DOCSLIB.ORG

Selective Insulin Signaling Through a and B Insulin Receptors Regulates Transcription of Insulin and Glucokinase Genes in Pancreatic ␤ Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Selective Insulin Signaling Through a and B Insulin Receptors Regulates Transcription of Insulin and Glucokinase Genes in Pancreatic ␤ Cells Molecular Cell, Vol. 7, 559±570, March, 2001, Copyright 2001 by Cell Press Selective Insulin Signaling through A and B Insulin Receptors Regulates Transcription of Insulin and Glucokinase Genes in Pancreatic ␤ Cells Barbara Leibiger,*§ Ingo B. Leibiger,*§k ceptors as the primary target, include signaling via mito- Tilo Moede,* Sabine Kemper,* gen-activated protein (MAP) kinases and phosphoinosi- Rohit N. Kulkarni,² C. Ronald Kahn,² tol-3 kinase (PI3K). The insulin receptor (IR), the first Lina Moitoso de Vargas,³ and Per-Olof Berggren* step in these cascades, exists in two isoforms as a result *The Rolf Luft Center for Diabetes Research of alternative mRNA splicing of the 11th exon of the insulin Department of Molecular Medicine proreceptor transcript (Seino et al., 1989). The A type Karolinska Institutet (IR-A), or Ex11Ϫ (Ullrich et al., 1985), lacks whereas the S-171 76 Stockholm B type (IR-B), or Ex11ϩ (Ebina et al., 1985), contains Sweden the respective sequence coding for 12 amino acids in ² Research Division the C terminus of the ␣ chain of the receptor. To date, Joslin Diabetes Center and no insulin-induced effect has been reported that dis- Department of Medicine criminates signaling via A- and B-type receptors. In fact, Harvard Medical School the functional significance of these IR isoforms remains Boston, Massachusetts 02215 unclear. ³ Department of Medicine Recent studies have shown that the insulin-producing New England Medical Center and pancreatic ␤ cell is a target for insulin action, with insulin Tufts University School of Medicine effects on transcription, translation, Ca2ϩ flux, and exo- Boston, Massachusetts 02111 cytosis (Leibiger et al., 1998a, 2000; Xu and Rothenberg, 1998; Xu et al., 1998; Aspinwall et al., 1999; Kulkarni et al., 1999a). In an animal model with a ␤ cell±specific Summary knockout for IR, there is a decrease in glucose-stimu- lated insulin release and a decrease in the insulin content Insulin signaling is mediated by a complex network of of the cell (Kulkarni et al., 1999a). In addition, disruption diverging and converging pathways, with alternative of insulin signaling in the ␤ cell at the level of insulin proteins and isoforms at almost every step in the pro- receptor substrate (IRS)-1 (Kulkarni et al., 1999b) or cess. We show here that insulin activates the tran- IRS-2 (Withers et al., 1998) leads to altered growth and scription of its own gene and that of the ␤ cell glucoki- function of the ␤ cell. Consequently, insulin resistance nase gene (␤GK) by different mechanisms. Whereas may not only affect the function of the ªclassicalº insulin insulin gene transcription is promoted by signaling target tissues muscle, fat and liver, but also apply to through insulin receptor A type (Ex11Ϫ), PI3K class the pancreatic ␤ cell and thereby affect ␤ cell function. Ia, and p70s6k, insulin stimulates the ␤GK gene by In the present study, we show selective insulin signal- signaling via insulin receptor B type (Ex11ϩ), PI3K ing via the two isoforms of the insulin receptor (i.e., IR-A class II±like activity, and PKB (c-Akt). Our data provide and IR-B) in the pancreatic ␤ cell. Insulin that is secreted evidence for selectivity in insulin action via the two by ␤ cells upon glucose stimulation up-regulates tran- isoforms of the insulin receptor, the molecular basis scription of its own gene as well as that of the ␤ cell being preferential signaling through different PI3K and transcription unit of the glucokinase (␤GK) gene in an protein kinases. autocrine feedback loop. More interestingly, while the insulin gene is activated by insulin signaling via IR-A Introduction involving PI3K class Ia, p70 s6 kinase (p70s6k), and Ca2ϩ/calmodulin dependent kinases, insulin-stimulated Understanding selectivity in signal transduction is one ␤GK transcription occurs via IR-B, PI3K class II±like of the most challenging tasks in current cell biology. activity, and protein kinase B (PKB/c-Akt). These results Over the years, insulin signaling has served as one of provide evidence that signaling via either IR-A or IR-B the model examples in hormone-induced signal trans- and the subsequent activation of different classes of duction. Malfunction of insulin signaling, referred to