There are a number of theoretical advantages to islet transplantation over multiple daily injection (MDI) insulin regimens for patients with type 1 diabetes. The most obvious benefit is the achievement of "physiologic" insulin secretion in those patients who are able to achieve insulin independence. Even before the landmark Diabetes Complications and Control Trial (DCCT), the challenge for most diabetic patients and their health care providers has been to maintain blood glucose levels as close to normal as possible while minimizing the risk of hypoglycemia (45). This balance has been difficult to achieve in many patients and the risk of severe hypoglycemia remains the major limiting factor in the management of type 1 diabetes (48). For this reason, the ability to replace destroyed beta cells and re-establish endogenous insulin secretion is an attractive solution.
Accordingly, the most immediate benefit of islet transplantation is stabilization of blood glucose (Figure 6). This effect is often observed after the first islet infusion, even though most recipients still require insulin at this stage. Presumably, the endogenous insulin secretion from their newly transplanted islets acts as a “buffer” for injected insulin, thereby reducing the amplitude of glycemic excursions. Among insulin-independent patients, glucose is even more stable, although glucose tolerance is usually not completely normal.
Figure 6. Representative continuous glucose monitor 72-hr glucose profiles demonstrating a marked improvement in glycemic stability post-islet transplant (B) compared to pre-islet transplant (A).
Compared to whole pancreas transplantation, islet transplantation offers some potential advantages. It is a much less invasive procedure and therefore is considered to be generally safer (49). Furthermore, islets have the potential to be manipulated in vitro prior to transplantation to possibly improve graft survival and function (50). However, the decline in insulin independence observed after islet transplantation has reduced the expectation that this technique in its current state can deliver long-term freedom from insulin in the majority of patients. Finally, although cadaveric islets are currently the mainstay of endocrine cell replacement, alternative cell sources, such as stem cells or cloned beta cells, hold great promise to provide a ready source of transplantable insulin-secreting tissue that would not be limited by the supply of donor organs (51-53).
A number of questions also remain regarding the physiologic impact of intrahepatically transplanted islets. It appears that alpha cells within transplanted islets may not respond appropriately to hypoglycemia (54) although mixed results have been seen (55). In the native pancreas, alpha cells secrete glucagon in response to hypoglycemia (plasma glucose < 60 mg/dl), this does not appear to occur in transplanted islets. A study comparing the glucagon response in intrahepatically-transplanted dogs with those transplanted in the gastric omentum demonstrated that glucagon secretion was absent in the intrahepatically-transplanted animals but intact in the omentally-transplanted ones (56). The physiologic explanation for this finding is not clear, although it may involve a failure of the intrahepatic site to adequately stimulate transplanted islets during periods of hypoglycemia. Clearly many unanswered questions remain regarding the physiologic impact of transplanted islets on glucose homeostasis and hepatic metabolism.