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Yang Y, Song WJ, Zhang JJ. Ras homolog enriched in brain 1 regulates β cell mass and β cell function via mTORC1/AMPK/Notch1 pathways. World J Diabetes 2025; 16:104973. [DOI: 10.4239/wjd.v16.i6.104973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/19/2025] [Accepted: 04/03/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND The identification of key regulators of β cell mass and function is crucial in developing effective therapeutic interventions for diabetes. Ras homolog enriched in brain 1 (Rheb1), an upstream binding protein of mTOR, is a potential therapeutic target for β cell in diabetes, while the underlying mechanisms remains unknown.
AIM To assess the effect and potential mechanism of Rheb1 on β cell mass and function.
METHODS Islets samples were collected from mouse and human donors. Min6 transformed cell line and mouse models including pancreatic or β-cell specific knockout of Rheb1mice were established. Rapamycin (an mTORC1 inhibitor) and AICAR (an AMPK activator) was used to investigate mTORC1 or AMPK signaling in β cells. The effect of Rheb1 on β cell function via mTORC1, AMPK or other pathways were assessed using western blotting and immunofluorescence, etc.
RESULTS In this study, we demonstrate that Rheb1 is highly expressed in islets from young human donors (below the age of 18) compared to adults. Furthermore, our findings reveal that Rheb1 facilitates β-cell proliferation through both mTORC1 and AMPK signaling pathways, rather than solely relying on mTORC1. Specifically, we observed that either AICAR or rapamycin alone could partially inhibit Rheb1-induced β cell proliferation, while the combination of AICAR and rapamycin fully inhibits Rheb1-induced β cell proliferation in Min6 transformed cell line and mouse islets. In addition, our study highlights the role of Rheb1 in maintaining β cell identity through activation of mTORC1 and Notch1 signaling pathways. Moreover, we also found that Rheb1 could positively regulate HNF4α in β cells, which is a significant transcription factor for β-cell development and differentiation.
CONCLUSION Overall, our findings reveal that Rheb1 regulates β cell proliferation and identity and β-cell development related significant marker, providing a promising novel therapeutic target for diabetes.
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Affiliation(s)
- Yan Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Wan-Juan Song
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Jing-Jing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
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2
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Cai Z, Satyanarayana G, Song P, Zhao F, You S, Liu Z, Mu J, Ding Y, He B, Zou MH. Regulation of Ptbp1-controlled alternative splicing of pyruvate kinase muscle by liver kinase B1 governs vascular smooth muscle cell plasticity in vivo. Cardiovasc Res 2024; 120:1780-1793. [PMID: 39189621 PMCID: PMC11587553 DOI: 10.1093/cvr/cvae187] [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: 09/04/2023] [Revised: 04/12/2024] [Accepted: 06/13/2024] [Indexed: 08/28/2024] Open
Abstract
AIMS Vascular smooth muscle cell (VSMC) plasticity is a state in which VSMCs undergo phenotypic switching from a quiescent contractile phenotype into other functionally distinct phenotypes. Although emerging evidence suggests that VSMC plasticity plays critical roles in the development of vascular diseases, little is known about the key determinant for controlling VSMC plasticity and fate. METHODS AND RESULTS We found that smooth muscle cell-specific deletion of Lkb1 in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice spontaneously and progressively induced aortic/arterial dilation, aneurysm, rupture, and premature death. Single-cell RNA sequencing and imaging-based lineage tracing showed that Lkb1-deficient VSMCs transdifferentiated gradually from early modulated VSMCs to fibroblast-like and chondrocyte-like cells, leading to ossification and blood vessel rupture. Mechanistically, Lkb1 regulates polypyrimidine tract binding protein 1 (Ptbp1) expression and controls alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2. Lkb1 loss in VSMC results in an increased PKM2/PKM1 ratio and alters the metabolic profile by promoting aerobic glycolysis. Treatment with PKM2 activator TEPP-46 rescues VSMC transformation and aortic dilation in Lkb1flox/flox;Myh11-Cre/ERT2 mice. Furthermore, we found that Lkb1 expression decreased in human aortic aneurysm tissue compared to control tissue, along with changes in markers of VSMC fate. CONCLUSION Lkb1, via its regulation of Ptbp1-dependent alterative splicing of PKM, maintains VSMC in contractile states by suppressing VSMC plasticity.