as PI3K and protein kinases (i.e., p70s6k and PKB) repre- insulin resistance, is one of the major causes of type 2 sent a mechanism for selective insulin action. We fur- diabetes mellitus (non-insulin-dependent diabetes mel- thermore show a preferential activation of p70s6k and litus), the most common metabolic disorder in man. PKB as a result of insulin signaling via IR-A and IR-B, Insulin has been shown to exhibit pleiotropic effects respectively, in insulin-producing and non-insulin-pro- involving mitogenic and/or metabolic events. Moreover, ducing cells. the effect of insulin is tissue as well as development dependent. The fact that insulin may transduce its signal Results and Discussion through a variety of pathways has been discussed in extensive detail (White and Kahn, 1994). The two major Glucose Activates Glucokinase Gene Transcription pathways described to date, which employ insulin re- via Secreted Insulin Insulin, secreted upon glucose stimulation, is a key fac- k To whom correspondence should be addressed (e-mail: ingo@ tor in the up-regulation of insulin gene transcription (Lei- enk.ks.se). biger et al., 1998a). The promoters of both the insulin §These authors contributed equally to this work. gene and the ␤GK gene contain many similar cis ele- Molecular Cell 560 ments (Shelton et al., 1992; Leibiger et al., 1994a, 1994b; insulin gene, the addition of 20 ␮U per ml was required to Watada et al., 1996). To test whether transcription of gain an effect on ␤GK promoter activation (Figure 2E). ␤GK is regulated by similar mechanisms as the insulin Stimulation with 5 mU of insulin per ml of culture medium gene, we studied the role of glucose and insulin in regu- for 5 min led to an ␤GK promoter±driven increase in lation of ␤GK mRNA steady-state levels. Stimulation of GFP fluorescence in isolated primary pancreatic ␤ cells cultured islets (Figure 1A) or insulin-producing HIT-T15 (Figure 2C), HIT cells, and intact pancreatic islets (data cells with 16.7 mM glucose led to an increase in ␤GK not shown). mRNA levels 60 min following start of stimulation. This is Thus, our data support the view that the insulin gene similar in time course to the effect of glucose to stimulate and the ␤GK gene are both stimulated by insulin se- insulin mRNA levels (Leibiger et al., 1998a, 1998b). creted in response to glucose. Interestingly, a higher To define in more detail the dynamics of ␤GK mRNA, concentration of insulin is needed to activate ␤GK tran- we analyzed the half-life time, stability, and transcrip- scription when compared with the insulin gene. tional rate of the ␤GK mRNA pool. As shown in Figure ف ␤ 1B, the half-life time of GK mRNA was 60 min and Insulin-Stimulated Glucokinase Gene Transcription was not changed in the presence or absence of glucose. Utilizes Signal Transduction, which Is Different On the other hand, stimulation of HIT cells with 16.7 mM from that of the Insulin Gene ␤ glucose led to an increase in GK gene transcripts as Our studies on insulin-stimulated insulin gene transcrip- early as 15 min and reached a maximum of transcrip- tion have shown the involvement of PI3K, p70s6k, and tional activity at 30 min in a nuclear run-off assay (Figure Ca2ϩ/calmodulin-dependent kinase(s) in the signaling ␤ 1C). This effect of glucose on GK transcription initiation cascade (Leibiger et al., 1998a). Because previous data was also observed in normal pancreatic islets (Figure from others and our laboratory suggest that insulin- and 1D). To further corroborate these data, we established ␤GK-promoters can bind the same transcription factors ␤ a reporter gene assay using the GK promoter coupled (Shelton et al., 1992; Leibiger et al., 1994a, 1994b; Wa- ␤ to the green fluorescent protein (GFP) (pr GK.GFP). We tada et al., 1996) and both genes respond positively to ␤ used the rat GK promoter fragment up to nucleotide many of the same stimuli (glucose, insulin, secreta- Ϫ 278, since this has been shown to contain all cis ele- gogs) at the level of transcription, we questioned whether ments responsible for both glucose-dependent and cell- both genes might be regulated by the same signaling type-specific transcriptional control (Jetton et al., 1994, pathway. 