State of the art: islet transplantation for the cure of type 1 diabetes mellitus.

Abstract

Type 1 diabetes mellitus (T1DM) results from the immune destruction of insulin producing beta cells, located in the pancreatic islets of Langerhans [1]. Apart from the daily need for multiple insulin injections and blood glucose testing, individuals with T1DM are at greater risk for end organ complications, cardiovascular disease, and premature mortality. Although aggressive treatment aimed at keeping the blood sugar, blood pressure, and blood lipids within their normal ranges has been shown to markedly reduce diabetes complications [2], including a major impact on mortality [3], too few achieve these treatment goals, and aggressively treated patients have an increased risk of serious hypoglycemia [4]. The main reasons then to consider transplantation therapies (isolated islet or whole pancreas) are thus to overcome the lifelong need for daily insulin injections and frequent blood glucose testing, to promote maintenance of near normal blood glucose levels, and to avoid or even reverse the long-term diabetesassociated complications. In this review, we will critically look at current transplantation (pancreas or islet) therapies as they relate to these laudable goals. Transplanting beta cells by means of a whole pancreas transplant, for those with successful transplants, appears to improve quality of life while potentially ameliorating or preventing the complications associated with chronic hyperglycemia [5–12]. More specifically, the freedom from daily insulin injections and blood glucose monitoring is reported to improve the successfully transplanted recipient’s sense of well being, independence, and promote a perception of normality [5,7,10,13,14]. Over all however, when considering risks and toxicities associated with immunosuppressive medications, peri-operative complications, and uncertain graft survival, whether or not transplantation reduces end organ complications, or mortality, is not established [15]. Nearly all individuals given a pancreas transplant have battled with the disease for many years, and thus many already have suffered end organ complications and/or have cardiovascular disease. Thus, unlike patients enrolled in the Diabetes Control and Complication Trial (DCCT), it is harder to measure the effects transplantation may have on already established secondary complications. Studies of diabetic nephropathy provide perhaps the best evidence for a beneficial effect of transplantation. Several large studies have shown less progression or even an improvement in nephropathy in naive kidneys and renal grafts [16–18], and yet conflicting data exists as well. For instance, three different groups have studied whether individuals with T1DM and endstage kidney disease and treated with a kidney transplant alone, or with a simultaneous pancreas and kidney transplant fare differently [19–21]. One found that both patient and kidney allograft survival were improved by the pancreas allograft [20], one found a moderate effect that did not achieve statistical significance until several years after the transplant [21], and one found no independent effect of the pancreas allograft [19]. Evidence supporting a salutary effect of pancreas transplantation for neuropathy or retinopathy is even less compelling [22,23], perhaps secondary to the chronicity of those secondary complications, and/or those tissues’ limited capacity for repair. Further, even though pancreas transplantation results in one-year insulin independence rates approximating 80% and one-year patient survival rates approximating 95% [24], the procedure remains controversial for several other reasons. One, simultaneous pancreas kidney transplantation is associated with higher morbidity compared to kidney transplantation alone [24,25]. That is, pancreas transplantation is usually performed using an intra-abdominal approach frequently resulting in a prolonged ileus and thus a delayed return of bowel function, complicating