Spontaneous Hypoglycemia After Islet Transplantation: The Case For Using Non-Hepatic Sites

Abstract

This Perspective provides a brief history of intrahepatic alloislet and autoislet transplantation in humans and an update of the recent success rates. It also examines the important role that hypoglycemia plays in clinical outcomes. On the one hand, recurrent serious hypoglycemic episodes related to insulin therapy are a major criterion for alloislet transplantation. On the other hand, spontaneous clinical hypoglycemia, perhaps related to the accompanying Roux-en-Y procedure for total pancreatectomy, is a complication of autoislet transplantation. Complex alterations in glucagon secretion compromise counter-regulation of hypoglycemia in both situations. The glucagon response to hypoglycemia is intrinsically defective in type 1 diabetes before transplant because of the absence of physiological regulation of α-cell secretion by neighboring β-cells. Glucagon secretion from intrahepatic islets during systemic hypoglycemia is also defective, although β-cells in the graft are normally regulated by glucose and arginine. My personal perspective is that the latter is caused by intrahepatic glycogenolysis stimulated by systemic hypoglycemia with consequent increases in intrahepatic glucose flux, which incorrectly signals intrahepatic α-cells to be quiescent. This defect is liver-specific, which strongly suggests modifying the current approach to islet transplantation by placing a portion of allo- and autoislets in nonhepatic sites in addition to hepatic sites to ensure physiological glucagon secretion as a strategy to ameliorate post-transplant hypoglycemia.

Brief History and Update

Intrahepatic pancreatic islet transplantation for type 1 diabetes (T1D) once again is enjoying a resurgence. As is characteristic with science in general, alloislet research has had its ups and downs, much like a roller-coaster ride. Clinical outcomes of this procedure in its early years from 1980 to 2000 were fairly dismal (see Ref. 1 for review), especially in contrast to its more successful sibling, whole pancreas transplantation. With the use of the Edmonton protocol (2), the year 2000 was marked by an impressive uptick of alloislet success, which caused great excitement. However, that huge advance slipped backward by the year 2005 (3). Since then, basic and clinical scientists have doggedly stayed the course in this field of endeavor and once again are reporting new progress. Most recently, the Clinical Islet Consortium has reported a success rate of 71% at 2 years after alloislet transplant (4, 5).

In contrast, the intrahepatic transplantation of autoislets after total pancreatectomy for chronic pancreatitis has been highly successful consistently since its inception in 1980 (6). Sutherland et al (7) recently published a summary of the University of Minnesota experience with 409 recipients of total pancreatectomy with islet autotransplantation (TPIAT) and reported that the use of approximately 5000 islets/kg body weight (approximately 350 000 islets or one-third of the number in a native human pancreas) yielded a 93% rate of glycosylated Hemoglobin A1C <7% and a 71% rate of insulin independence 3 years after transplant. Oddly, this highly successful procedure has received much less attention and is not even mentioned in most textbooks of medicine and surgery. This is unfortunate because many important lessons have been learned from the TPIAT experience that are relevant to alloislet transplantation (1). The magnitude of TPIAT success has set the bar for islet transplantation and optimistically predicts greater success for alloislet transplantation. To be fair, TPIAT enjoys important advantages over alloislet transplantation in T1D. Autoislets are obtained from fresh, viable tissue from living donors. They are transplanted within hours after pancreatectomy and islet isolation, and they require no immunosuppressive drugs, which ironically can be toxic to β-cells. In contrast, alloislets are isolated from pancreases of brain-dead donors on life support; they undergo prolonged procural times because of travel and require the use of immunosuppressive drugs.

Role of Hypoglycemia in Clinical Outcomes

A key criterion for choosing type 1 diabetic candidates for alloislet transplantation is recurrent, serious hypoglycemia despite optimal medical treatment with exogenous insulin by an endocrinologist. Recurrent hypoglycemia is arguably the major contributor to poor quality of life in T1D. Whereas most people with T1D successfully maintain reasonable levels of glycosylated Hemoglobin A1C using insulin therapy via daily injections or use of insulin pumps without recurrent serious hypoglycemia, many others do not. The reasons for this difference are not always clear, but it exists nonetheless. What is clear is that after successful alloislet transplantation, the frequency of hypoglycemic episodes dramatically decreases (4). This is not surprising, of course, because criteria for successful islet transplantation include a marked diminution in, if not the absence of, daily insulin administration, and it is the use of exogenous insulin that is responsible for the hypoglycemia.

