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1
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Choi E, Duan C, Bai XC. Regulation and function of insulin and insulin-like growth factor receptor signalling. Nat Rev Mol Cell Biol 2025:10.1038/s41580-025-00826-3. [PMID: 39930003 DOI: 10.1038/s41580-025-00826-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2025] [Indexed: 03/24/2025]
Abstract
Receptors of insulin and insulin-like growth factors (IGFs) are receptor tyrosine kinases whose signalling controls multiple aspects of animal physiology throughout life. In addition to regulating metabolism and growth, insulin-IGF receptor signalling has recently been linked to a variety of new, cell type-specific functions. In the last century, key questions have focused on how structural differences of insulin and IGFs affect receptor activation, and how insulin-IGF receptor signalling translates into pleiotropic biological functions. Technological advances such as cryo-electron microscopy have provided a detailed understanding of how native and engineered ligands activate insulin-IGF receptors. In this Review, we highlight recent structural and functional insights into the activation of insulin-IGF receptors, and summarize new agonists and antagonists developed for intervening in the activation of insulin-IGF receptor signalling. Furthermore, we discuss recently identified regulatory mechanisms beyond ligand-receptor interactions and functions of insulin-IGF receptor signalling in diseases.
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Affiliation(s)
- Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Cunming Duan
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
| | - Xiao-Chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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2
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Chen X, Song Y, Hong Y, Zhang X, Li Q, Zhou H. "NO" controversy?: A controversial role in insulin signaling of diabetic encephalopathy. Mol Cell Endocrinol 2024; 593:112346. [PMID: 39151653 DOI: 10.1016/j.mce.2024.112346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/14/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Insulin, a critical hormone in the human body, exerts its effects by binding to insulin receptors and regulating various cellular processes. While nitric oxide (NO) plays an important role in insulin secretion and acts as a mediator in the signal transduction pathway between upstream molecules and downstream effectors, holds a significant position in the downstream signal network of insulin. Researches have shown that the insulin-NO system exhibits a dual regulatory effect within the central nervous system, which is crucial in the regulation of diabetic encephalopathy (DE). Understanding this system holds immense practical importance in comprehending the targets of existing drugs and the development of potential therapeutic interventions. This review extensively examines the characterization of insulin, NO, Nitric oxide synthase (NOS), specific NO pathway, their interconnections, and the mechanisms underlying their regulatory effects in DE, providing a reference for new therapeutic targets of DE.
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Affiliation(s)
- Xi Chen
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China; Hangzhou King's Bio-pharmaceutical Technology Co., Ltd, Hangzhou, Zhejiang, 310007, China.
| | - Ye Hong
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Xiaomin Zhang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Qisong Li
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Hongling Zhou
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
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3
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Guzman H, Mitteer LM, Chen P, Juliana CA, Boodhansingh K, Lord K, Ganguly A, De Leon DD. Case Report: Functional characterization of a missense variant in INSR associated with hypoketotic hypoglycemia. Front Pediatr 2024; 12:1493280. [PMID: 39483531 PMCID: PMC11524959 DOI: 10.3389/fped.2024.1493280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 10/04/2024] [Indexed: 11/03/2024] Open
Abstract
Hypoketotic hypoglycemia due to dysregulated insulin secretion is the most common cause of persistent hypoglycemia in children. However, this type of hypoglycemia can also result from defects in the insulin signaling pathway. Distinguishing between the two is important for informing treatment decisions. Here we describe the case of a 10-year-old female with fasting and postprandial hypoglycemia who was found to have a missense variant in the INSR gene, which we functionally characterized. The proband presented with fasting and postprandial hypoglycemia at age six. Diagnostic evaluation was consistent with hypoketotic hypoglycemia suspected to be due to hyperinsulinism, and she was treated with diazoxide. Whole exome sequencing identified a maternally inherited heterozygous missense variant in INSR. Phenotypic studies on the mother were consistent with postprandial hypoglycemia. Phosphorylated Akt and ERK1/2 levels were higher at baseline and in response to stimulation with insulin in 3T3-L1 cells expressing mutant INSR compared to cells expressing wild type INSR. Thus, herein we present a heterozygous missense variant in INSR (c.1151A>G, p.Asn384Ser) that results in constitutive and increased activation of the human insulin receptor, leading to both fasting and postprandial hypoglycemia.
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Affiliation(s)
- Herodes Guzman
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Lauren M. Mitteer
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Pan Chen
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Christine A. Juliana
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kara Boodhansingh
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Katherine Lord
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Arupa Ganguly
- Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Diva D. De Leon
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
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4
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Tomuleasa C, Tigu AB, Munteanu R, Moldovan CS, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct Target Ther 2024; 9:201. [PMID: 39138146 PMCID: PMC11323831 DOI: 10.1038/s41392-024-01899-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/29/2024] [Accepted: 06/14/2024] [Indexed: 08/15/2024] Open
Abstract
Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.
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Affiliation(s)
- Ciprian Tomuleasa
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj Napoca, Romania.
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania.
| | - Adrian-Bogdan Tigu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Raluca Munteanu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Cristian-Silviu Moldovan
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - David Kegyes
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Academy of Romanian Scientists, Ilfov 3, 050044, Bucharest, Romania
| | - Anca Onaciu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Gabriel Ghiaur
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Department of Leukemia, Sidney Kimmel Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hermann Einsele
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
- Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany
| | - Carlo M Croce
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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An W, Hall C, Li J, Hung A, Wu J, Park J, Wang L, Bai XC, Choi E. Activation of the insulin receptor by insulin-like growth factor 2. Nat Commun 2024; 15:2609. [PMID: 38521788 PMCID: PMC10960814 DOI: 10.1038/s41467-024-46990-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/15/2024] [Indexed: 03/25/2024] Open
Abstract
Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.
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Affiliation(s)
- Weidong An
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Catherine Hall
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Jie Li
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Albert Hung
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Jiayi Wu
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Junhee Park
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Liwei Wang
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Xiao-Chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
| | - Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
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Li J, Huang G. Insulin receptor alternative splicing in breast and prostate cancer. Cancer Cell Int 2024; 24:62. [PMID: 38331804 PMCID: PMC10851471 DOI: 10.1186/s12935-024-03252-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/01/2024] [Indexed: 02/10/2024] Open
Abstract
Cancer etiology represents an intricate, multifactorial orchestration where metabolically associated insulin-like growth factors (IGFs) and insulin foster cellular proliferation and growth throughout tumorigenesis. The insulin receptor (IR) exhibits two splice variants arising from alternative mRNA processing, namely IR-A, and IR-B, with remarkable distribution and biological effects disparities. This insightful review elucidates the structural intricacies, widespread distribution, and functional significance of IR-A and IR-B. Additionally, it explores the regulatory mechanisms governing alternative splicing processes, intricate signal transduction pathways, and the intricate association linking IR-A and IR-B splicing variants to breast and prostate cancer tumorigenesis. Breast cancer and prostate cancer are the most common malignant tumors with the highest incidence rates among women and men, respectively. These findings provide a promising theoretical framework for advancing preventive strategies, diagnostic modalities, and therapeutic interventions targeting breast and prostate cancer.
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Affiliation(s)
- Jinyu Li
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian, 116023, Liaoning, China
| | - Gena Huang
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian, 116023, Liaoning, China.
