Endoplasmic reticulum stress-induced cellular dysfunction and cell death in insulin-producing cells results in diabetes-like phenotypes in Drosophila.

The destruction of pancreatic ß cells leads to reduced insulin secretion and eventually causes diabetes. Various types of cellular stress are thought to be involved in destruction and/or malfunction of these cells. We show that endoplasmic reticulum (ER) stress accumulation in insulin-producing cells (IPCs) generated diabetes-like phenotypes in Drosophila To promote the accumulation of extra ER stress, we induced a dominant-negative form of a Drosophila ER chaperone protein (Hsc70-3DN) and demonstrate that it causes the unfolded-protein response (UPR) in various tissues. The numbers of IPCs decreased owing to apoptosis induction mediated by caspases. The apoptosis was driven by activation of Dronc, and subsequently by Drice and Dcp-1. Accordingly, the relative mRNA-expression levels of Drosophila insulin-like peptides significantly decreased. Consistent with these results, we demonstrate that glucose levels in larval haemolymph were significantly higher than those of controls. Accumulation of ER stress induced by continuous Hsc70-3DN expression in IPCs resulted in the production of undersized flies. Ectopic expression of Hsc70-3DN can induce more efficient ER stress responses and more severe phenotypes. We propose that ER stress is responsible for IPC loss and dysfunction, which results in diabetes-related pathogenesis in this Drosophila diabetes model. Moreover, inhibiting apoptosis partially prevents the ER stress-induced diabetes-like phenotypes.

Drosophila Models to Investigate Insulin Action and Mechanisms Underlying Human Diabetes Mellitus.

Diabetes is a group of metabolic diseases in which the patient shows elevated levels of blood sugar. In healthy condition, there is the regulatory system that maintains constant glucose levels in blood. It is accomplished by two hormones, insulin and glucagon acting antagonistically. Insulin is produced in ß cells in pancreas and secreted to blood. It specifically binds to its receptors on plasma membrane and activates the intracellular signaling pathways. At the end, glucose in blood are taken into the cells. The diabetes is classified into two types. In type 1 diabetes (T1D), patients' pancreas fails to produce sufficient insulin. Hence, in type 2 diabetes (T2D), the target cells of insulin fail to respond to the hormone. The metabolic syndrome (MS) is characterized as a prediabetes showing lowered responsiveness to insulin. Drosophila has been expected to be a usefulness model animal for the diabetes researches. The regulatory system maintaining homeostasis of circulating sugar in hemolymph is highly conserved between Drosophila and mammals. Here, we summarize findings to date on insulin production and its acting mechanism essential for glucose homeostasis both in mammals and Drosophila. Subsequently, we introduce several Drosophila models for T1D, T2D, and MS. As a consequence of unique genetic approaches, new genes involved in fly's diabetes have been identified. We compare their cellular functions with those of mammalian counterparts. At least three antidiabetic drugs showed similar effects on Drosophila. We discuss whether these Drosophila models are available for further comparative studies to comprehend the metabolic diseases.