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MESH Headings
- Animals
- Polypyrimidine Tract-Binding Protein/metabolism
- Polypyrimidine Tract-Binding Protein/genetics
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/metabolism
- Cell Plasticity
- Protein Serine-Threonine Kinases/metabolism
- Protein Serine-Threonine Kinases/genetics
- Alternative Splicing
- Phenotype
- Mice, Knockout
- Heterogeneous-Nuclear Ribonucleoproteins/metabolism
- Heterogeneous-Nuclear Ribonucleoproteins/genetics
- Humans
- Cells, Cultured
- Male
- Disease Models, Animal
- Glycolysis
- Mice, Inbred C57BL
- Vascular Remodeling
- Signal Transduction
- Mice
- AMP-Activated Protein Kinase Kinases/metabolism
- AMP-Activated Protein Kinase Kinases/genetics
- Pyruvate Kinase
- AMP-Activated Protein Kinases
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Affiliation(s)
- Zhaohua Cai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 241 Huaihai West Road, Shanghai 200030, China
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Ganesh Satyanarayana
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Ping Song
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Fujie Zhao
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Shaojin You
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Zhixue Liu
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Jing Mu
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Ye Ding
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA
| | - Ben He
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 241 Huaihai West Road, Shanghai 200030, China
| | - Ming-Hui Zou
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China
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3
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. FASEB J 2024; 38:e23885. [PMID: 39139039 PMCID: PMC11378476 DOI: 10.1096/fj.202401078r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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Affiliation(s)
- Nejc Haberman
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Rebecca Cheung
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Grazia Pizza
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Nevena Cvetesic
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Dorka Nagy
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Hannah Maude
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Lorea Blazquez
- Department of Neurosciences, Biogipuzkoa Health Research Institute, San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- CIBERNED, ISCIII (CIBER, Carlos III Institute, Spanish Ministry of Sciences and Innovation), Madrid, Spain
| | - Boris Lenhard
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
- Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Faculté de Médecine, Université de Montréal, Montréal, Quebec, Canada
- Lee Kong Chian Medical School, Nanyang Technological University, Singapore, Singapore
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
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4
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593867. [PMID: 38798508 PMCID: PMC11118353 DOI: 10.1101/2024.05.13.593867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell- selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors important for β-cell identity, such as FOXA, MAFA or RFX6 and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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5
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Cai Z, Jiang Y, Tong H, Liang M, Huang Y, Fang L, Liang F, Hu Y, Shi X, Wang J, Wang Z, Ji Q, Huo H, Shen L, He B. Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing. J Pathol 2024; 263:47-60. [PMID: 38389501 DOI: 10.1002/path.6259] [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: 06/26/2023] [Revised: 10/17/2023] [Accepted: 01/04/2024] [Indexed: 02/24/2024]
Abstract
Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Zhaohua Cai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yangjing Jiang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Huan Tong
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Min Liang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yijie Huang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Liang Fang
- Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Feng Liang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yunwen Hu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Xin Shi
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jian Wang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zi Wang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Qingqi Ji
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Huanhuan Huo
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Ben He
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
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6
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Rivera Nieves AM, Wauford BM, Fu A. Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes. Front Mol Biosci 2024; 11:1354199. [PMID: 38404962 PMCID: PMC10884328 DOI: 10.3389/fmolb.2024.1354199] [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: 12/12/2023] [Accepted: 01/17/2024] [Indexed: 02/27/2024] Open
Abstract