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7
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Koca SB, Kulali MA, Göğüş B, Demirbilek H. Type A insulin resistance syndrome due to a novel heterozygous c.3486_3503del (p.Arg1163_Ala1168del) INSR gene mutation in an adolescent girl and her mother. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e210305. [PMID: 38289143 PMCID: PMC10948035 DOI: 10.20945/2359-4292-2021-0305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 12/05/2022] [Indexed: 02/01/2024]
Abstract
Mutations in the insulin receptor (INSR) gene may present with variable clinical phenotypes. We report herein a novel heterozygous INSR mutation in an adolescent girl with type A insulin resistance syndrome and her mother.The index case was a 12-year-old girl without obesity who presented with excessive hair growth, especially in the chest and back area, and hyperpigmentation on the back of the neck (acanthosis nigricans). Acanthosis nigricans was first observed at the age of 11 years. On physical examination, the patient had acanthosis nigricans and hypertrichosis with no acne. Systolic and diastolic blood pressure measurement was within the normal range for age and sex. Laboratory tests revealed fasting hyperglycemia, fasting and postprandial hyperinsulinemia, elevated HbA1c level, and biochemical hyperandrogenemia. Fasting plasma lipids were normal. A diagnosis of type A insulin resistance syndrome was considered, and INSR gene mutation analysis was performed. Next generation sequence analysis was performed with the use of primers containing exon/exon-intron junctions in the INSR gene, and a novel heterozygous c.3486_3503delGAGAAACTGCATGGTCGC/p.Arg1163_Ala1168del change was detected in exon 19 of the INSR gene. In segregation analysis, the same variant was detected in the patient's mother, who had a milder clinical phenotype.We reported a novel, heterozygous, p.Arg1163_Ala1168del mutation in exon 19 of the INSR gene in a patient with type A insulin resistance syndrome, expanding the mutation database. The same mutation was associated with variable phenotypical severity in two subjects within the same family.
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Affiliation(s)
- Serkan Bilge Koca
- Afyonkarahisar Health Sciences University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Afyonkarahisar, Turkey,
| | - Melike Ataseven Kulali
- Afyonkarahisar Health Sciences University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Genetics, Afyonkarahisar, Turkey
| | - Başak Göğüş
- Afyonkarahisar Health Sciences University, Faculty of Medicine, Department of Medical Genetics, Afyonkarahisar, Turkey
| | - Hüseyin Demirbilek
- Hacettepe University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Ankara, Turkey
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Thompson KD, Suber W, Nicholas R, Arnosti DN. Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene. Fly (Austin) 2023; 17:2242238. [PMID: 37621079 PMCID: PMC10461493 DOI: 10.1080/19336934.2023.2242238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 08/26/2023] Open
Abstract
The insulin signalling pathway is evolutionarily conserved throughout metazoans, playing key roles in development, growth, and metabolism. Misregulation of this pathway is associated with a multitude of disease states including diabetes, cancer, and neurodegeneration. The human insulin receptor gene (INSR) is widely expressed throughout development and was previously described as a 'housekeeping' gene. Yet, there is abundant evidence that this gene is expressed in a cell-type specific manner, with dynamic regulation in response to environmental signals. The Drosophila insulin-like receptor gene (InR) is homologous to the human INSR gene and was previously shown to be regulated by multiple transcriptional elements located primarily within the introns of the gene. These elements were roughly defined in ~1.5 kbp segments, but we lack an understanding of the potential detailed mechanisms of their regulation. We characterized the substructure of these cis-regulatory elements in Drosophila S2 cells, focusing on regulation through the ecdysone receptor (EcR) and the dFOXO transcription factor. By identifying specific locations of activators and repressors within 300 bp subelements, we show that some previously identified enhancers consist of relatively compact clusters of activators, while others have a distributed architecture not amenable to further reduction. In addition, these assays uncovered a long-range repressive action of unliganded EcR. The complex transcriptional circuitry likely endows InR with a highly flexible and tissue-specific response to tune insulin signalling. Further studies will provide insights to demonstrate the impact of natural variation in this gene's regulation, applicable to human genetic studies.
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Affiliation(s)
- Katie D. Thompson
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Will Suber
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Rachel Nicholas
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - David N. Arnosti
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
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Galal MA, Alouch SS, Alsultan BS, Dahman H, Alyabis NA, Alammar SA, Aljada A. Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance. Int J Mol Sci 2023; 24:15006. [PMID: 37834454 PMCID: PMC10573852 DOI: 10.3390/ijms241915006] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Samhar Samer Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Buthainah Saad Alsultan
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Nouf Abdullah Alyabis
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Sarah Ammar Alammar
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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10
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Tunc-Ata M, Altunay ZM, Alphan A, Kucukatay V. Effect of insulin on IR and GLP1-R expressions in HT22 cells. Med Oncol 2023; 40:301. [PMID: 37712993 DOI: 10.1007/s12032-023-02172-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 08/22/2023] [Indexed: 09/16/2023]
Abstract
Insulin is a significant growth factor that specifically binds to the insulin receptor (IR) in the brain and then activates the PI3K-AKT pathway. Glucagon-like peptide 1 (GLP-1) has a variety of functions including neuroprotection, support for neurogenesis, and increasing insulin signal. This study aims to investigate the effect of insulin administered to immortalized clonal mouse hippocampal cell line (HT22) at different doses and intervals on IR, insulin receptor A (IRA), insulin receptor B (IRB), and Glucagon-like peptide 1 receptor (GLP1-R) mRNA expression and protein levels. The cells were planted in 6 well plates at a density of 3 × 105/4 × 105. Cells treated with insulin at different concentrations (5, 10, and 40 nM) were collected at 0.5, 2, 8, 16, and 24 h. RT-PCR and western blot analysis were used to measure mRNA expression and protein levels. Our results showed that insulin has short and long-term effects on IR and GLP1-R expression depending on dose and time. These findings may guide future studies targeting IR isoforms and GLP1-R in particular, as well as determining the optimal dose and duration of insulin stimulation in insulin signaling research.
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Affiliation(s)
- Melek Tunc-Ata
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey.
| | - Zeynep Mine Altunay
- Department of Neuroscience, School of Medicine, University of Connecticut, Farmington, CT, USA
| | - Aysel Alphan
- Department of Neuroscience, Institute of Health Sciences, Pamukkale University, Denizli, Turkey
| | - Vural Kucukatay
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
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11
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Liu A, Hao S, Liu F, Huang H, Ye H. Isolation of an Insulin-Like Receptor Involved in the Testicular Development of the Mud Crab Scylla paramamosain. Int J Mol Sci 2023; 24:13639. [PMID: 37686442 PMCID: PMC10487528 DOI: 10.3390/ijms241713639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/29/2023] [Accepted: 09/02/2023] [Indexed: 09/10/2023] Open
Abstract
Insulin-like androgenic gland hormone (IAG) is a key regulator of male sexual differentiation in crustaceans that plays important roles in secondary sexual characteristics and testicular development. As a hormone, IAG interacts with its membrane receptor to initiate downstream signal pathways to exert its biological functions. In this study, we isolated a full-length cDNA of an insulin-like receptor (Sp-IR) from the mud crab Scylla paramamosain. Sequence analysis revealed that this receptor consists of a Fu domain, two L domains, three FN-III domains, a transmembrane domain, and a tyrosine kinase domain, classifying it as a member of the tyrosine kinase insulin-like receptors family. Our results also suggested that Sp-IR was highly expressed in the testis and AG in males. Its expression in the testis peaked in stage I but significantly decreased in stages II and III (p < 0.01). Next, both short- and long-term RNA interference (RNAi) experiments were performed on males in stage I to explore Sp-IR function in mud crabs. The results showed that Sp-vasa and Sp-Dsx expression levels in the testis were significantly down-regulated after the specific knockdown of Sp-IR by RNAi. Additionally, the long-term knockdown of Sp-IR led to a considerable decrease in the volume of seminiferous tubules, accompanied by large vacuoles and a reduced production of secondary spermatocytes and spermatids. In conclusion, our results indicated that Sp-IR is involved in testicular development and plays a crucial role in transitioning from primary to secondary spermatocytes. This study provided a molecular basis for the subsequent analysis of the mechanism on male sexual differentiation in Brachyuran crabs.
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Affiliation(s)
- An Liu
- College of Fisheries, Jimei University, Xiamen 361021, China; (A.L.); (F.L.)
| | - Shuang Hao
- College of Ocean and Earth Sciences, Xiamen University, Xiamen 361102, China; (S.H.); (H.H.)
| | - Fang Liu
- College of Fisheries, Jimei University, Xiamen 361021, China; (A.L.); (F.L.)
| | - Huiyang Huang
- College of Ocean and Earth Sciences, Xiamen University, Xiamen 361102, China; (S.H.); (H.H.)
| | - Haihui Ye
- College of Fisheries, Jimei University, Xiamen 361021, China; (A.L.); (F.L.)
