The novel satiety factor nesfatin-1 and its precursor NUCB2 are the neuropeptides widely expressed in the central nervous system. Nesfatin-1/NUCB2 is also localized in peripheral tissues and regulates the glucose and energy metabolism on multiple processes. Nesfatin-1 potentiates both insulin release from pancreatic β-cells and insulin action in liver, contributing to energy storage. Furthermore, nesfatin-1/NUCB2 regulates adipocyte differentiation. The polymorphism of the NUCB2 gene is associated with obesity. Thus, nesfatin- 1/NUCB2 plays a role in integrating feeding, glucose homeostasis, and energy storage/expenditure. Dysfunction of expression, secretion and/or action of nesfatin-1/NUCB2 might be involved in the type 2 diabetes, obesity and metabolic syndrome. Nesfatin-1/NUCB2 and its regulatory processes may provide novel targets for treating associated diseases of the metabolic syndrome. Here, we review the by now published studies on nesfatin-1/NUCB2 localization and action in islets and discuss the physiological and pathophysiological roles of the nesfatin-1/NUCB2 in glucose and energy metabolism.