1998). Stimulation with 16.7 mM glucose led to an in- To test whether the same protein kinases that are crease in ␤GK promoter±driven GFP fluorescence in HIT involved in insulin-triggered insulin gene transcription cells, isolated primary pancreatic ␤ cells, and intact pan- contribute to insulin-triggered transcription of ␤GK, we creatic islets (Figure 1E). As with the nuclear run-off studied the effect of pharmacological inhibitors on insu- assay, the dynamics of the activation of ␤GK promoter± lin-stimulated ␤GK promoter activity (Figure 3). We com- driven GFP expression were similar, if not identical, to bined insulin stimulation (5 mU/ml for 5 min at substimu- those of the glucose-stimulated insulin gene promoter latory glucose concentrations) with the cotreatment of (Leibiger et al., 1998a, 1998b). islet cells and HIT cells with inhibitors of protein kinase To determine whether glucose metabolism per se or C (PKC; 150 nM bisindolylmalemide I [BIM]), PI3K (25 secreted insulin is a requirement for the up-regulation ␮M LY294002 [LY]), p70s6k (10 nM rapamycin [rap]), of ␤GK transcription, we investigated the effect of insulin MAP kinases Erk1/2 (20 ␮M PD98059 [PD9]) and p38/ secretagogues on ␤GK mRNA steady-state levels and RK/SAPK2a ϩ SAPK1/JNK (10 ␮M PD169316 [PD1]), IR ␤GK promoter±driven GFP expression.
Load more

Recommended publications
  • DNA Damage and the Activation of the P53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes
    3062 Diabetes Volume 65, October 2016 Bastien Vergoni,1,2 Pierre-Jean Cornejo,1,2 Jérôme Gilleron,1,2 Mansour Djedaini,1,2 Franck Ceppo,1,2 Arnaud Jacquel,2,3 Gwennaelle Bouget,1,2 Clémence Ginet,1,2 Teresa Gonzalez,1,2,4 Julie Maillet,5,6,7 Véronique Dhennin,5,6,7 Marie Verbanck,5,6,7 Patrick Auberger,2,3 Philippe Froguel,5,6,7,8 Jean-François Tanti,1,2 and Mireille Cormont1,2 DNA Damage and the Activation of the p53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes Diabetes 2016;65:3062–3074 | DOI: 10.2337/db16-0014 Activation of the p53 pathway in adipose tissue contributes Insulin resistance is associated with obesity and is a major to insulin resistance associated with obesity. However, the risk factor for type 2 diabetes. Adipose tissue (AT) plays mechanisms of p53 activation and the effect on adipocyte an important role in glucose and lipid homeostasis (1,2), functions are still elusive. Here we found a higher level of and AT dysfunction associated with obesity has emerged DNA oxidation and a reduction in telomere length in adipose as a critical event for the development of insulin resis- tissueofmicefedahigh-fatdietandanincreaseinDNA tance. Low-grade inflammation and oxidative and hypoxic damage and activation of the p53 pathway in adipocytes. stresses both develop in obese AT and are involved in the Interestingly, hallmarks of chronic DNA damage are visible alteration of adipocyte functions (3–6). Therefore, activa- at the onset of obesity. Furthermore, injection of lean mice tion of stress-signaling pathways in adipocytes is critically with doxorubicin, a DNA damage-inducing drug, increased involved in AT dysfunction and insulin resistance (7–10).
    [Show full text]
  • Insulin–Insr Signaling Drives Multipotent Progenitor Differentiation Toward Lymphoid Lineages
    Article Insulin–InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages Pengyan Xia,1* Shuo Wang,1* Ying Du,1 Guanling Huang,1,2 Takashi Satoh,3 Shizuo Akira,3 and Zusen Fan1 1Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2University of Chinese Academy of Sciences, Beijing 100049, China 3Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, Osaka 565-0871, Japan The lineage commitment of HSCs generates balanced myeloid and lymphoid populations in hematopoiesis. However, the un- derlying mechanisms that control this process remain largely unknown. Here, we show that insulin–insulin receptor (InsR) signaling is required for lineage commitment of multipotent progenitors (MPPs). Deletion of Insr in murine bone marrow causes skewed differentiation of MPPs to myeloid cells. mTOR acts as a downstream effector that modulates MPP differentiation. mTOR activates Stat3 by phosphorylation at serine 727 under insulin stimulation, which binds to the promoter of Ikaros, lead- ing to its transcription priming. Our findings reveal that the insulin–InsR signaling drives MPP differentiation into lymphoid lineages in early lymphopoiesis, which is essential for maintaining a balanced immune system for an individual organism. Hematopoiesis is the process of producing all compo- Insulin, as the primary anabolic hormone, modulates a nents of the blood system from hematopoietic stem cells variety of physiological processes, including growth, differ- (HSCs; Naik et al., 2013; Mendelson and Frenette, 2014; entiation, apoptosis, and synthesis and breakdown of lipid, Walter et al., 2015). HSCs are quiescent, self-renewable pro- protein, and glucose (Samuel and Shulman, 2012).