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12
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Rojek A, Wikiera B, Noczynska A, Niedziela M. Syndrome of Congenital Insulin Resistance Caused by a Novel INSR Gene Mutation. J Clin Res Pediatr Endocrinol 2023; 15:312-317. [PMID: 34965699 PMCID: PMC10448552 DOI: 10.4274/jcrpe.galenos.2021.2021.0256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 11/22/2021] [Indexed: 12/01/2022] Open
Abstract
Mutations in the INSR gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin resistance type A. Leprechaunism is an autosomal recessive disorder associated with extreme insulin resistance that leads to hyperinsulinemia, impaired glucose homeostasis, fasting hypoglycemia and postprandial hyperglycemia. Impaired insulin action causes prenatal and postnatal growth retardation. Lipoatrophy, dysmorphic facies, hypertrichosis, macrogenitosomia and hypertrophy of internal organs are also present. A male infant with congenital insulin resistance was born at term after a normal pregnancy with a weight of 1905 g (<3 c), a length of 48 cm (<3 c), and an Apgar score of 10. Intrauterine growth retardation, transient hypoglycemia, pneumonia, urinary tract infection and heart defects [patent foramen ovale (PFO); patent ductus arteriosus (PDA)] were diagnosed after birth. At 5 weeks of age, he was admitted to the regional hospital with severe fever, diarrhea and dehydration. Hyperglycemia was observed (672 mg/dL), and insulin was administered. He was referred to a hospital at 7 weeks of age for suspected neonatal diabetes and hypertrophic cardiomyopathy. The physical examination revealed a loud systolic heart murmur, tachycardia, tachypnea, dysmorphic facies, hypertrichosis, acanthosis nigricans, hypotonia, swollen nipples and enlarged testicles. Glycemic fluctuations (50-250 mg/dL) were observed. The serum insulin concentration was high (maximum 1200 IU/mL) at normoglycemia. Ultrasound of the heart confirmed progressive hypertrophic cardiomyopathy. Leprechaunism was confirmed by genetic analysis of INSR, in which a novel c.320C>G; p. Thr107Arg homozygous missense mutation was found in exon 2.
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Affiliation(s)
- Aleksandra Rojek
- Poznan University of Medical Sciences, Institute of Pediatrics, Department of Pediatric Endocrinology and Rheumatology, Poznan, Poland
| | - Beata Wikiera
- Wroclaw Medical University, Department of Endocrinology and Diabetology for Children and Adolescents, Wroclaw, Poland
| | - Anna Noczynska
- Wroclaw Medical University, Department of Endocrinology and Diabetology for Children and Adolescents, Wroclaw, Poland
| | - Marek Niedziela
- Poznan University of Medical Sciences, Institute of Pediatrics, Department of Pediatric Endocrinology and Rheumatology; Karol Jonscher’s Clinical Hospital, Poznan, Poland
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13
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Abstract
The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo-electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including (a) the detailed binding modes and functions of insulin at site 1 and site 2 and (b) the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.
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Affiliation(s)
- Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA;
| | - Xiao-Chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA;
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14
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Abstract
Insulin is a peptide hormone essential for maintaining normal blood glucose levels. Individuals unable to secrete sufficient insulin or not able to respond properly to insulin develop diabetes. Since the discovery of insulin its structure and function has been intensively studied with the aim to develop effective diabetes treatments. The three-dimensional crystal structure of this 51 amino acid peptide paved the way for discoveries, outlined in this review, of determinants important for receptor binding and hormone stability that have been instrumental in development of insulin analogs used in the clinic today. Important for the future development of effective diabetes treatments will be a detailed understanding of the insulin receptor structure and function. Determination of the three-dimensional structure of the insulin receptor, a receptor tyrosine kinase, proved challenging but with the recent advent of high-resolution cryo-electron microscopy significant progress has been made. There are now >40 structures of the insulin:insulin receptor complex deposited in the Protein Data Bank. From these structures we have a detailed picture of how insulin binds and activates the receptor. Still lacking are details of the initial binding events and the exact sequence of structural changes within the receptor and insulin. In this review, the focus will be on the most recent structural studies of insulin:insulin receptor complexes and how they have contributed to the current understanding of insulin receptor activation and signaling outcome. Molecular mechanisms underlying insulin receptor signaling bias emerging from the latest structures are described.
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Affiliation(s)
- Briony E Forbes
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia.
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15
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Mendoza C, Hanegan C, Sperry A, Vargas L, Case T, Bikman B, Mizrachi D. Insulin receptor-inspired soluble insulin binder. Eur J Cell Biol 2023; 102:151293. [PMID: 36739671 DOI: 10.1016/j.ejcb.2023.151293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
The insulin receptor (IR) is a 320 kDa membrane receptor tyrosine kinase mediating the pleiotropic actions of insulin, leading to phosphorylation of several intracellular substrates including serine/threonine-protein kinase (AKT1), and IR autophosphorylation. Structural details of the IR have been recently revealed. A high-binding insulin site, L1 (Kd =2 nM), consists of two distant domains in the primary sequence of the IR. Our design simplified the L1 binding site and transformed it into a soluble insulin binder (sIB). The sIB, a 17 kDa protein, binds insulin with 38 nM affinity. The sIB competes with IR for insulin and reduces by more than 50% phosphorylation of AKT1 in HEK 293 T cells, with similar effects on IR autophosphorylation. The sIB represents a new tool for research of insulin binding and signaling properties.
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Affiliation(s)
- Christopher Mendoza
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT, United States
| | - Cameron Hanegan
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT, United States
| | - Alek Sperry
- Mechanical Engineering, College of Engineering, Brigham Young University, Provo, UT, United States
| | - Logan Vargas
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT, United States
| | - Trevor Case
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT, United States
| | - Benjamin Bikman
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT, United States
| | - Dario Mizrachi
- Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT, United States.
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16
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Thompson K, Suber W, Nicholas R, Arnosti DN. Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.23.541945. [PMID: 37293119 PMCID: PMC10245858 DOI: 10.1101/2023.05.23.541945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The insulin signaling pathway is evolutionarily conserved throughout metazoans, playing key roles in development, growth, and metabolism. Misregulation of this pathway is associated with a multitude of disease states including diabetes, cancer, and neurodegeneration. Genome-wide association studies indicate that natural variants in putative intronic regulatory elements of the human insulin receptor gene ( INSR) are associated with metabolic conditions, however, this gene's transcriptional regulation remains incompletely studied. INSR is widely expressed throughout development and was previously described as a 'housekeeping' gene. Yet, there is abundant evidence that this gene is expressed in a cell-type specific manner, with dynamic regulation in response to environmental signals. The Drosophila insulin-like receptor gene ( InR ) is homologous to the human INSR gene and was previously shown to be regulated by multiple transcriptional elements located primarily within the introns of the gene. These elements were roughly defined in ∼1.5 kbp segments, but we lack an understanding of the potential detailed mechanisms of their regulation, as well as the integrative output of the battery of enhancers in the entire locus. Using luciferase assays, we characterized the substructure of these cis-regulatory elements in Drosophila S2 cells, focusing on regulation through the ecdysone receptor (EcR) and the dFOXO transcription factor. The direct action of EcR on Enhancer 2 reveals a bimodal form of regulation, with active repression in the absence of the ligand, and positive activation in the presence of 20E. By identifying the location of activators of this enhancer, we characterized a long-range of repression acting over at least 475 bp, similar to the action of long-range repressors found in the embryo. dFOXO and 20E have contrasting effects on some of the individual regulatory elements, and for the adjacent enhancers 2 and 3, their influence was/was not found to be additive, indicating that enhancer action on this locus can/cannot be characterized in part by additive models. Other characterized enhancers from within this locus exhibited "distributed" or "localized" modes of action, suggesting that predicting the joint functional output of multiple regulatory regions will require a deeper experimental characterization. The noncoding intronic regions of InR have demonstrated dynamic regulation of expression and cell type specificity. This complex transcriptional circuitry goes beyond the simple conception of a 'housekeeping' gene. Further studies are aimed at identifying how these elements work together in vivo to generate finely tuned expression in tissue- and temporal-specific manners, to provide a guide to understanding the impact of natural variation in this gene's regulation, applicable to human genetic studies.
