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Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signalling Pathway Impairs  Cell Function in Vivo

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Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signalling Pathway Impairs  Cell Function in Vivo Page 1 of 39 Diabetes 1 Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signalling Pathway Impairs Cell Function In Vivo Roi Isaac, Yaron Vinik, Sigalit Boura-Halfon, Lydia Farack, Sarina Streim, Eytan Elhanany, Zvi Kam, and Yehiel Zick Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel Running Title: Effects of IRS2 on -cell functionin vivo Corresponding Author: Yehiel Zick, Department of Molecular Cell Biology, Weizmann Institute of Science Rehovot,76100 Israel; Tel: +972-89-342380; Fax: +972-89-344125; e-mail: [email protected] Words : 3,999 Figures: 8 Diabetes Publish Ahead of Print, published online April 19, 2017 Page 2 of 39 Diabetes Abstract 2 Cellular stress and pro-inflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signalling. We therefore examined the effects of mutation of five ‘inhibitory’Ser phosphorylation sitesonIRS2 function in transgenic mice that overexpress, selectively in pancreatic cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A).Islets size, number, and mRNA levels of catalase and superoxide dismutase, were increased, while those of nitric oxide synthase were decreased in 7-10 weeks old IRS25A-β micecompared to IRS2WT-β mice. However, glucose homeostasis and insulin secretion in IRS25A-β mice were impaired, when compared to IRS2WT-β mice or to non-transgenic animals. This was associated withreduced mRNA levels of Glut2 and islet cell transcription factors such as Nkx6.1 and MafA.Similarly, components mediating the unfolded protein response (UPR) were decreased in islets of IRS25A-β micein accordance with their decreased insulin secretion.The beneficial effects of IRS25Aon cell proliferation and cell transcription factorswere evident only in 5-8 days old mice.These findings suggest that elimination of ‘inhibitory’ Ser phosphorylation sites of IRS2exertsshort-term beneficial effectsin vivo, howevertheir sustained elimination leads to impaired cell function. Page 3 of 39 Diabetes Introduction 3 Insulin and IGF-1 actionsare mediated by theirreceptorsthat function as Tyr-kinases. Key substrates for these receptors are the Insulin Receptor Substrate (IRS) proteins, IRS1 and IRS2that integrate many of the pleiotropic effects of insulin and IGF-1. IRS proteins, mainly IRS2, play critical roles in pancreatic -cells(1). Decreased IRS2 expression causes cell apoptosis (1; 2) and mice lacking IRS2 develop diabetes 8–10 weeks after birth due to reduced -cell mass and impaired -cell function (1). Conversely, increased IRS2 expression promotes -cell survival (3) and prevents diabetes in Irs2-/- mice (4). IRS proteins have conserved amino terminus, which contains a pleckstrin homology domain flanked by a P-Tyr binding (PTB) domain that interacts with the juxtamembrane domains of the insulin and IGF-1 receptors(5; 6). IRS proteins undergo phosphorylation on multiple Tyr residues at their C-terminal region, which serves as a docking site for SH2-containing proteins that further propagate insulin and IGF-I signals (7). IRS proteins contain >70 potential Ser/Thr phosphorylation sites for kinases such as PKA, PKC and Akt [reviewed in (8; 9)]. Insulin-induced Ser/Thr phosphorylation of IRS proteins dissociates them from the IR; prevents their Tyr phosphorylation and inhibits their interactions with downstream effectors (10). This serves as a physiological negative feed-back control mechanism, utilized by insulin and IGF-1, to turn off their own signaling cascades. However, pro-inflammatory cytokines and other inducers of insulin resistance take advantage of this mechanism. By activating a number of IRS kinases they uncouple the IRS proteins from IR or IGF-1R and inhibit their biological activities (11). Accordingly, mutation of selected inhibitory Ser sites of IRS1, located in close proximity to its PTB domain, renders it less prone to the action of IRS kinases. As a result, the mutated IRS1 better propagates insulin and IGF-1 actions (12; 13). Similarly, introduction into pancreatic cells of IRS2 proteins mutated at five potential inhibitory Ser sites (IRS25A) for a short time period,better promoted insulin signaling and improved-cell survival and function in culture.Furthermore, when islets expressing IRS25Aare transplanted into diabetic mice they supported glucose homeostasisbetter than IRS2WT(14). These findings suggest thatshort- termelimination of negative feedback control mechanisms along the insulin/IGF-1 signalling pathway improves -cell function under stress. To further assess the physiological significance of permanently eliminating ‘inhibitory’ Ser phosphorylation sites, we