Original Article Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes Michael R. Rickels, 1 Mark H. Schutta, 1 Rebecca Mueller, 1 James F. Markmann, 2 Clyde F. Barker, 2 Ali Naji, 2 and Karen L. Teff 1,3 Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypo- glycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven con- trol subjects underwent a paired hyperinsulinemic-eugly- cemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and con- trol subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recip- ients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients com- pared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperin- sulinemia during the euglycemic clamp and was signifi- cantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endoge- nous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored. Diabetes 54: 3205–3211, 2005 T ype 1 diabetic patients with absolute insulin deficiency are at greatly increased risk for hypo- glycemic events because of the requirement for exogenous insulin and impaired glucose counterregulatory defenses (1). Recent work from Ed- monton, Alberta, clearly demonstrates that intrahepatic transplantation of isolated pancreatic islets can eliminate the development of severe hypoglycemic episodes in patients with type 1 diabetes (2). Islet transplantation may abolish hypoglycemia by reducing exogenous insulin requirements, but whether improvement in glucose coun- terregulatory mechanisms against hypoglycemia also con- tributes has not been fully studied. The primary defenses against hypoglycemia are an inhibition in endogenous insulin secretion and an activation in glucagon secretion, which together serve to increase hepatic glucose produc- tion and prevent or correct low blood glucose (1). Both responses are lost in established (i.e., C-peptide–negative) type 1 diabetes in which near total destruction of insulin- producing -cells occurs together with an associated defect in glucagon secretion from -cells (3). The final defenses against hypoglycemia are augmented by activa- tion of the sympathoadrenal system and are mediated through epinephrine secretion, which contributes to he- patic glucose production and decreases peripheral glucose utilization, and symptom generation, which alerts the individual to ingest food (1). Recurrent episodes of hypo- glycemia blunt these latter responses, leading to a syn- drome of hypoglycemia unawareness that increases the occurrence of life-threatening hypoglycemia by sixfold in type 1 diabetic patients (4). Previous studies of islet transplant recipients have dem- onstrated restored inhibition in endogenous insulin secre- tion during hypoglycemia (5,6) and improvement in epinephrine and symptom responses to hypoglycemia in some but not all subjects (6,7). Curiously, it has been reported that glucagon secretion is not improved by islet transplantation (5,6). In type 1 diabetes, the -cell dysfunc- tion is specific for hypoglycemia because type 1 diabetic patients secrete glucagon normally in response to other stimuli such as arginine (3). This specific defect in gluca- gon secretion in response to hypoglycemia might be explained by the loss of endogenous insulin secretion because -cells appear to require sensing an intraislet decrease in insulin to respond to hypoglycemia (8 –12). Alternatively, impaired neural activation of -cells in type 1 diabetes might account for the defective glucagon re- sponse to hypoglycemia (13). The persistence of an impaired glucagon response to hypoglycemia after islet transplantation has not been fully explained, and prior studies have lacked either type 1 diabetic control subjects (5) or euglycemic control exper- iments (6). Therefore, we studied the glucagon response during a hyperinsulinemic-hypoglycemic clamp along with the C-peptide response, a measure of endogenous insulin secretion, and the pancreatic polypeptide response, a measure of islet neural activation, in islet transplant recipients and compared them with responses in nondia- betic control and type 1 diabetic subjects. Importantly, to control for the inhibitory effect of hyperinsulinemia on From the 1 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the 2 Division of Transplantation, Department of Surgery, Uni- versity of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and the 3 Monell Chemical Senses Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Address correspondence and reprint requests to Michael R. Rickels, MD, Division of Endocrinology, Diabetes & Metabolism, University of Pennsylva- nia School of Medicine, 778 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104-6149. E-mail: rickels@mail.med.upenn.edu. Received for publication 11 May 2005 and accepted in revised form 22 July 2005. HUP, Hospital of the University of Pennsylvania. © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES, VOL. 54, NOVEMBER 2005 3205