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Affiliation(s)
- Katie Thompson
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan
| | - Will Suber
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan
| | - Rachel Nicholas
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan
| | - David N Arnosti
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan
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17
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Bhat N, Mani A. Dysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease. Nutrients 2023; 15:2323. [PMID: 37242206 PMCID: PMC10222271 DOI: 10.3390/nu15102323] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/08/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent condition affecting approximately a quarter of the global population. It is associated with increased morbidity, mortality, economic burden, and healthcare costs. The disease is characterized by the accumulation of lipids in the liver, known as steatosis, which can progress to more severe stages such as steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). This review focuses on the mechanisms that contribute to the development of diet-induced steatosis in an insulin-resistant liver. Specifically, it discusses the existing literature on carbon flux through glycolysis, ketogenesis, TCA (Tricarboxylic Acid Cycle), and fatty acid synthesis pathways in NAFLD, as well as the altered canonical insulin signaling and genetic predispositions that lead to the accumulation of diet-induced hepatic fat. Finally, the review discusses the current therapeutic efforts that aim to ameliorate various pathologies associated with NAFLD.
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Affiliation(s)
| | - Arya Mani
- Cardiovascular Research Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA
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18
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Wang L, Hall C, Li J, Choi E, Bai XC. Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor. Nat Struct Mol Biol 2023; 30:661-669. [PMID: 37055497 PMCID: PMC10465182 DOI: 10.1038/s41594-023-00974-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 03/20/2023] [Indexed: 04/15/2023]
Abstract
The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose activation requires ligand binding, insulin receptor-related receptor (IRR)-the third member of the IR family-is activated by alkaline pH. However, the molecular mechanism underlying alkaline pH-induced IRR activation remains unclear. Here, we present cryo-EM structures of human IRR in both neutral pH inactive and alkaline pH active states. Combined with mutagenesis and cellular assays, we show that, upon pH increase, electrostatic repulsion of the pH-sensitive motifs of IRR disrupts its autoinhibited state and promotes a scissor-like rotation between two protomers, leading to a T-shaped active conformation. Together, our study reveals an unprecedented alkaline pH-dependent activation mechanism of IRR, opening up opportunities to understand the structure-function relationship of this important receptor.
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Affiliation(s)
- Liwei Wang
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Catherine Hall
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Jie Li
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Xiao-Chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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19
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Kilic F. The nature of the binding between insulin receptor and serotonin transporter in placenta (review). Placenta 2023; 133:40-44. [PMID: 36796293 DOI: 10.1016/j.placenta.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/28/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023]
Abstract
The interplay between the insulin receptor (IR) and serotonin transporter (SERT) allows reciprocal regulation of each other's physiological roles to ensure appropriate responses to specific environmental and developmental signals. The studies reported herein provided substantial evidence of how insulin signaling influences the modification and trafficking of SERT to the plasma membrane via enabling its association with specific endoplasmic reticulum (ER) proteins. While insulin signaling is important for the modifications of SERT proteins, the fact that phosphorylation of IR was significantly down-regulated in the placenta of SERT knock out (KO) mice suggests that SERT also regulates IR. Further suggestive of SERT functional regulation of IR, SERT-KO mice developed obesity and glucose intolerance with symptoms similar to those of type 2 diabetes. The picture emerging from those studies proposes that the interplay between IR and SERT maintains conditions supportive of IR phosphorylation and regulates insulin signaling in placenta which ultimately enables the trafficking of SERT to the plasma membrane. IR-SERT association thus appears to play a protective metabolic role in placenta and is impaired under diabetic conditions. This review focuses on recent findings describing the functional and physical associations between IR and SERT in placental cells, and the dysregulation of this process in diabetes.
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Affiliation(s)
- Fusun Kilic
- Biology Department, Merced College, Merced, CA, USA.
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20
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Mandal AK, Leask MP, Sumpter NA, Choi HK, Merriman TR, Mount DB. Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis. J Am Soc Nephrol 2023; 34:451-466. [PMID: 36735516 PMCID: PMC10103387 DOI: 10.1681/asn.0000000000000054] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 10/25/2022] [Indexed: 01/22/2023] Open
Abstract
SIGNIFICANCE STATEMENT Hyperinsulinemia induces hyperuricemia by activating net renal urate reabsorption in the renal proximal tubule. The basolateral reabsorptive urate transporter GLUT9a appears to be the dominant target for insulin. By contrast, IGF-1 infusion reduces serum urate (SU), through mechanisms unknown. Genetic variants of IGF1R associated with reduced SU have increased IGF-1R expression and interact with genes encoding the GLUT9 and ABCG2 urate transporters, in a sex-specific fashion, which controls the SU level. Activation of IGF-1/IGF-1R signaling in Xenopus oocytes modestly activates GLUT9a and inhibits insulin's stimulatory effect on the transporter, which also activates multiple secretory urate transporters-ABCG2, ABCC4, OAT1, and OAT3. The results collectively suggest that IGF-1 reduces SU by activating secretory urate transporters and inhibiting insulin's action on GLUT9a. BACKGROUND Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas IGF-1 infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels. METHODS Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes. RESULTS Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. CONCLUSIONS The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.
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Affiliation(s)
- Asim K. Mandal
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Megan P. Leask
- Biochemistry Department, University of Otago, Dunedin, South Island, New Zealand
- Division of Rheumatology and Clinical Immunology, University of Alabama, Birmingham, Alabama
| | - Nicholas A. Sumpter
- Division of Rheumatology and Clinical Immunology, University of Alabama, Birmingham, Alabama
| | - Hyon K. Choi
- Division of Rheumatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tony R. Merriman
- Biochemistry Department, University of Otago, Dunedin, South Island, New Zealand
- Division of Rheumatology and Clinical Immunology, University of Alabama, Birmingham, Alabama
| | - David B. Mount
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Renal Division, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts
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21
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Wang Z, Wang C, Zhang Y, Liu S, Cheng Y, Wang S, Xia P, Hao L. Porcine IGF-1R synonymous mutations in the extracellular domain affect proliferation and differentiation of skeletal muscle cells. Gene 2023; 854:147098. [PMID: 36496177 DOI: 10.1016/j.gene.2022.147098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Miniature pigs are considered ideal organ donors for xenotransplantation in humans, but the mechanism underlying their dwarfism remains to be elucidated. IGF-1R is a crucial factor in body size formation in mammals, including skeletal muscle formation and development. The extracellular domain (ECD) binds to the ligand, a phenomenon that results in the activation of downstream pathways. METHODS In this study, the coding sequences of two IGF-1R ECD haplotypes of the large Landrace (LP) pig and the small Bama Xiang (BM) pig were cloned into pcDNA3.1 vectors to generate pcDNA3.1-LP and pcDNA3.1-BM. The two recombinant vectors were then transfected into skeletal muscle cells. RESULTS IGF-1R transcript was found to be expressed at higher levels in the pcDNA3.1-LP group than in the pcDNA3.1-BM group. The IGF-1R ECD from LP promoted cell proliferation and CyclinD1 expression, and promoted the phosphorylation of protein kinase B (to yield p-AKT). Moreover, the IGF-1R ECD from LP increased cell differentiation and the expression of myogenic determination factor (MyoD). CONCLUSION Our data indicated that the IGF-1R ECD haplotypes between pig breeds with different body sizes affect IGF-1R expression, in turn affecting the proliferation and differentiation of skeletal muscle cells by activating downstream signalling pathways.
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Affiliation(s)
- Zhaoguo Wang
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China
| | - Chunli Wang
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China
| | - Ying Zhang
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China
| | - Songcai Liu
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China.
| | - Yunyun Cheng
- Ministry of Health Key Laboratory of Radiobiology, College of Public Health, Jilin University, Changchun, Jilin 130061, China
| | - Siyao Wang
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China
| | - Peijun Xia
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China
| | - Linlin Hao
- College of Animal Science, Jilin University, Changchun, Jilin 130061, China.