    [Show full text]
  • PSM, a Mediator of PDGF-BB-, IGF-I-, and Insulin-Stimulated Mitogenesis
    Oncogene (2000) 19, 39 ± 50 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis Heimo Riedel*,1,2, Nasim Yousaf1, Yuyuan Zhao4, Heping Dai1,3, Youping Deng1 and Jian Wang1 1Department of Biological Sciences, Wayne State University, Detroit, Michigan, MI 48202, USA; 2Member, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, MI 48201, USA PSM/SH2-B has been described as a cellular partner of Introduction the FceRI receptor, insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR), and nerve The platelet-derived growth factor (PDGF) family growth factor receptor (TrkA). A function has been represents key mitogenic and chemotactic factors that proposed in neuronal dierentiation and development but have been exploited by the Simian sarcoma virus v-sis its role in other signaling pathways is still unclear. To oncogene which results in altered PDGF expression further elucidate the physiologic role of PSM we have (Water®eld et al., 1983). Normal cellular PDGF identi®ed additional mitogenic receptor tyrosine kinases appears in three distinct isoforms as any combination as putative PSM partners including platelet-derived of the PDGF A and B chains which act in paracrine growth factor (PDGF) receptor (PDGFR) beta, hepato- and autocrine mechanisms (Heldin, 1993). PDGF cyte growth factor receptor (Met), and ®broblast growth receptor (PDGFR) signal transduction appears to be factor receptor. We have mapped Y740 as a site of a largely membrane delineated event (Hughes et al., PDGFR beta that is involved in the association with 1996).
    [Show full text]
  • Structure of the Tie2 RTK Domain: Self-Inhibition by the Nucleotide Binding Loop, Activation Loop, and C-Terminal Tail
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure, Vol. 8, 1105±1113, November, 2000, 2000 Elsevier Science Ltd. All rights reserved. PII S0969-2126(00)00516-5 Structure of the Tie2 RTK Domain: Self-Inhibition by the Nucleotide Binding Loop, Activation Loop, and C-Terminal Tail Lisa M. Shewchuk,* Anne M. Hassell, Byron Ellis, binding domain and an intracellular kinase domain. Binding of W. D. Holmes, Roderick Davis, Earnest L. Horne, extracellular ligand is believed to promote dimerization, which Sue H. Kadwell, David D. McKee, leads to autophosphorylation and activation of the kinase do- and John T. Moore main [reviewed in 15]. Stringent regulation of the phosphoryla- GlaxoWellcome tion state and activity of the Tie2 kinase domain is crucial to Research Triangle Park, North Carolina 27709 normal vasculature development and maintenance. Tie2 activ- ity is precisely regulated by the opposing actions of agonistic and antagonistic extracellular ligands [16±18]. Tie2 activation Summary requires autophosporylation in response to binding its agonists angiopoietin 1 (Ang1) and Ang4, whereas inactivation occurs Background: Angiogenesis, the formation of new vessels from in response to Ang2 and Ang3. Tie2 mutations, which result the existing vasculature, is a critical process during early devel- in ligand-independent and enhanced autophosphorylation, opment as well as in a number of disease processes. Tie2 (also cause hereditary venous malformations [19, 20]. Conversely, known as Tek) is an endothelium-specific receptor tyrosine transgenic mice that express a kinase-inactive form of Tie2 or kinase involved in both angiogenesis and vasculature mainte- Tie2 null mice die in utero due to defects in their microvascula- nance.