In Type 1 and Type 2 diabetes, pancreatic β-cell survival and function are impaired. Additional etiologies of diabetes include dysfunction in insulin-sensing hepatic, muscle, and adipose tissues as well as immune cells. An important determinant of metabolic health across these various tissues is mitochondria function and structure. This review focuses on the role of mitochondria in diabetes pathogenesis, with a specific emphasis on pancreatic β-cells. These dynamic organelles are obligate for β-cell survival, function, replication, insulin production, and control over insulin release. Therefore, it is not surprising that mitochondria are severely defective in diabetic contexts. Mitochondrial dysfunction poses challenges to assess in cause-effect studies, prompting us to assemble and deliberate the evidence for mitochondria dysfunction as a cause or consequence of diabetes. Understanding the precise molecular mechanisms underlying mitochondrial dysfunction in diabetes and identifying therapeutic strategies to restore mitochondrial homeostasis and enhance β-cell function are active and expanding areas of research. In summary, this review examines the multidimensional role of mitochondria in diabetes, focusing on pancreatic β-cells and highlighting the significance of mitochondrial metabolism, bioenergetics, calcium, dynamics, and mitophagy in the pathophysiology of diabetes. We describe the effects of diabetes-related gluco/lipotoxic, oxidative and inflammation stress on β-cell mitochondria, as well as the role played by mitochondria on the pathologic outcomes of these stress paradigms. By examining these aspects, we provide updated insights and highlight areas where further research is required for a deeper molecular understanding of the role of mitochondria in β-cells and diabetes.
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Affiliation(s)
- Alejandra María Rivera Nieves
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Brian Michael Wauford
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Accalia Fu
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, United States
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
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Xu R, Wang K, Yao Z, Zhang Y, Jin L, Pang J, Zhou Y, Wang K, Liu D, Zhang Y, Sun P, Wang F, Chang X, Liu T, Wang S, Zhang Y, Lin S, Hu C, Zhu Y, Han X. BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes. J Mol Cell Biol 2023; 15:mjad033. [PMID: 37188647 PMCID: PMC10782904 DOI: 10.1093/jmcb/mjad033] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/20/2023] [Accepted: 05/12/2023] [Indexed: 05/17/2023] Open
Abstract
Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in β cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible β-cell-specific Brsk2 knockout (βKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, βKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature β cells reversibly triggers hyperglycemia due to β-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.
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Affiliation(s)
- Rufeng Xu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Kaiyuan Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Zhengjian Yao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Yan Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Li Jin
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Jing Pang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Yuncai Zhou
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Kai Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Dechen Liu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Yaqin Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Fuqiang Wang
- Analysis Center, Nanjing Medical University, Nanjing 210029, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Tengli Liu
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Yalin Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Shuyong Lin
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Cheng Hu
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
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8
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Stamateris RE, Landa-Galvan HV, Sharma RB, Darko C, Redmond D, Rane SG, Alonso LC. Noncanonical CDK4 signaling rescues diabetes in a mouse model by promoting β cell differentiation. J Clin Invest 2023; 133:e166490. [PMID: 37712417 PMCID: PMC10503800 DOI: 10.1172/jci166490] [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: 10/24/2022] [Accepted: 07/27/2023] [Indexed: 09/16/2023] Open
Abstract
Expanding β cell mass is a critical goal in the fight against diabetes. CDK4, an extensively characterized cell cycle activator, is required to establish and maintain β cell number. β cell failure in the IRS2-deletion mouse type 2 diabetes model is, in part, due to loss of CDK4 regulator cyclin D2. We set out to determine whether replacement of endogenous CDK4 with the inhibitor-resistant mutant CDK4-R24C rescued the loss of β cell mass in IRS2-deficient mice. Surprisingly, not only β cell mass but also β cell dedifferentiation was effectively rescued, despite no improvement in whole body insulin sensitivity. Ex vivo studies in primary islet cells revealed a mechanism in which CDK4 intervened downstream in the insulin signaling pathway to prevent FOXO1-mediated transcriptional repression of critical β cell transcription factor Pdx1. FOXO1 inhibition was not related to E2F1 activity, to FOXO1 phosphorylation, or even to FOXO1 subcellular localization, but rather was related to deacetylation and reduced FOXO1 abundance. Taken together, these results demonstrate a differentiation-promoting activity of the classical cell cycle activator CDK4 and support the concept that β cell mass can be expanded without compromising function.
