Abstract
Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINSC96Y and hINSLB15YB16delinsH, neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINSC96Y also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.
Highlights
Diabetes is a group of metabolic diseases wherein patients show a condition of elevated blood sugar levels called hyperglycemia
To clarify whether the expression of human mutant preproinsulin was responsible for causing the permanent neonatal diabetes mellitus (PNDM), we induced the expression of the mutant proteins hINSC96Y and hINSLB15YB16delinsH (Figure S1) in Drosophila melanogaster
The signal in the wing discs expressing hINSLB15YB16delinsH (Bx > hINSLB15YB16delinsH) was faint, but slightly higher than that in the control discs. These results suggested that the endoplasmic reticulum (ER) stress induced by two human mutant preproinsulins could result in the weak activation of the Jun NH2-terminal kinases (JNK) pathway, but the level was not strong enough to induce apoptosis in Drosophila tissues
Summary
Diabetes is a group of metabolic diseases wherein patients show a condition of elevated blood sugar levels called hyperglycemia. Type 1 diabetes is considered to be an autoimmune disease characterized by inflammatory responses that leads to the gradual destruction of pancreatic β-cells This type of cell damage causes insulin deficiency, and results in deregulation of glucose metabolism [2]. Mutations in the human insulin gene (INS) are a common cause of permanent neonatal diabetes mellitus (PNDM). When some of these mutant proinsulin genes are expressed in human cultured cells, folding and/or secretion of the mutant polypeptides are disrupted [3,4,5]. It is crucial to identify factors involved in the pathogenesis and understand the mechanisms by which the onset of PNDM using animal models for development of more effective therapeutic agents
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
