α- or β-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes

Abstract

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to post-transplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (β-adrenergic blockage), or placebo infusion. Participants (5 female/4 male) were median (range) age 53 (34-63) years, diabetes duration 29 (18-56) years, post-transplant 7.0 (1.9-8.4) years, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate lower with propranolol vs. placebo ( P <0.05). There was no difference in suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and while levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo ( P < 0.05). Pancreatic polypeptide was greater with phentolamine vs. placebo during the euglycemic phase ( P < 0.05), and free fatty acids were lower and the glucose infusion rate higher with propranolol vs. placebo during the hypoglycemic phase ( P < 0.05). These results indicate that neither physiologic α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic re-innervation of the islet graft is not necessary for post-transplant glucose counterregulation.