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Affiliation(s)
- Rachel E. Stamateris
- MD/PhD Program, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Huguet V. Landa-Galvan
- Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. Weill Center for Metabolic Health and
| | - Rohit B. Sharma
- Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. Weill Center for Metabolic Health and
| | - Christine Darko
- Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. Weill Center for Metabolic Health and
| | - David Redmond
- Hartman Institute for Therapeutic Regenerative Medicine, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Sushil G. Rane
- Integrative Cellular Metabolism Section, Diabetes, Endocrinology and Obesity Branch, National Institute for Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Laura C. Alonso
- Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. Weill Center for Metabolic Health and
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9
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Bitsi S, El Eid L, Manchanda Y, Oqua AI, Mohamed N, Hansen B, Suba K, Rutter GA, Salem V, Jones B, Tomas A. Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice. SCIENCE ADVANCES 2023; 9:eadf7737. [PMID: 37134170 PMCID: PMC10156113 DOI: 10.1126/sciadv.adf7737] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 04/04/2023] [Indexed: 05/05/2023]
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell-specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics.
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Affiliation(s)
- Stavroula Bitsi
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Liliane El Eid
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Yusman Manchanda
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Affiong I. Oqua
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Nimco Mohamed
- Department of Bioengineering, Imperial College London, London, UK
| | - Ben Hansen
- Department of Bioengineering, Imperial College London, London, UK
| | - Kinga Suba
- Department of Bioengineering, Imperial College London, London, UK
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- CHUM Research Centre, Faculty of Medicine, University of Montreal, Quebec H2X 0A9, Canada
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Singapore
| | - Victoria Salem
- Department of Bioengineering, Imperial College London, London, UK
| | - Ben Jones
- Section of Endocrinology and Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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10
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Lei L, Huan Y, Liu Q, Li C, Cao H, Ji W, Gao X, Fu Y, Li P, Zhang R, Abliz Z, Liu Y, Liu S, Shen Z. Morus alba L. (Sangzhi) Alkaloids Promote Insulin Secretion, Restore Diabetic β-Cell Function by Preventing Dedifferentiation and Apoptosis. Front Pharmacol 2022; 13:841981. [PMID: 35308210 PMCID: PMC8927674 DOI: 10.3389/fphar.2022.841981] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/14/2022] [Indexed: 11/25/2022] Open
Abstract
Background:Morus alba L. (Sangzhi) alkaloids (SZ-A), extracted from the Chinese herb Morus alba L. (mulberry twig), have been shown to ameliorate hyperglycemia in type 2 diabetes and have been approved for diabetes treatment in the clinic. However, their versatile pharmacologic effects and regulatory mechanisms are not yet completely understood. Purpose: This study explored the protective effects of SZ-A on islet β cells and the underlying mechanism. Methods: Type 2 diabetic KKAy mice were orally administered SZ-A (100 or 200 mg/kg, once daily) for 11 weeks, and oral glucose tolerance, insulin tolerance, intraperitoneal glucose tolerance and hyperglycemia clamp tests were carried out to evaluate the potency of SZ-A in vivo. The morphology and β-cell dedifferentiation marker of KKAy mouse islets were detected via immunofluorescence. The effect of SZ-A on glucose-stimulated insulin secretion was investigated in both the islet β-cell line MIN6 and mouse primary islets. Potential regulatory signals and pathways in insulin secretion were explored, and cell proliferation assays and apoptosis TUNEL staining were performed on SZ-A-treated MIN6 cells. Results: SZ-A alleviated hyperglycemia and glucose intolerance in type 2 diabetic KKAy mice and improved the function and morphology of diabetic islets. In both MIN6 cells and primary islets, SZ-A promoted insulin secretion. At a normal glucose level, SZ-A decreased AMPKα phosphorylation, and at high glucose, SZ-A augmented the cytosolic calcium concentration. Additionally, SZ-A downregulated the β-cell dedifferentiation marker ALDH1A3 and upregulated β-cell identifying genes, such as Ins1, Ins2, Nkx2.2 and Pax4 in KKAy mice islets. At the same time, SZ-A attenuated glucolipotoxicity-induced apoptosis in MIN6 cells, and inhibited Erk1/2 phosphorylation and caspase 3 activity. The major active fractions of SZ-A, namely DNJ, FAG and DAB, participated in the above regulatory effects. Conclusion: Our findings suggest that SZ-A promotes insulin secretion in islet β cells and ameliorates β-cell dysfunction and mass reduction under diabetic conditions both in vivo and in vitro, providing additional supportive evidence for the clinical application of SZ-A.
