Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes

Abstract

Context: Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia episodes and symptom unawareness, but long-term data are lacking.

Objective: To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period.

Design, setting, and participants: Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects.

Intervention: All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania.

Main outcome measures: Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose.

Results: Near-normal glycemia (HbA1c ≤ 6.5%; time 70-180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant.

Conclusions: In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.

Figures

Figure 1.. Clinical measures of glycemic control (HbA1c) (A), insulin requirements (B), hypoglycemia unawareness (Clarke score) (C), and glycemic LI (D) in subjects with T1D (n = 10) before and at various intervals after islet transplantation to 24 months.

A, Normal data for HbA1c are derived from the nondiabetic control subjects (n = 10). B, Post-transplant insulin use is accounted for by one subject who received a second islet infusion after 6 months, was insulin free at 12 months after this second islet infusion, and returned to insulin use thereafter. C, A Clarke score of 4 or more indicates reduced awareness of hypoglycemia. D, The LI requires records of four or more self-monitoring blood glucose values daily, which were only available for a subset of the cohort at 12 months after transplant (n = 6). The box plots represent the median, upper, and lower quartiles, mean (□), and range (error bars).

Figure 2.. Plasma insulin (A) and glucose (B) during the hyperinsulinemic hypoglycemic clamp in T1D subjects before () and at 6 months () and 18 months () after islet transplantation (n = 10), and in nondiabetic control subjects (; n = 10).

The shaded area represents the 95% confidence interval for data derived from the hyperinsulinemic euglycemic control experiments (n = 40).

Figure 3.. Counterregulatory hormone [glucagon (A), pancreatic polypeptide (B), epinephrine (C)], autonomic symptom (D), EGP (E), and free fatty acid (F) responses during the hyperinsulinemic hypoglycemic clamp in T1D subjects before () and at 6 months () and 18 months () after islet transplantation (n = 10) and in nondiabetic control subjects (; n = 10).

The shaded areas represent the 95% confidence interval for data derived from the hyperinsulinemic euglycemic control experiments (n = 40). The pre-transplant data and 6-month post-transplant data contributed to a prior report (19).