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22
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Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily. Int J Mol Sci 2023; 24:ijms24043906. [PMID: 36835322 PMCID: PMC9965288 DOI: 10.3390/ijms24043906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions. In this work, using high-resolution NMR spectroscopy supported by atomistic computer modeling, conformational variability of the transmembrane domains and their interactions with surrounding lipids were found to differ significantly between representatives of the subfamily. Therefore, we suggest that the heterogeneous and highly dynamic membrane environment should be taken into account in the observed diversity of the structural/dynamic organization and mechanisms of activation of InsR, IGF1R, and IRR receptors. This membrane-mediated control of receptor signaling offers an attractive prospect for the development of new targeted therapies for diseases associated with dysfunction of insulin subfamily receptors.
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23
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Cannabinoids Transmogrify Cancer Metabolic Phenotype via Epigenetic Reprogramming and a Novel CBD Biased G Protein-Coupled Receptor Signaling Platform. Cancers (Basel) 2023; 15:cancers15041030. [PMID: 36831374 PMCID: PMC9954791 DOI: 10.3390/cancers15041030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/29/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
The concept of epigenetic reprogramming predicts long-term functional health effects. This reprogramming can be activated by exogenous or endogenous insults, leading to altered healthy and different disease states. The exogenous or endogenous changes that involve developing a roadmap of epigenetic networking, such as drug components on epigenetic imprinting and restoring epigenome patterns laid down during embryonic development, are paramount to establishing youthful cell type and health. This epigenetic landscape is considered one of the hallmarks of cancer. The initiation and progression of cancer are considered to involve epigenetic abnormalities and genetic alterations. Cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer development, including DNA methylation, histone modifications, nucleosome positioning, non-coding RNAs, and microRNA expression. Endocannabinoids are natural lipid molecules whose levels are regulated by specific biosynthetic and degradative enzymes. They bind to and activate two primary cannabinoid receptors, type 1 (CB1) and type 2 (CB2), and together with their metabolizing enzymes, form the endocannabinoid system. This review focuses on the role of cannabinoid receptors CB1 and CB2 signaling in activating numerous receptor tyrosine kinases and Toll-like receptors in the induction of epigenetic landscape alterations in cancer cells, which might transmogrify cancer metabolism and epigenetic reprogramming to a metastatic phenotype. Strategies applied from conception could represent an innovative epigenetic target for preventing and treating human cancer. Here, we describe novel cannabinoid-biased G protein-coupled receptor signaling platforms (GPCR), highlighting putative future perspectives in this field.
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24
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Scalia P, Williams SJ, Fujita-Yamaguchi Y, Giordano A. Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation. Cell Cycle 2023; 22:1-37. [PMID: 36005738 PMCID: PMC9769454 DOI: 10.1080/15384101.2022.2108117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.
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Affiliation(s)
- Pierluigi Scalia
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states,CONTACT Pierluigi Scalia ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA9102, USA
| | - Stephen J Williams
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states
| | - Yoko Fujita-Yamaguchi
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Antonio Giordano
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,School of Medical Biotechnology, University of Siena, Italy
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25
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Arya P, Kumar P. Diosgenin: An ingress towards solving puzzle for diabetes treatment. J Food Biochem 2022; 46:e14390. [PMID: 36106684 DOI: 10.1111/jfbc.14390] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/16/2022] [Accepted: 08/26/2022] [Indexed: 01/13/2023]
Abstract
The consumption and composition of food in daily life predict our health in long run. The relation of diabetes to sweets is quite popular. Diabetes hampers the glucose and insulin regulation in the human body by damaging pancreatic β cells. Diabetes has a strong potential towards altering cellular mechanisms of organs causing unlawful performance. Diabetes alters pathways like TLR4, AChE, NF-ĸB, LPL, and PPAR at different sites that affect the normal cellular machinery and cause damage to the local tissue and organ. The long-lasting effect of diabetes was observed in vascular, cardia, nervous, skeletal, reproductive, hepatic, ocular, and renal systems. The increasing awareness of diabetes and its concern has awakened the common people more enthusiastically. Due to rising harm from diabetes, scientific researchers tend to have more eyes toward it. While searching for diabetes solutions, fenugreek diosgenin could pop up with some positive effects in curing the same. Diosgenin helps to lower the scathe of diabetes by modifying cellular pathways in favor of healthy bodily functions. Diosgenin altered the pathways for renewal of pancreatic β cells for better insulin secretion, initiate GLUT4, enhanced DHEA, modify ER-α-mediated PI3K/Akt pathways. Diosgenin can be an appropriate insult for diabetes in a much evolving way for a healthy lifestyle. PRACTICAL APPLICATIONS: Diabetes is one of the most death causing diseases in the medical world. Regrettably the cure of diabetes is yet to be found. Various scientific team working on the same to look after the most appropriate way for diabetes treatment. There is enormous growth of nutraceutical in the market claiming for cure of different metabolic disorders. Among various bioactive compound fenugreek's diosgenin could took a leap over other in curing and preventing the damage caused by diabetes to different organs. The role of diosgenin in curing various metabolic disorders is quite popular from some time. This article also emphasizes over beneficiary effect of diosgenin in curing the damages caused by diabetes by altering cellular metabolism processes. Hence diosgenin could be a better way for researchers to develop a method for diabetes treatment.
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Affiliation(s)
- Prajya Arya
- Department of Food Engineering and Technology, Sant Longowal Institute of Engineering and Technology, Longowal, India
| | - Pradyuman Kumar
- Department of Food Engineering and Technology, Sant Longowal Institute of Engineering and Technology, Longowal, India
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Abstract
Single-pass transmembrane receptors (SPTMRs) represent a diverse group of integral membrane proteins that are involved in many essential cellular processes, including signal transduction, cell adhesion, and transmembrane transport of materials. Dysregulation of the SPTMRs is linked with many human diseases. Despite extensive efforts in past decades, the mechanisms of action of the SPTMRs remain incompletely understood. One major hurdle is the lack of structures of the full-length SPTMRs in different functional states. Such structural information is difficult to obtain by traditional structural biology methods such as X-ray crystallography and nuclear magnetic resonance (NMR). The recent rapid development of single-particle cryo-electron microscopy (cryo-EM) has led to an exponential surge in the number of high-resolution structures of integral membrane proteins, including SPTMRs. Cryo-EM structures of SPTMRs solved in the past few years have tremendously improved our understanding of how SPTMRs function. In this review, we will highlight these progresses in the structural studies of SPTMRs by single-particle cryo-EM, analyze important structural details of each protein involved, and discuss their implications on the underlying mechanisms. Finally, we also briefly discuss remaining challenges and exciting opportunities in the field.
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Affiliation(s)
- Kai Cai
- Departments of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
| | - Xuewu Zhang
- Departments of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Departments of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Corresponding Author: Xuewu Zhang, Department of pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Xiao-chen Bai
- Departments of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Corresponding Author: Xiao-chen Bai, Department of Biophysics, UT Southwestern Medical Center, Dallas, TX 75390, USA;
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De Meyts P. [The insulin receptor discovery is 50 years old - A review of achieved progress]. Biol Aujourdhui 2022; 216:7-28. [PMID: 35876517 DOI: 10.1051/jbio/2022007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Indexed: 06/15/2023]
Abstract
The isolation of insulin from the pancreas and its purification to a degree permitting its safe administration to type 1 diabetic patients were accomplished 100 years ago at the University of Toronto by Banting, Best, Collip and McLeod and constitute undeniably one of the major medical therapeutic revolutions, recognized by the attribution of the 1923 Nobel Prize in Physiology or Medicine to Banting and McLeod. The clinical spin off was immediate as well as the internationalization of insulin's commercial production. The outcomes regarding basic research were much slower, in particular regarding the molecular mechanisms of insulin action on its target cells. It took almost a half-century before the determination of the tri-dimensional structure of insulin in 1969 and the characterization of its cell receptor in 1970-1971. The demonstration that the insulin receptor is in fact an enzyme named tyrosine kinase came in the years 1982-1985, and the crystal structure of the intracellular kinase domain 10 years later. The crystal structure of the first intracellular kinase substrate (IRS-1) in 1991 paved the way for the elucidation of the intracellular signalling pathways but it took 15 more years to obtain the complete crystal structure of the extracellular receptor domain (without insulin) in 2006. Since then, the determination of the structure of the whole insulin-receptor complex in both the inactive and activated states has made considerable progress, not least due to recent improvement in the resolution power of cryo-electron microscopy. I will here review the steps in the development of the concept of hormone receptor, and of our knowledge of the structure and molecular mechanism of activation of the insulin receptor.
