Crucial roles of neuronatin in insulin secretion and high glucose-induced apoptosis in pancreatic β-cells

Neuronatin (Nnat) was initially identified as a selectively-expressed gene in neonatal brains, but its expression has been also identified in pancreatic β-cells. Therefore, to investigate the possible functions that Nnat may serve in pancreatic β-cells, two Nnat isotypes (α and β) were expressed using adenoviruses in murine MIN6N8 pancreatic β-cells, and the cellular fates and the effects of Nnat on insulin secretion, high glucose-induced apoptosis, and functional impairment were examined. Nnatα and Nnatβ were primarily localized in the endoplasmic reticulum (ER), and their expressions increased insulin secretion by increasing intracellular calcium levels. However, under chronic high glucose conditions, the Nnatβ to Nnatα ratio gradually increased in proportion to the length of exposure to high glucose levels. Moreover, adenovirally-expressed Nnatβ was inclined to form aggresome-like structures, and we found that Nnatβ aggregation inhibited the function of the proteasome. Therefore, when glucose is elevated, the expression of Nnatβ sensitizes MIN6N8 cells to high glucose stress, which in turn, causes ER stress. As a result, expression of Nnatβ increased hyperglycemia-induced apoptosis. In addition, the expression of Nnatβ under high glucose conditions decreased the expression of genes important for β-cell function, such as glucokinase (GCK), pancreas duodenum homeobox-1 (PDX-1), and insulin. Collectively, Nnat may play a critical factor in normal β-cell function, as well as in the pathogenesis of type 2 diabetes.