Restoring Glucose Counterregulation by Islet Transplantation
Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ~30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.
Defective glucose counterregulation develops in long-standing type 1 diabetes (T1D) due to progressive impairments in defense mechanisms against a falling plasma glucose concentration in the setting of therapeutic hyperinsulinemia. This includes loss of inhibition in endogenous insulin secretion with associated loss of activation in glucagon secretion, which together normally increase endogenous (primarily hepatic) glucose production (EGP); impairment in sympathoadrenal epinephrine secretion, which contributes to EGP; and symptom generation, which leads to a syndrome of hypoglycemia unawareness also known as hypoglycemia-associated autonomic failure (HAAF). Hypoglycemia unawareness in T1D is associated with a 20-fold increased risk for experiencing severe hypoglycemia, which itself contributes importantly to increased morbidity and mortality.
In cross-sectional studies of long-standing T1D, after intrahepatic islet transplantation, insulin-induced hypoglycemia is associated with normal inhibition of endogenous insulin secretion and either defective or partially restored glucagon secretion, epinephrine secretion, and symptom responses. We sought to determine whether the recovery of islet responses to hypoglycemia after transplantation together with avoidance of hypoglycemia afforded by functioning islet grafts would reverse HAAF and restore the EGP response by studying longitudinally the same patients before and 6 months after transplantation.
Abstract and Introduction
Abstract
Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ~30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.
Introduction
Defective glucose counterregulation develops in long-standing type 1 diabetes (T1D) due to progressive impairments in defense mechanisms against a falling plasma glucose concentration in the setting of therapeutic hyperinsulinemia. This includes loss of inhibition in endogenous insulin secretion with associated loss of activation in glucagon secretion, which together normally increase endogenous (primarily hepatic) glucose production (EGP); impairment in sympathoadrenal epinephrine secretion, which contributes to EGP; and symptom generation, which leads to a syndrome of hypoglycemia unawareness also known as hypoglycemia-associated autonomic failure (HAAF). Hypoglycemia unawareness in T1D is associated with a 20-fold increased risk for experiencing severe hypoglycemia, which itself contributes importantly to increased morbidity and mortality.
In cross-sectional studies of long-standing T1D, after intrahepatic islet transplantation, insulin-induced hypoglycemia is associated with normal inhibition of endogenous insulin secretion and either defective or partially restored glucagon secretion, epinephrine secretion, and symptom responses. We sought to determine whether the recovery of islet responses to hypoglycemia after transplantation together with avoidance of hypoglycemia afforded by functioning islet grafts would reverse HAAF and restore the EGP response by studying longitudinally the same patients before and 6 months after transplantation.