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Affiliation(s)
- Pierre De Meyts
- de Duve Institute, Department of Cell Signalling, Avenue Hippocrate 74, B-1200 Bruxelles, Belgique - Novo Nordisk A/S, Department of Stem Cell Research, Novo Nordisk Park 1, DK-2760 Maaloev, Danemark
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Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism. Nutrients 2022; 14:nu14071516. [PMID: 35406129 PMCID: PMC9002971 DOI: 10.3390/nu14071516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 11/17/2022] Open
Abstract
Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to β-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.
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Li J, Park J, Mayer JP, Webb KJ, Uchikawa E, Wu J, Liu S, Zhang X, Stowell MH, Choi E, Bai XC. Synergistic activation of the insulin receptor via two distinct sites. Nat Struct Mol Biol 2022; 29:357-368. [PMID: 35361965 PMCID: PMC9115778 DOI: 10.1038/s41594-022-00750-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 02/17/2022] [Indexed: 01/29/2023]
Abstract
Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation.
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Affiliation(s)
- Jie Li
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Junhee Park
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - John P. Mayer
- Department of Molecular, Cellular & Developmental Biology, University of Colorado, Boulder, CO 80309, USA
| | - Kristofor J. Webb
- Department of Molecular, Cellular & Developmental Biology, University of Colorado, Boulder, CO 80309, USA
| | - Emiko Uchikawa
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiayi Wu
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Shun Liu
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xuewu Zhang
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Michael H.B. Stowell
- Department of Molecular, Cellular & Developmental Biology, University of Colorado, Boulder, CO 80309, USA,Correspondence: ; ;
| | - Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA,Correspondence: ; ;
| | - Xiao-chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA,Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA,Correspondence: ; ;
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Design, synthesis and biological evaluation of novel FAK inhibitors with better selectivity over IR than TAE226. Bioorg Chem 2022; 124:105790. [DOI: 10.1016/j.bioorg.2022.105790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/27/2022] [Accepted: 04/01/2022] [Indexed: 12/21/2022]
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Iqbal J, Jiang HL, Wu HX, Li L, Zhou YH, Hu N, Xiao F, Wang T, Xu SN, Zhou HD. Hereditary severe insulin resistance syndrome: Pathogenesis, pathophysiology, and clinical management. Genes Dis 2022. [PMID: 37492723 PMCID: PMC10363564 DOI: 10.1016/j.gendis.2022.03.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.
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Wang M, Wang C, Ren S, Pan J, Wang Y, Shen Y, Zeng Z, Cui H, Zhao X. Versatile Oral Insulin Delivery Nanosystems: From Materials to Nanostructures. Int J Mol Sci 2022; 23:3362. [PMID: 35328783 PMCID: PMC8952690 DOI: 10.3390/ijms23063362] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes is a chronic metabolic disease characterized by lack of insulin in the body leading to failure of blood glucose regulation. Diabetes patients usually need frequent insulin injections to maintain normal blood glucose levels, which is a painful administration manner. Long-term drug injection brings great physical and psychological burden to diabetic patients. In order to improve the adaptability of patients to use insulin and reduce the pain caused by injection, the development of oral insulin formulations is currently a hot and difficult topic in the field of medicine and pharmacy. Thus, oral insulin delivery is a promising and convenient administration method to relieve the patients. However, insulin as a peptide drug is prone to be degraded by digestive enzymes. In addition, insulin has strong hydrophilicity and large molecular weight and extremely low oral bioavailability. To solve these problems in clinical practice, the oral insulin delivery nanosystems were designed and constructed by rational combination of various nanomaterials and nanotechnology. Such oral nanosystems have the advantages of strong adaptability, small size, convenient processing, long-lasting pharmaceutical activity, and drug controlled-release, so it can effectively improve the oral bioavailability and efficacy of insulin. This review summarizes the basic principles and recent progress in oral delivery nanosystems for insulin, including physiological absorption barrier of oral insulin and the development of materials to nanostructures for oral insulin delivery nanosystems.
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Affiliation(s)
| | | | | | | | | | - Yue Shen
- Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (M.W.); (C.W.); (S.R.); (J.P.); (Y.W.); (Z.Z.); (H.C.)
| | | | | | - Xiang Zhao
- Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (M.W.); (C.W.); (S.R.); (J.P.); (Y.W.); (Z.Z.); (H.C.)
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Falsetti L, Viticchi G, Zaccone V, Guerrieri E, Moroncini G, Luzzi S, Silvestrini M. Shared Molecular Mechanisms among Alzheimer’s Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review. Biomedicines 2022; 10:biomedicines10020439. [PMID: 35203654 PMCID: PMC8962428 DOI: 10.3390/biomedicines10020439] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/27/2022] [Accepted: 02/12/2022] [Indexed: 12/12/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common type of dementia, affecting 24 million individuals. Clinical and epidemiological studies have found several links between vascular risk factors (VRF), neurovascular unit dysfunction (NVUd), blood-brain barrier breakdown (BBBb) and AD onset and progression in adulthood, suggesting a pathogenetic continuum between AD and vascular dementia. Shared pathways between AD, VRF, and NVUd/BBB have also been found at the molecular level, underlining the strength of this association. The present paper reviewed the literature describing commonly shared molecular pathways between adult-onset AD, VRF, and NVUd/BBBb. Current evidence suggests that VRF and NVUd/BBBb are involved in AD neurovascular and neurodegenerative pathology and share several molecular pathways. This is strongly supportive of the hypothesis that the presence of VRF can at least facilitate AD onset and progression through several mechanisms, including NVUd/BBBb. Moreover, vascular disease and several comorbidities may have a cumulative effect on VRF and worsen the clinical manifestations of AD. Early detection and correction of VRF and vascular disease by improving NVUd/BBBd could be a potential target to reduce the overall incidence and delay cognitive impairment in AD.
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Affiliation(s)
- Lorenzo Falsetti
- Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria “Ospedali Riuniti” di Ancona, 60100 Ancona, Italy;
- Correspondence: ; Tel.: +39-071-596-5269
| | - Giovanna Viticchi
- Neurologic Clinic, Marche Polytechnic University, 60126 Ancona, Italy; (G.V.); (S.L.); (M.S.)
| | - Vincenzo Zaccone
- Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria “Ospedali Riuniti” di Ancona, 60100 Ancona, Italy;
| | - Emanuele Guerrieri
- Emergency Medicine Residency Program, Università Politecnica delle Marche, 60121 Ancona, Italy;
| | | | - Simona Luzzi
- Neurologic Clinic, Marche Polytechnic University, 60126 Ancona, Italy; (G.V.); (S.L.); (M.S.)
| | - Mauro Silvestrini
- Neurologic Clinic, Marche Polytechnic University, 60126 Ancona, Italy; (G.V.); (S.L.); (M.S.)
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Pokorny R, Stenehjem DD, Gilreath JA. Impact of metformin on tyrosine kinase inhibitor response in chronic myeloid leukemia. J Oncol Pharm Pract 2022; 28:916-923. [PMID: 35132891 PMCID: PMC9047107 DOI: 10.1177/10781552221077254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objective Oral tyrosine kinase inhibitors (TKIs) are first line therapy for chronic myeloid leukemia (CML). A complete cytogenetic response (CCyR) correlates with increased overall survival, however only 66%–88% of patients achieve CCyR after one year of TKI treatment. Because TKI therapy alone cannot eliminate CML stem cells, strategies aimed at achieving faster and deeper responses are needed to improve long-term survival. Metformin is a widely prescribed glucose-lowering agent for patients with diabetes and in preclinical studies, has been shown to suppress cell viability, induce apoptosis, and downregulate the mTORC1 signaling pathway in imatinib resistant CML cell lines (K562R). This study aims to investigate the utility of metformin added to TKI therapy in patients with CML. Data Sources An observational study at an academic medical center (Salt Lake City, UT) was performed for adults with newly diagnosed, chronic-phase CML to evaluate attainment of CCyR from TKI therapy with or without concomitant metformin use. Descriptive analyses were used to describe baseline characteristics and attainment of response to TKI therapy. Data Summary Fifty-nine patients were evaluated. One hundred percent (5 of 5) in the metformin group and 73.6% (39 of 54) in the non-metformin group achieved CCyR. Approximately 20% of patients in both groups relapsed (defined by a loss of CCyR during study) after a median 34.5 months of follow-up. Conclusions Future research is warranted to validate these findings and determine the utility of metformin added to TKI therapy.
