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

Abstract

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 β 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.

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

“…However, this decline was less pronounced compared with the 70% decrease seen in adults raised under continuous Hsc70-3 DN expression in IPCs through development. These observations support the conclusion that ER stress accumulating in IPCs triggered similar diabetes-like phenotypes, such as growth inhibition (Rulifson et al, 2002;Inoue et al, 2018). Moreover, our findings suggest that expression of Hsc70-3 DN generated more severe and more distinctive responses, resulting in the production of ER stress-induced phenotypes in Drosophila tissues compared with a known Psn-induction protocol.…”

“…Next, we observed the phenotype of adults in which Hsc70-3 DN was continuously expressed in IPCs throughout development (ilp2>hsc70-3 DN ). It is known that induction of IPC-specific apoptosis results in similar growth defects including hyperglycemia in larval hemolymph, a developmental delay and growth retardation at larval stage, and finally undersized adult flies emerged (Rulifson, et al, 2002;Ikeya, et al, 2002;Broughton et al, 2005;Inoue et al, 2018). Adults raised under this condition showed smaller whole bodies with smaller wings compared with controls (ilp2-Gal4/+) ( Fig.…”

“…The fruit fly Drosophila melanogaster has served as an excellent model for many diseases during the past decade, including metabolic diseases (Allocca et al, 2018;Ugur et al, 2016;Inoue et al, 2018;Yamaguchi, 2018). Insulin, its receptor and the insulin-signaling pathway are highly conserved between mammals and Drosophila (Teleman, 2010).…”

“…Using Drosophila as a model organism can enable investigation of the conserved mechanisms whereby IPCs become damaged, leading to IPC dysfunction and/or loss in diabetes. To establish T1D models in Drosophila, genetic ablation to remove only the IPCs has been performed by ectopic induction of proapoptotic gene reaper in the cells (Rulifson et al, 2002;Ikeya, et al, 2002;Broughton et al, 2005;Ueishi et al, 2009;Inoue et al, 2018). It resulted in a reduced viability, a delay in development and production of undersized adults.…”

Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors

“…Such findings could enhance novel genetic solutions to reduce mosquito-borne infections by targeting insulin signaling with small molecules (Zhang et al, 1999) or through the use of CRISPR in mosquitoes (Gantz et al, 2015). With respect to human infections, given that diabetes is a risk factor for flaviviral disease (Guo et al, 2017; Mavrouli et al, 2018) and that ERK- and Akt-dependent pathways control viral replication in human cells as noted above, D. melanogaster models of diabetes (Inoue et al, 2018; Musselman and Kühnlein, 2018) could extend our understanding of the mechanisms of increased risk for flavivirus infection and guide the identification of strategies to lessen human disease burden.…”