What is known in today’s literature is that diabetes cannot ensue without the loss of islet beta-cell function and mass.  Therefore, fundamental studies on the molecular and biochemical mechanisms underlying beta-cell dysfunction are vital to understand the development of this disease.  Two mechanisms which can lead to beta cell dysfunction are the oxidative and endoplasmic reticulum (ER) stress pathways.  While both pathways can operate independently, there is evidence that they can intersect as they share common links.  Therefore a better understanding of the pathways regulating ER-stress in beta-cells may be instrumental for the design of novel therapies to prevent beta-cell loss in diabetes.  Herpud1 is a mammalian ubiquitin domain containing protein, which is highly induced by the unfolded protein response in response to ER-stress, however very little is known about the biological function of this gene. 

To investigate the role of Herpud1 in beta cell function we have either knocked down or overexpressed this gene in-vitro using isolated mouse islets to examine the effects on insulin secretion.  Following a 48 hour incubation period with Herpud1 siRNA, which resulted in a 40% gene knock down, we observed a significant decrease in insulin secretion in islets when compared with the negative controls.  Conversely, the overexpression of Herpud1 did not show any insulin secretory changes under normal conditions.  However, under stress conditions, such as exposure to high glucose, the control islets showed a blunted response to glucose-stimulated insulin secretion while islets overexpressing Herpud1 retained their insulin secretory capacity comparable to the control.  Taken together, these results not only provide the first functional evidence for Herpud1 in insulin secretion but also highlight an important role for this gene to protect against stress-induced beta-cell dysfunction.  If these findings hold true, Herpud1 may be a new target for the prevention of beta-cell dysfunction and diabetes.