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Affiliation(s)
- Rebecca Pokorny
- Department of Pharmacy, 20270Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - David D Stenehjem
- Department of Pharmacy Practice and Pharmaceutical Sciences, 14713University of Minnesota, College of Pharmacy, Duluth, MN, USA
| | - Jeffrey A Gilreath
- Department of Pharmacotherapy, College of Pharmacy and 20270Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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35
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Xue Z, Li J, Feng J, Han H, Zhao J, Zhang J, Han Y, Wu X, Zhang Y. Research Progress on the Mechanism Between Polycystic Ovary Syndrome and Abnormal Endometrium. Front Physiol 2022; 12:788772. [PMID: 34975540 PMCID: PMC8718643 DOI: 10.3389/fphys.2021.788772] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/22/2021] [Indexed: 12/22/2022] Open
Abstract
As a highly dynamic tissue, the endometrium is periodically shed in response to the secretion of estrogen and progesterone. After menarche, the endometrium of healthy women proliferates and differentiates under the action of steroid hormones (e.g., 17β-estradiol and progesterone) that are secreted by the ovaries to provide appropriate conditions for embryo implantation. Polycystic ovary syndrome (PCOS), a prevalent endocrine and metabolic disorder in reproductive-aged women, is usually associated with multiple cysts within the ovaries and excess levels of androgen and is characterized by hirsutism, acne, menstrual irregularity, infertility, and increased risk of insulin resistance. Multiple factors, such as anovulation, endocrine-metabolic abnormalities, and inflammation, can disrupt the endometrium in PCOS patients and can lead to endometrial hyperplasia, pregnancy complications, or even cancer. Despite many recent studies, the relationship between PCOS and abnormal endometrial function is still not fully understood. In this review, we investigate the correlation of PCOS patient endometrium with anovulation, hyperandrogenemia, insulin resistance, progesterone resistance, and inflammatory cytokines, aiming to provide a theoretical basis for the treatment of disorders caused by endometrial dysfunction in PCOS patients.
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Affiliation(s)
- Zhu Xue
- The graduate school, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Juanli Li
- The graduate school, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiaxing Feng
- The graduate school, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Han Han
- The First Clinical Hospital Affiliated to Harbin Medical University, Harbin, China
| | - Jing Zhao
- Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
| | - Jiao Zhang
- Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yanhua Han
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiaoke Wu
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yuehui Zhang
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Li J, Wu J, Hall C, Bai XC, Choi E. Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor. eLife 2022; 11:81286. [PMID: 36413010 PMCID: PMC9731570 DOI: 10.7554/elife.81286] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022] Open
Abstract
The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.
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Affiliation(s)
- Jie Li
- Department of Biophysics, University of Texas Southwestern Medical CenterDallasUnited States
| | - Jiayi Wu
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityNew YorkUnited States
| | - Catherine Hall
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityNew YorkUnited States
| | - Xiao-chen Bai
- Department of Biophysics, University of Texas Southwestern Medical CenterDallasUnited States,Department of Cell Biology, University of Texas Southwestern Medical CenterDallasUnited States
| | - Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityNew YorkUnited States
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Saisana M, Griffin SM, May FEB. Insulin and the insulin receptor collaborate to promote human gastric cancer. Gastric Cancer 2022; 25:107-123. [PMID: 34554347 PMCID: PMC8732810 DOI: 10.1007/s10120-021-01236-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. METHODS Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. RESULTS INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. CONCLUSIONS The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.
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Affiliation(s)
- Marina Saisana
- grid.1006.70000 0001 0462 7212Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK
| | - S. Michael Griffin
- grid.1006.70000 0001 0462 7212Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK ,grid.420004.20000 0004 0444 2244Department of Surgery, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, NE1 4LP UK
| | - Felicity E. B. May
- grid.1006.70000 0001 0462 7212Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK ,grid.1006.70000 0001 0462 7212Department of Pathology, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK ,grid.420004.20000 0004 0444 2244Department of Oncology, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, NE1 4LP UK
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Nielsen J, Brandt J, Boesen T, Hummelshøj T, Slaaby R, Schluckebier G, Nissen P. Structural investigations of full-length insulin receptor dynamics and signalling. J Mol Biol 2022; 434:167458. [DOI: 10.1016/j.jmb.2022.167458] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/28/2021] [Accepted: 01/14/2022] [Indexed: 12/21/2022]
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Bou Malhab LJ, Abdel-Rahman WM. Obesity and Inflammation: Colorectal Cancer Engines. Curr Mol Pharmacol 2022; 15:620-646. [PMID: 34488607 DOI: 10.2174/1874467214666210906122054] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/14/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022]
Abstract
The prevalence of obesity continues to increase to the extent that it became a worldwide pandemic. An accumulating body of evidence has associated obesity with the development of different types of cancer, including colorectal cancer, which is a notorious disease with a high mortality rate. At the molecular level, colorectal cancer is a heterogenous disease characterized by a myriad of genetic and epigenetic alterations associated with various forms of genomic instability (detailed in Supplementary Materials). Recently, the microenvironment has emerged as a major factor in carcinogenesis. Our aim is to define the different molecular alterations leading to the development of colorectal cancer in obese patients with a focus on the role of the microenvironment in carcinogenesis. We also highlight all existent molecules in clinical trials that target the activated pathways in obesity-associated colorectal cancer, whether used as single treatments or in combination. Obesity predisposes to colorectal cancer via creating a state of chronic inflammation with dysregulated adipokines, inflammatory mediators, and other factors such as immune cell infiltration. A unifying theme in obesity-mediated colorectal cancer is the activation of the PI3K/AKT, mTOR/MAPK, and STAT3 signaling pathways. Different inhibitory molecules towards these pathways exist, increasing the therapeutic choice of obesity-associated colon cancer. However, obese patients are more likely to suffer from chemotherapy overdosing. Preventing obesity through maintaining a healthy and active lifestyle remains to be the best remedy.
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Affiliation(s)
- Lara J Bou Malhab
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Wael M Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
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40
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Class I PI3K Biology. Curr Top Microbiol Immunol 2022; 436:3-49. [DOI: 10.1007/978-3-031-06566-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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41
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Wen L, Li Y, Li S, Hu X, Wei Q, Dong Z. Glucose Metabolism in Acute Kidney Injury and Kidney Repair. Front Med (Lausanne) 2021; 8:744122. [PMID: 34912819 PMCID: PMC8666949 DOI: 10.3389/fmed.2021.744122] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
The kidneys play an indispensable role in glucose homeostasis via glucose reabsorption, production, and utilization. Conversely, aberrant glucose metabolism is involved in the onset, progression, and prognosis of kidney diseases, including acute kidney injury (AKI). In this review, we describe the regulation of glucose homeostasis and related molecular factors in kidneys under normal physiological conditions. Furthermore, we summarize recent investigations about the relationship between glucose metabolism and different types of AKI. We also analyze the involvement of glucose metabolism in kidney repair after injury, including renal fibrosis. Further research on glucose metabolism in kidney injury and repair may lead to the identification of novel therapeutic targets for the prevention and treatment of kidney diseases.
