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 posttransplant 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. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA_1c 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 was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although 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 versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or β-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor β-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

Keywords: glucagon secretion; glucose counterregulation; insulin secretion; islet transplantation; type 1 diabetes.

Graphical abstract

Figure 1.

Study design.

Figure 2.

Interstitial glucose concentrations investigated for the 9 study participants with type 1 diabetes a median (range) of 7.0 (1.9–8.4) yr following intrahepatic islet transplantation according to the Clinical Islet Transplantation Consortium protocol for islet-alone transplantation (Ref. 35). Interstitial sensor glucose concentrations determined from 7-day blinded continuous glucose monitor (CGM; iPro2 Professional Continuous Glucose Monitor, Medtronic, Northridge, CA) and based on 7 (5–8) days of sensor wear. Black line gives the median, darker shades represent the interquartile ranges, and lighter shades represent the 5th percentile ranges demonstrating near-normal glycemic control and essentially no time (1 [0–3] %) spent in the range of hypoglycemia <70 mg/dL.

Figure 3.

Diastolic blood pressure (A), resting heart rate (B), plasma insulin (C), and glucose (D) with infusion of phentolamine, propranolol , or placebo at baseline (B) and under hyperinsulinemic-euglycemic (E) followed by hypoglycemic (H) clamp conditions. *P < 0.05 for individual time points.

Figure 4.

Plasma C-peptide (A), glucagon (B), pancreatic polypeptide (C), and autonomic symptom score (D) with infusion of phentolamine, propranolol, or placebo at baseline (B) and under hyperinsulinemic-euglycemic (E) followed by hypoglycemic (H) clamp conditions. *P < 0.05, £P = 0.06 for mean results obtained during the eu- and hypoglycemic clamp phases.

Figure 5.

Plasma epinephrine (A), norepinephrine (B), free fatty acids (C), and the glucose infusion rate (D) with infusion of phentolamine, propranolol, or placebo at baseline (B) and under hyperinsulinemic-euglycemic (E) followed by hypoglycemic (H) clamp conditions. *P < 0.05, **P < 0.01 for mean results obtained during the eu- and hypoglycemic clamp phases.