    [Show full text]
  • LCZ696) Compared to Valsartan Attenuates Hepatotoxicity in STZ-Induced Hyperglycemic Rats Faleh Alqahtani#, Mohamed Mohany#, Abdullah F Alasmari, Ahmed Z
    Int. J. Med. Sci. 2020, Vol. 17 3098 Ivyspring International Publisher International Journal of Medical Sciences 2020; 17(18): 3098-3106. doi: 10.7150/ijms.49373 Research Paper Angiotensin II receptor Neprilysin inhibitor (LCZ696) compared to Valsartan attenuates Hepatotoxicity in STZ-induced hyperglycemic rats Faleh Alqahtani#, Mohamed Mohany#, Abdullah F Alasmari, Ahmed Z. Alanazi, Osamah M. Belali, Mohammed M Ahmed, and Salim S Al-Rejaie Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh – 1145, Saudi Arabia. #These authors contributed equally to this work. Corresponding author: E-mail: [email protected]; Tel.: +966114677178. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.06.11; Accepted: 2020.10.09; Published: 2020.10.22 Abstract Background and objectives: Although diabetic-induced hepatotoxicity is less common, it can be included in the list of target organ pathologies associated with diabetes. This study aimed to investigate the potential therapeutic role of sacubitril/valsartan (LCZ696) in modulating oxidative and inflammatory injuries and liver fibrosis in STZ-induced hyperglycemic rats in comparison to valsartan alone. Materials and Methods: Following the induction of diabetes using a single dose of streptozotocin (STZ), STZ-induced hyperglycemic animals were administered LCZ696 or valsartan for 6 weeks. Glucose, transaminases, lipid profile, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin - 6 (IL-6), were estimated using the obtained serum. Oxidative stress biomarkers including thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were measured in the liver homogenate.
    [Show full text]
  • The Insulin and IGF-1 Receptors
    The insulin and IGF-1 receptors Author: Pierre De Meyts Author title: MD, PHD, F.A.C.E. A bit of history The birth of the receptor concept dates back to the early work of John Newport Langley (1852-1925), a Cambridge physiologist, who postulated in 1905 that a "receptive substance" on the surface of skeletal muscle mediated the action of nicotine (1). At about the same time, Paul Ehrlich (1854-1915), a German immunologist who was the founding father of chemotherapy, came up with a "side chain theory" of cell receptors to explain the selectivity of immune reactions, winning him the Nobel Prize in Physiology or Medicine in 1908. His famous adage "Corpora non agunt nisi fixata" ("Substances do not act unless they are bound") is an elegant and concise early statement of the receptor theory (2). The receptor concept was put on more solid ground with the seminal 1948 paper of Raymond P. Ahlquist (1914-1983), an American pharmacologist of Swedish descent at the Medical College of Georgia, who proposed that the excitatory and inhibitory effects of adrenotropic agents were mediated by two separate receptors which he termed a and b (3). The receptors would however remain hypothetical entities until the late 60's, when direct methods to study their biochemistry were developed. The concept that insulin exerts its effects by acting at the membrane of target cells was proposed over 60 years ago by Rachmiel Levine (1910-1991), considered by many as one of the founding fathers of modern diabetology, then working at Walter Reese Hospital in Chicago.
    [Show full text]
  • Five Mutant Alleles of the Insulin Receptor Gene in Patients with Genetic Forms of Insulin Resistance
    Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. T Kadowaki, … , P Gorden, S I Taylor J Clin Invest. 1990;86(1):254-264. https://doi.org/10.1172/JCI114693. Research Article The nucleotide sequence was determined for all 22 exons of the insulin receptor gene from three patients with genetic syndromes associated with extreme insulin resistance. In all three patients, insulin resistance was caused by decreased insulin binding to the cell surface. The patient with leprechaunism (leprechaun/Winnipeg) came from a consanguineous pedigree and was homozygous for a missense mutation substituting arginine for His209 in the alpha-subunit of the insulin receptor. The other two patients were both compound heterozygotes with a nonsense mutation in one allele of the insulin receptor gene, and a missense mutation in the other allele. In the patient with the Rabson-Mendenhall syndrome (patient RM-1), the missense mutation substituted lysine for Asn15 in the alpha-subunit. In the patient with type A extreme insulin resistance (patient A-1), the missense mutation substituted serine for Asn462 in the alpha-subunit. Both nonsense mutations markedly reduced the levels of insulin receptor mRNA transcribed from the alleles with the nonsense mutation as compared to the transcripts from the other allele. The reduction in the level of mRNA would be predicted to greatly reduce the rate at which the truncated receptors would be synthesized. Furthermore, the truncated receptors would be severely impaired in their ability to mediate insulin action. Find the latest version: https://jci.me/114693/pdf Five Mutant Alleles of the Insulin Receptor Gene in Patients with Genetic Forms of Insulin Resistance Takashi Kadowaki,* Hiroko Kadowaki,* Matthew M.