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Affiliation(s)
- Lu Wen
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Ying Li
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Siyao Li
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Xiaoru Hu
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Zheng Dong
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Research Department, Charlie Norwood VA Medical Center, Augusta, GA, United States
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42
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Arora A, Behl T, Sehgal A, Singh S, Sharma N, Chigurupati S, Kaur R, Bhatia S, Al-Harrasi A, Vargas-De-La-Cruz C, Bungau S. Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus. Inflammopharmacology 2021; 29:1625-1639. [PMID: 34669065 DOI: 10.1007/s10787-021-00879-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 09/21/2021] [Indexed: 12/25/2022]
Abstract
Free fatty acid receptor 1 (FFAR1) is a G-protein coupled receptor with prominent expression on pancreatic beta cells, bones, intestinal cells as well as the nerve cells. This receptor mediates a multitude of functions in the body including release of incretins, secretion of insulin as well as sensation of pain. Since FFAR1 causes secretion of insulin and regulates glucose metabolism, efforts were made to unfold its structure followed by discovering agonists for the receptor and the utilization of these agonists in the therapy of type 2 diabetes mellitus. Development of such functional FFAR1 agonists is a necessity because the currently available therapy for type 2 diabetes mellitus has numerous drawbacks, of which, the major one is hypoglycemia. Since the most prominent effect of the FFAR1 agonists is on glucose concentration in the body, so the major research is focused on treating type 2 diabetes mellitus, though the agonists could benefit other metabolic disorders and neurological disorders as well. The agonists developed so far had one major limitation, i.e., hepatotoxicity. Although, the only agonist that could reach phase 3 clinical trials was TAK-875 developed by Takeda Pharmaceuticals but it was also withdrawn due to toxic effects on the liver. Thus, there are numerous agonists for the varied binding sites of the receptor but no drug available yet. There does seem to be a ray of hope in the drugs that target FFAR1 but a lot more efforts towards drug discovery would result in the successful management of type 2 diabetes mellitus.
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Affiliation(s)
- Arpita Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah, Kingdom of Saudi Arabia
| | - Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Natural and Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Celia Vargas-De-La-Cruz
- Faculty of Pharmacy and Biochemistry, Academic Department of Pharmacology, Bromatology and Toxicology, Centro Latinoamericano de Ensenanza e Investigacion en Bacteriologia Alimentaria, Universidad Nacional Mayor de San Marcos, Lima, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima, Peru
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Brierley GV, Semple RK. Insulin at 100 years - is rebalancing its action key to fighting obesity-related disease? Dis Model Mech 2021; 14:273551. [PMID: 34841432 PMCID: PMC8649170 DOI: 10.1242/dmm.049340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
One hundred years ago, insulin was purified and administered to people with diabetes to lower blood glucose, suppress ketogenesis and save lives. A century later, insulin resistance (IR) lies at the heart of the obesity-related disease pandemic. Multiple observations attest that IR syndrome is an amalgamation of gain and loss of insulin action, suggesting that IR is a misnomer. This misapprehension is reinforced by shortcomings in common model systems and is particularly pronounced for the tissue growth disorders associated with IR. It is necessary to move away from conceptualisation of IR as a pure state of impaired insulin action and to appreciate that, in the long term, insulin can harm as well as cure. The mixed state of gain and loss of insulin action, and its relationship to perturbed insulin-like growth factor (IGF) action, should be interrogated more fully in models recapitulating human disease. Only then may the potential of rebalancing insulin action, rather than simply increasing global insulin signalling, finally be appreciated.
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Affiliation(s)
- Gemma V Brierley
- Biomedical Research Group, School of Life Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK.,The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Robert K Semple
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
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44
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Insulin Resistance and Cancer: In Search for a Causal Link. Int J Mol Sci 2021; 22:ijms222011137. [PMID: 34681797 PMCID: PMC8540232 DOI: 10.3390/ijms222011137] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.
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Abstract
BACKGROUND Insulin's discovery 100 years ago and its ongoing use since that time to treat diabetes belies the molecular complexity of its structure and that of its receptor. Advances in single-particle cryo-electron microscopy have over the past three years revolutionized our understanding of the atomic detail of insulin-receptor interactions. SCOPE OF REVIEW This review describes the three-dimensional structure of insulin and its receptor and details on how they interact. This review also highlights the current gaps in our structural understanding of the system. MAJOR CONCLUSIONS A near-complete picture has been obtained of the hormone receptor interactions, providing new insights into the kinetics of the interactions and necessitating a revision of the extant two-site cross-linking model of hormone receptor engagement. How insulin initially engages the receptor and the receptor's traversed trajectory as it undergoes conformational changes associated with activation remain areas for future investigation.
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Affiliation(s)
- Michael C Lawrence
- WEHI, Parkville, Victoria, 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, 3050, Australia.
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Batty MJ, Chabrier G, Sheridan A, Gage MC. Metabolic Hormones Modulate Macrophage Inflammatory Responses. Cancers (Basel) 2021; 13:cancers13184661. [PMID: 34572888 PMCID: PMC8467249 DOI: 10.3390/cancers13184661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Macrophages are a type of immune cell which play an important role in the development of cancer. Obesity increases the risk of cancer and obesity also causes disruption to the normal levels of hormones that are produced to coordinate metabolism. Recent research now shows that these metabolic hormones also play important roles in macrophage immune responses and so through macrophages, disrupted metabolic hormone levels may promote cancer. This review article aims to highlight and summarise these recent findings so that the scientific community may better understand how important this new area of research is, and how these findings can be capitalised on for future scientific studies. Abstract Macrophages are phagocytotic leukocytes that play an important role in the innate immune response and have established roles in metabolic diseases and cancer progression. Increased adiposity in obese individuals leads to dysregulation of many hormones including those whose functions are to coordinate metabolism. Recent evidence suggests additional roles of these metabolic hormones in modulating macrophage inflammatory responses. In this review, we highlight key metabolic hormones and summarise their influence on the inflammatory response of macrophages and consider how, in turn, these hormones may influence the development of different cancer types through the modulation of macrophage functions.
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48
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Lee SH, Yoon KH. A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future. Diabetes Metab J 2021; 45:629-640. [PMID: 34610718 PMCID: PMC8497924 DOI: 10.4093/dmj.2021.0163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/08/2021] [Indexed: 12/15/2022] Open
Abstract
The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances in medical science. A rapid bench-to-bedside application of the lifesaving pancreatic extract and its immediate commercialization was the result of a promising idea, positive drive, perseverance, and collaboration of Banting and colleagues. As one of the very few proteins isolated in a pure form at that time, insulin also played a key role in the development of important methodologies and in the beginning of various fields of modern science. Since its discovery, insulin has evolved continuously to optimize the care of people with diabetes. Since the 1980s, recombinant DNA technology has been employed to engineer insulin analogs by modifying their amino acid sequence, which has resulted in the production of insulins with various profiles that are currently used. However, unmet needs in insulin treatment still exist, and several forms of future insulins are under development. In this review, we discuss the past, present, and future of insulin, including a history of ceaseless innovations and collective intelligence. We believe that this story will be a solid foundation and an unerring guide for the future.
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Affiliation(s)
- Seung-Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kun-Ho Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Corresponding author: Kun-Ho Yoon, https://orcid.org/0000-0002-9109-2208, Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul 06591, Korea E-mail:
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White MF, Kahn CR. Insulin action at a molecular level - 100 years of progress. Mol Metab 2021; 52:101304. [PMID: 34274528 PMCID: PMC8551477 DOI: 10.1016/j.molmet.2021.101304] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/07/2021] [Accepted: 07/13/2021] [Indexed: 12/15/2022] Open
Abstract
The discovery of insulin 100 years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine. The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketones, the determination of its amino acid sequence, and the solving of its structure. Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling-or resistance-in the progression of type 2 diabetes. It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions. Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states.
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Affiliation(s)
- Morris F White
- Boston Children's Hospital and Harvard Medical School, Boston, MA, 02215, USA.
| | - C Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.
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Chandra NC. A comprehensive account of insulin and LDL receptor activity over the years: A highlight on their signaling and functional role. J Biochem Mol Toxicol 2021; 35:e22840. [PMID: 34227185 DOI: 10.1002/jbt.22840] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 05/13/2021] [Accepted: 06/25/2021] [Indexed: 11/08/2022]
Abstract
Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.
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Affiliation(s)
- Nimai C Chandra
- Department of Biochemistry, All India Institute of Medical Sciences, Patna, India
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