Intrahepatic Islet Transplantation in Type 1 Diabetic Patients Does Not Restore Hypoglycemic Hormonal Counterregulation or Symptom Recognition After Insulin Independence

Abstract

Islet allotransplantation can provide prolonged insulin independence in selected individuals with type 1 diabetes. Whether islet transplantation also restores hypoglycemic counterregulation is unclear. To determine if hypoglycemic counterregulation is restored by islet transplantation, we studied hormone responses and hypoglycemic symptom recognition in seven insulinindependent islet transplant recipients using a 3-h stepped hypoglycemic clamp, and compared their responses to those of nontransplanted type 1 diabetic subjects and nondiabetic control subjects. Glucagon responses of islet transplant recipients to hypoglycemia were significantly less than that observed in control subjects (incremental glucagon [mean ؎ SE]: ؊12 ؎ 12 vs. 64 ؎ 22 pg/ml, respectively; P < 0.05), and not significantly different from that of nontransplanted type 1 diabetic subjects (؊17 ؎ 10 pg/ml). Epinephrine responses and symptom recognition were also not restored by islet transplantation (incremental epinephrine [

Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes

“…The significantly greater suppression of the incremental glucagon response during hypoglycemia in the type 1 diabetic subjects compared with the islet transplant recipients has not been previously demonstrated. In the study by Paty et al (6), there was no difference in incremental glucagon during hypoglycemia between seven type 1 diabetic subjects and seven islet transplant recipients; however, the two groups were studied at different times and at different institutions, and so their results may not be directly comparable. Furthermore, the type 1 diabetic subjects in the present study were selected from our waiting list for islet transplantation and so would be expected to share a similar severity of defective glucose counterregulation as the islet recipients had experienced before transplantation.…”

“…These studies indicate that intrahepatic islets respond appropriately to hypoglycemia by suppressing endogenous insulin secretion (5,6) and preventing a decline in glucagon levels by secreting glucagon to near baseline levels. Importantly, the hyperinsulinemic-euglycemic clamp ex- ‫؍‬ 3).…”

“…Previous studies of islet transplant recipients have demonstrated restored inhibition in endogenous insulin secretion 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).…”

“…Curiously, it has been reported that glucagon secretion is not improved by islet transplantation (5,6). In type 1 diabetes, the ␣-cell dysfunction is specific for hypoglycemia because type 1 diabetic patients secrete glucagon normally in response to other stimuli such as arginine (3).…”

“…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 experiments (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 nondiabetic control and type 1 diabetic subjects.…”