    [Show full text]
  • The Insulin Receptor: a Prototype for Dimeric, Allosteric Membrane Receptors?
    Review The insulin receptor: a prototype for dimeric, allosteric membrane receptors? Pierre De Meyts Receptor Systems Biology Laboratory, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820, Gentofte, Denmark The recent crystallographic structure of the insulin receptor (IR) extracellular domain has brought us closer Glossary to ending several decades of speculation regarding the Allosteric: this refers to the regulation of the affinity or activity of a ligand stoichiometry and mechanism of insulin-receptor bind- binding to a protein (e.g. enzyme or receptor) by another ligand binding to a ing and negative cooperativity. It supports a bivalent different site than the ligand of reference (referred to as the orthosteric-binding site). The name comes from the Greek allos (meaning ‘other’) and stereos crosslinking model whereby two sites on the insulin (meaning ‘space’). It was initially used in the restricted sense of the Monod– molecule alternately crosslink two partial-binding sites Wyman–Changeux model of concerted ligand-induced conformational and on each insulin-receptor half. Ligand-induced or -stabil- affinity changes in proteins like haemoglobin, which can only generate positive cooperativity in ligand binding, but has recently been more loosely used in a ized receptor dimerization or oligomerization is a gen- broader sense equivalent to homotropic or heterotropic cooperativity, both eral feature of receptor tyrosine kinases (RTKs), in positive or negative, especially in the GPCR community. Cooperativity: a mechanism whereby binding of a ligand to one site of a addition to cytokine receptors, but the kinetic con- multimeric binding protein (like an enzyme or a receptor) affects the affinity of sequences of this mechanism have been less well stu- another ligand binding to another subunit of the same protein.
    [Show full text]
  • Structural Basis and Genotype-Phenotype Correlations of INSR Mutations
    Diabetes Page 2 of 62 Structural Basis and Genotype-phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance Jun Hosoe1*, Hiroko Kadowaki2*, Fuyuki Miya1,3,4,5*, Katsuya Aizu6, Tomoyuki Kawamura7, Ichiro Miyata8, Kenichi Satomura9, Takeru Ito10, Kazuo Hara11, Masaki Tanaka12, Hiroyuki Ishiura12, Shoji Tsuji12, Ken Suzuki1, Minaka Takakura1, Keith A. Boroevich4, Tatsuhiko Tsunoda3,4,5, Toshimasa Yamauchi1, Nobuhiro Shojima1** & Takashi Kadowaki1** * J.H., H.K., and F.M. contributed equally to this work. ** Corresponding authors: Takashi Kadowaki, [email protected], and Nobuhiro Shojima, [email protected]. 1Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2Department of Pediatrics, Sanno Hospital, Tokyo, Japan. 3Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 4Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical 1 Diabetes Publish Ahead of Print, published online August 1, 2017 Page 3 of 62 Diabetes Sciences, Yokohama, Japan 5CREST, JST, Tokyo, Japan 6Division of Endocrinology and Metabolism, Saitama Children's Medical Center, Saitama, Japan 7Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan 8Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan 9Department of Pediatric Nephrology and Metabolism, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan 10Department of Pediatrics, Atsugi City Hospital, Kanagawa, Japan 11Department of Endocrinology and Metabolism, Saitama Medical Center, Jichi Medical University, Saitama, Japan 12Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2 Diabetes Page 4 of 62 Abstract The insulin receptor (INSR) gene was analyzed in four patients with severe insulin resistance, revealing 5 novel mutations and a deletion that removed exon 2.
