Pancreas Transplantation Restores Epinephrine Response and Symptom Recognition During Hypoglycemia in Patients With Long-Standing Type I Diabetes and Autonomic Neuropathy

Abstract

Impaired epinephrine secretion and symptom unawareness are characteristic of severe hypoglycemia in individuals with long-standing type I diabetes. Recently, the avoidance of clinical hypoglycemia has been reported to improve epinephrine and symptom responses to hypoglycemia in type I patients. However, the extent to which these defects can be restored in individuals with long-standing type I diabetes and autonomic neuropathy has not been assessed, nor has it been determined whether pancreas transplantation, which not only obviates hypoglycemia but also prevents hyperglycemia, results in the complete recovery of either epinephrine response or symptom awareness during insulin-induced hypoglycemia. We performed stepped hypoglycemic clamp studies in successful pancreas transplantation recipients to assess epinephrine and other counterregulatory hormone responses during hypoglycemia and to determine the degree to which hypoglycemic symptom recognition could be restored. Thirteen pancreas transplant recipients and matched control subjects were studied utilizing stepped hypoglycemic clamp protocol to achieve target glucose levels of 3.9, 3.3, 2.8, and 2.2 mmol/l (70, 60, 50, and 40 mg/dl, respectively). Plasma epinephrine response was significantly greater in healthy control subjects and pancreas transplant patients compared with type I subjects at the glucose plateaus of 3.9, 3.3, and 2.8 mmol/l. However, epinephrine response in pancreas transplant recipients was significantly less than that seen in either healthy control subjects or nondiabetic kidney transplant recipients at each of these glucose plateaus. The magnitude of the epinephrine response in pancreas transplant type I patients did not correlate with either the duration of diabetes, the duration of transplantation, or the measures of autonomic nerve function. Hypoglycemic symptom recognition was significantly greater in pancreas transplant subjects than type I patients and did not differ between pancreas transplant and control groups. No improvement in norepinephrine response was observed after pancreas transplantation, while glucagon responses to hypoglycemia were normalized in pancreas transplant patients. In conclusion, these studies uniquely demonstrate that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long-standing diabetes and established autonomic neuropathy. No correlation was observed between the severity of autonomic neuropathy or the duration of diabetes and the recovery of either the epinephrine or symptom responses to hypoglycemia.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

“…This trial also shows, in contrast to prior studies (1), that protection from SHEs can be achieved without accepting an elevated HbA 1c target. Vascularized pancreas transplantation, which is generally reserved for patients needing a simultaneous kidney transplant (26), is the only other intervention capable of achieving similar results (27,28), but is uncommonly used in nonuremic T1D patients (26). …”

Clinical islet transplantation

“…Impaired hypoglycemia-induced glucagon secretion has also been observed in subjects receiving an intrahepatic islet autotransplant [38]. This stands in contrast to diabetic patients receiving whole pancreas transplants, in whom restoration of glucagon and epinephrine secretion in response to hypoglycemia has been observed [39][40][41]. Studies in a canine model of islet transplantation demonstrated a similar lack of glucagon response to hypoglycemia following intrahepatic transplantation of islets, whereas glucagon secretion was normal following transplantation of the islets into the peritoneal cavity [42].…”

Islet transplantation: Travels up the learning curve

“…Measurements of C-peptide mitigated against this explanation because they fell appropriately during the hypoglycemic clamps, indicating that the intrahepatic islet senses low glucose levels in the blood supplying the transplanted islet. Pilot studies in two islet recipients with type 1 diabetes mellitus also indicated a lack of glucagon responses to insulin-induced hypoglycemia [13]. It should be noted, however, that the degree of hypoglycemia in this trial was minimal, ie, a level of approximately 56 mg/dL.…”

“…Previously, it had been observed that pancreas transplantation successfully restored glucagon responses to insulin-induced hypoglycemia in type 1 diabetic recipients [13]. Therefore, it was expected that successful autoislet transplantation would do the same.…”