Impaired function in transplanted islets may be ascribed in part to disturbed reinnervation. The objectives of this study were to determine whether islet transplantation to the pancreas in the presence of nerve growth factor (NGF) would restore islet innervation and endocrine and exocrine pancreatic function. Streptozotocin-diabetic Lewis rats received 800 syngeneic islets beneath the pancreatic capsule in the presence or absence of NGF (20 ng/d for 14 days). Fasting blood glucose was measured for 3 months. The pancreata were isolated and perfused in situ. Pancreatic juice was collected for amylase determination. The sympathetic trunks were isolated and stimulated electrically. The tissues were immunostained for nerve markers. All islet recipients remained euglycemic (4.2 +/- 0.6 mmol/L glucose). Ductal amylase concentrations were restored to near normal levels in contrast to diabetic controls (normal rat 98 +/- 8 U/L, islet transplant 78.4 +/- 9 U/L, diabetic control 14.5 +/- 8 U/L). NGF enhanced the innervation of transplanted islets in contrast to control islet transplants. Sympathetic adrenergic innervation was significantly increased by NGF (tyrosine hydroxylase [P < .001] and neuropeptide Y [P < .05]). No differences in parasympathetic innervation were observed (vesicular acetylcholine transporter). Electrical stimulation of the sympathetic trunks in the presence of 4 micromol/L phentolamine and 5 micromol/L atropine resulted in increased insulin secretion in NGF-treated islet transplants (164%) compared with control transplants (30%). The combination of growth factors and the pancreatic site may allow the use of fewer islets than conventional islet transplant sites and promote more normal transplanted islet function by the enhancement of islet reinnervation.