxicity of immune therapy with lower risk of complications makes it an ideal future prospect of treatment in the pediatric age group. The major limiting factor in transplant success is the wide gorge between demand and supply due to organ shortage, however, new avenues of research have led to numerous developments that seem to overcome the existing barriers. Still, multicentric trials on follow-up of the transplant procedure are needed before recommending it as a routine therapeutic option for T1DM.