    [Show full text]
  • Insulin and Leptin As Adiposity Signals
    Insulin and Leptin as Adiposity Signals STEPHEN C. BENOIT,DEBORAH J. CLEGG,RANDY J. SEELEY, AND STEPHEN C. WOODS Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267 ABSTRACT There is now considerable consensus that the adipocyte hormone leptin and the pancreatic hormone insulin are important regulators of food intake and energy balance. Leptin and insulin fulfill many of the requirements to be putative adiposity signals to the brain. Plasma leptin and insulin levels are positively correlated with body weight and with adipose mass in particular. Furthermore, both leptin and insulin enter the brain from the plasma. The brain expresses both insulin and leptin receptors in areas important in the control of food intake and energy balance. Consistent with their roles as adiposity signals, exogenous leptin and insulin both reduce food intake when administered locally into the brain in a number of species under different experimental paradigms. Additionally, central administration of insulin antibodies increases food intake and body weight. Recent studies have demonstrated that both insulin and leptin have additive effects when administered simulta- neously. Finally, we recently have demonstrated that leptin and insulin share downstream neuropep- tide signaling pathways. Hence, insulin and leptin provide important negative feedback signals to the central nervous system, proportional to peripheral energy stores and coupled with catabolic circuits. I. Overview When maintained on an ad libitum diet, most animals — including humans — are able to precisely match caloric intake with caloric expenditure, resulting in relatively stable energy stores as adipose tissue (Kennedy, 1953; Keesey, 1986). Growing emphasis has been placed on the role of the central nervous system (CNS) in controlling this precision of energy homeostasis.
    [Show full text]
  • Anaplastic Lymphoma Kinase (ALK): Structure, Oncogenic Activation, and Pharmacological Inhibition
    Pharmacological Research 68 (2013) 68–94 Contents lists available at SciVerse ScienceDirect Pharmacological Research jo urnal homepage: www.elsevier.com/locate/yphrs Invited review Anaplastic lymphoma kinase (ALK): Structure, oncogenic activation, and pharmacological inhibition ∗ Robert Roskoski Jr. Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA a r t i c l e i n f o a b s t r a c t Article history: Anaplastic lymphoma kinase was first described in 1994 as the NPM-ALK fusion protein that is expressed Received 14 November 2012 in the majority of anaplastic large-cell lymphomas. ALK is a receptor protein-tyrosine kinase that was Accepted 18 November 2012 more fully characterized in 1997. Physiological ALK participates in embryonic nervous system develop- ment, but its expression decreases after birth. ALK is a member of the insulin receptor superfamily and Keywords: is most closely related to leukocyte tyrosine kinase (Ltk), which is a receptor protein-tyrosine kinase. Crizotinib Twenty different ALK-fusion proteins have been described that result from various chromosomal rear- Drug discovery rangements, and they have been implicated in the pathogenesis of several diseases including anaplastic Non-small cell lung cancer large-cell lymphoma, diffuse large B-cell lymphoma, and inflammatory myofibroblastic tumors. The Protein kinase inhibitor EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development Targeted cancer therapy Acquired drug resistance in about 5% of non-small cell lung cancers. The formation of dimers by the amino-terminal portion of the ALK fusion proteins results in the activation of the ALK protein kinase domain that plays a key role in the tumorigenic process.
    [Show full text]
  • Expression of Insulin Receptor and C-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients
    applied sciences Article Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients Nehad M. Ayoub 1,* , Rami J. Yaghan 2 , Alia H. Al-Mohtaseb 3 , Najla Aldaoud 3 , Ismail I. Matalka 3 and Muwada E. Elhassan 3 1 Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan 2 Department of Surgery, College of Medicine and Medical Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain; [email protected] 3 Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; [email protected] (A.H.A.-M.); [email protected] (N.A.); [email protected] (I.I.M.); [email protected] (M.E.E.) * Correspondence: [email protected]; Tel.: +962-796-855-653 Received: 9 January 2020; Accepted: 24 February 2020; Published: 29 February 2020 Abstract: Receptor Tyrosine Kinases (RTKs) represent a class of transmembrane receptors known to play an important role in cancer development and progression. In this study, the expression of insulin receptor (IR) and the hepatocyte growth factor receptor (c-MET) was examined in breast cancer patients. Immunohistochemistry for IR and c-MET was performed on 71 cases of invasive breast cancer and expression scores were correlated with clinicopathologic characteristics and molecular subtypes and further stratified based on a menopausal status. Expression of IR was significantly associated with the tumor grade (p = 0.017) and estrogen receptor (ER) expression (p = 0.015). There was a significant positive correlation between IR and c-MET expression scores (rho = 0.458, p < 0.001).
    [Show full text]