have generated transgenic mice that constitutively overexpress either IRS2WTor IRS25A selectively in pancreatic -cells. Our findings indicate that while the overexpressed IRS2 proteins, mainly IRS25A,exert beneficial effects on the animals, mainly at a very young age (5-8 days), a long–term expression ofIRS25A impairs -cell function. These findings Page 4 of 39 Diabetes 4 indicate that the beneficial effects of IRS25A(14)are limited in durationand, in the long run, are overridden by its negative effects, leading eventually to -cell exhaustion and demise. Page 5 of 39 Diabetes 5 Research Design and Methods Mice Male C57BL/6J mice were housed under standard light/dark conditions and were given access to food and water ad libitum; Experiments were approved by the Animal Care and Use Committee of the Weizmann institute of Science. Generation of IRS2WT and IRS25A transgenic mice Double-transgenic heterozygous mice that express Myc-Irs2proteins (WT or 5A) selectively in pancreatic cellswere generated by crossing mice that express Myc-Irs2 proteins (WT or 5A) driven by the tetracycline-operator based promoter, with mice that express the reverse tetracycline-regulated trans-activator (rtTA) driven by the rat insulin 2 promoter fragment (RIP)(15). In brief, pTet-Splice1 plasmids containing the tetracycline response element (TRE) and Myc-tagged Irs2WT or Irs25A were generated as described (14). The plasmids were linearized by digestion with Xho1 and Not1,gel-purified,and were microinjected into the pronuclei of CB6F1 zygotes. The born mice (F generation) were scanned for the presence of Myc-Irs25A or Myc-Irs2WT by PCR (vide infra), and positive mice were out-bred with wild type CB6F1 mice to generate heterozygote mice (F1 generation). Heterozygote mice were crossed with ICR mice expressing the reverse tetracycline transactivator (rtTA) under the control of the rat insulin II promoter, consisting of the 9.5-kb 5′ flanking region of the gene (Rip7-rtTA) (16). Crossbreeding of the two Tg lines yielded a double-transgenic heterozygote mice (Irs25A-β; Irs2WT- β) that activate their transgene following administration of tetracyclin to their drinking water. Since the original Tg mice were offsprings of a crossbreeding of CB6F1 and ICR, the mice were back- crossed with C57BL/6 mice to achieve homogeneous genetic background. Following six backcrosses, the new litters expressed at least ~98% of the genetic background of C57BL/6 mice. Densitometry and statistical analysis The intensity of bands in autoradiograms was determined by densitometry carried out on exposures within the linear range. Graphic analysis was performed with NIH image software. Results were analyzed using Non-parametric comparisons, based upon Mann- Whitney U tests. p< 0.05 were considered significant.In those studies for which the n’s were low, the experiments may be underpowered. To quantify the difference between glucose tolerance tests the area under the curve (AUC) was calculated by the trapezoid rule. The mean AUC ± SEM was determined from at least 3 individual curves for each experimental condition reported. Additional Materials and Methods The source of materials, antibodies,and detailed methods concerningmouse genotyping; metabolic studies; mouse diet;preparation of cell extracts; isolation and treatment of murine islets; islet morphology; RNA analysis; glucose stimulated insulin Page 6 of 39 Diabetes 6 secretion (GSIS); immunofluorescence microscopy, and immunostaining analysisare provided in the online supplement. Pag e 7 o f 39 Diabetes 7 Results 5A Characterization of Irs2 -β mice.Transient expression in pancreatic islets of IRS2 proteinsmutatedat five potential inhibitory Ser sites (IRS25A; S303A, S343A, S362A, S381A, S480A)improvedinsulin signaling, as well as -cell survival and function in culture (14). Furthermore, when islets expressing Irs25A were transplanted into diabetic mice they supported glucose homeostasisbetter thanIrs2WT(14). Our goal was to follow on these findingsand determine the sustained effects of Irs25Aexpression under in vivo settings. To this end, double heterozygous transgenic mice that overexpress both Myc-IRS2 proteins (WT or 5A),driven by the tetracycline- operator based promoter, and the reverse tetracycline-regulated trans-activator (rtTA), driven by the rat insulin-2 promoter fragment,were generated. These mice were expected to express Myc-IRS2 (WT or 5A) selectively in pancreatic cells in an inducible manner. To examine expression of the IRS2 proteins in pancreatic β cells, doxycycline was administered in the drinking water of Irs25A-β and Irs2WT-βmice. After six days islets were isolated and analyzed for Myc expression. As shown in Fig. 1, there was no expression of Myc in the control non-Tganimals both at the mRNA and protein levels, however, there was a significant
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