Vagal parasympathetic input to the islets of Langerhans is a regulator of islet hormone secretion, but factors promoting parasympathetic islet innervation are unknown. Neurturin signaling via glial cell line-derived neurotrophic factor family receptor ␣2 (GFR␣2) has been demonstrated to be essential for the development of subsets of parasympathetic and enteric neurons. Here, we show that the parasympathetic nerve fibers and glial cells within and around the islets express GFR␣2 and that islet parasympathetic innervation in GFR␣2 knockout (KO) mice is reduced profoundly. In wild-type mice, neuroglucopenic stress produced a robust increase in plasma levels of islet hormones. In the GFR␣2-KO mice, however, pancreatic polypeptide and insulin responses were completely lost and glucagon response was markedly impaired. Islet morphology and sympathetic innervation, as well as basal secretions of the islet hormones, were unaffected. Moreover, a glucose tolerance test failed to reveal differences between the genotypes, indicating that direct glucose-stimulated insulin secretion was not affected by GFR␣2 deficiency. These results show that GFR␣2 signaling is needed for development of the parasympathetic islet innervation that is critical for vagally induced hormone secretion. The GFR␣2-KO mouse represents a useful model to study the role of parasympathetic innervation of the endocrine pancreas in glucose homeostasis. Diabetes 54:1324 -1330, 2005 E ndocrine cells in the islets of Langerhans are well innervated by sympathetic, parasympathetic, and sensory nerve fibers. The parasympathetic branch is thought to be a regulator of the physiological islet hormone secretion (1-4). The parasympathetic fibers in the endocrine pancreas originate from neurons in the intrapancreatic ganglia (5) that receive preganglionic input from the brainstem via the vagus nerve, as well as direct input from enteric (6) and other intrapancreatic neurons (7). Activation of the vagus nerve is known to stimulate the secretion of insulin and other pancreatic hormones, although the relative contributions of noncholinergic parasympathetic neurotransmitters and the enteropancreatic projection to islet hormone secretion remain elusive (3). Meal-induced insulin secretion is traditionally divided into a preabsorptive or cephalic phase that is vagally mediated (3,4) and a subsequent and much larger postabsorptive or postprandial phase that is thought to be mainly controlled by circulating glucose levels. However, several studies (8 -10) suggest that parasympathetic regulation of postprandial insulin secretion may be more important than previously believed.Sympathetic innervation of the pancreatic islets is promoted by the nerve growth factor (11,12). Factors that control the development and maintenance of islet parasympathetic innervation, by contrast, are poorly known. Neurturin, a member of the glial cell line-derived factor family, signals through glial cell line-derived factor family receptor ␣2 (GFR␣2) and has been found to be essential for the developmen...