An unanticipated and ironic twist in this story is that the more successful of the two islet transplantation procedures has become associated with post-transplant hypoglycemia. Hypoglycemia is not associated with chronic pancreatitis before transplant. In contrast, a high prevalence of hypoglycemia after TPIAT, documented by home glucose monitoring and/or continual glucose monitoring, after exercise and/or high-carbohydrate meals has recently been reported (8). In this issue of the JCEM, Lin et al (9) report that six of 12 autoislet recipients developed post-transplant hypoglycemia and fortunately responded to an intervention of small, frequent meals. It was also previously reported that TPIAT recipients did not experience symptoms of hypoglycemia until their glucose levels reached approximately 40 mg/dL (8). This is consistent with recurrent hypoglycemia and consequent desensitization to low glucose levels during daily living. The use of exogenous insulin therapy does not explain the hypoglycemia in this case because most TPIAT recipients do not use exogenous insulin, or if they do, they usually use only minimal amounts (5–10 U of long-acting insulin at bedtime). These observations suggest that there is something intrinsic to the TPIAT procedure that predisposes recipients to hypoglycemia. Intrahepatic islets per se are not likely to be a primary cause of hypoglycemia because successful alloislet recipients do not spontaneously report hypoglycemia; quite the contrary. However, a major difference between these two types of transplants is that autoislet recipients undergo a Roux-en-Y procedure to free up the pancreas during its removal. This involves mobilization and resection of a portion of the proximal small bowel with unavoidable damage to its vagal innervation. Could changes in alimentary handling of ingested food or interruption of vagal innervation be a factor in the development of hypoglycemia? That this might be the case in people who have undergone bariatric surgery has been previously suggested (10–16) and is now reinforced by a new manuscript by Nannipieri et al (17) in this issue of the JCEM. With the goal of identifying risk factors for postsurgical hypoglycemia in people undergoing bariatric surgery, the authors identified a subgroup of 21 from a group 34 people who spontaneously self-reported postoperative hypoglycemia. This subgroup had higher insulin sensitivity and β-cell glucose sensitivity as well as lower glucose nadirs and insulin clearances during their preoperative oral glucose tolerance tests.

Mechanism for Intrahepatic α-Cell Nonresponse to Hypoglycemia

Historically, the lack of normal glucagon responses from intrahepatically transplanted islets was first noted over 20 years ago in human recipients of autoislets (13, 14) and was noted later in alloislet recipients (14, 15). Of interest, both types of islet recipients had intact glucagon responses to iv arginine, which demonstrated that the islet grafts contained viable α-cells that synthesized glucagon and had intact glucagon exocytosis. Measurements of glucagon responses during hypoglycemic clamps revealed a distinct difference between the use of hepatic and nonhepatic sites. Recipients with exclusively intrahepatic autoislet islets had no glucagon response to hypoglycemia at glucose levels < 50 mg/dL, whereas those with intrahepatic plus intraperitoneal autoislets had glucagon responses that were not different from those of normal control subjects (8).

What might be the mechanism whereby islets placed into the liver do not release glucagon during hypoglycemia? Our hypothesis derives from the knowledge that islets infused into the liver via portal vein blood flow lodge in sinusoids near hepatocytes containing glycogen. During systemic hypoglycemia in physiologically intact humans, central nervous system inputs, catecholamines, and glucagon stimulate hepatic glycogenolysis to release free glucose into the systemic circulation. Free glucose released in the liver that directly contacts intrahepatic islets is likely to incorrectly signal their α-cells that there is no need to secrete glucagon, even when blood glucose levels are low in the rest of the body (Figure 1). This hypothesis was tested by studies in diabetic streptozotocin-treated Lewis rats (18). In the fed state, diabetic rats provided with intrahepatic islets failed to release glucagon during insulin-induced hypoglycemia, but when such rats were fasted to deplete liver glycogen, they successfully secreted glucagon during hypoglycemia. Refeeding such fasted rats restored liver glycogen, and again intrahepatic islets failed to release glucagon during hypoglycemia.

Figure 1.

Schema illustrating a putative mechanism to explain the lack of glucagon secretion from intrahepatic islets during hypoglycemia. Low systemic blood glucose levels normally stimulate central nervous system inputs, catecholamines, and glucagon secretion, which in turn stimulate hepatic glycogenolysis and thereby glucose production and release into systemic blood (see black text and arrows lines). In the case of intrahepatic islets (see red dashed lines), it is hypothesized that free glucose derived from glycogenolysis within the liver parenchyma comes into direct contact with α-cells and nullifies the hypoglycemic signal coming from the systemic circulation. At the same time, intrahepatic β-cells release insulin in response to free glucose in the liver, which also dampens the glycogenolysis and hepatic glucose output.

What are the implications of these findings for choosing sites for human islet transplantation? My perspective suggests that serious consideration should be given to adding nonhepatic sites for autoislet as well as alloislet transplantation in the future. This is now rarely done, but as mentioned, when it has been done, increased glucagon levels in systemic blood during hypoglycemia have been documented (8). It would be an easy task to put at least a portion of islets into the peritoneal cavity, the omentum, or some other nonhepatic site. That the intraperitoneal site permits islets to become vascularized and flourish was demonstrated by the glucagon response to hypoglycemia in recipients of nonhepatic islets (8), whereas those receiving only hepatic islets had no such response, as was shown in earlier studies in rodents and dogs (18, 19). This may not completely prevent hypoglycemia if its initial cause is directly related to the Roux-en-Y procedure or some other factor, but it would certainly be likely to improve counter-regulation of hypoglycemia once it occurred during exercise and after meals. Moreover, this approach could be important for type 1 diabetic recipients, some of whom lose a significant proportion of successfully intrahepatically transplanted alloislets and return to using full doses of exogenous insulin and to the renewed risk for hypoglycemia. This is an important area of inquiry that could easily be approached by a randomized clinical trial comparing hepatic vs combined hepatic and nonhepatic sites for alloislet as well as autoislet transplantation.