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Affiliation(s)
- Lei Lei
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Huan
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Yi Huan, ; Shuainan Liu,
| | - Quan Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Caina Li
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Cao
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenming Ji
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuefeng Gao
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yaxin Fu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pingping Li
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruiping Zhang
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zeper Abliz
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuling Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuainan Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Yi Huan, ; Shuainan Liu,
| | - Zhufang Shen
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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11
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Barella LF, Rossi M, Pydi SP, Meister J, Jain S, Cui Y, Gavrilova O, Fulgenzi G, Tessarollo L, Wess J. β-Arrestin-1 is required for adaptive β-cell mass expansion during obesity. Nat Commun 2021; 12:3385. [PMID: 34099679 PMCID: PMC8184739 DOI: 10.1038/s41467-021-23656-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 05/11/2021] [Indexed: 01/14/2023] Open
Abstract
Obesity is the key driver of peripheral insulin resistance, one of the key features of type 2 diabetes (T2D). In insulin-resistant individuals, the expansion of beta-cell mass is able to delay or even prevent the onset of overt T2D. Here, we report that beta-arrestin-1 (barr1), an intracellular protein known to regulate signaling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice maintained on an obesogenic diet. Specifically, insulin-resistant beta-cell-specific barr1 knockout mice display marked reductions in beta-cell mass and the rate of beta-cell proliferation, associated with pronounced impairments in glucose homeostasis. Mechanistic studies suggest that the observed metabolic deficits are due to reduced Pdx1 expression levels caused by beta-cell barr1 deficiency. These findings indicate that strategies aimed at enhancing barr1 activity and/or expression in beta-cells may prove useful to restore proper glucose homeostasis in T2D.
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Affiliation(s)
- Luiz F Barella
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
| | - Mario Rossi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Sai P Pydi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Jaroslawna Meister
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Shanu Jain
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Yinghong Cui
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Oksana Gavrilova
- Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Bethesda, MD, USA
| | - Gianluca Fulgenzi
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA
| | - Lino Tessarollo
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA
| | - Jürgen Wess
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
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12
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Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells 2021; 13:193-207. [PMID: 33815669 PMCID: PMC8006013 DOI: 10.4252/wjsc.v13.i3.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/19/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.
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Affiliation(s)
- Zi-Yi Sun
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Fang-Xu Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China.
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13
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Zhang X, Wang X, Yuan Z, Radford SJ, Liu C, Libutti SK, Zheng XFS. Amino acids-Rab1A-mTORC1 signaling controls whole-body glucose homeostasis. Cell Rep 2021; 34:108830. [PMID: 33730578 PMCID: PMC8062038 DOI: 10.1016/j.celrep.2021.108830] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/28/2020] [Accepted: 02/16/2021] [Indexed: 12/17/2022] Open
Abstract
Rab1A is a small GTPase known for its role in vesicular trafficking. Recent evidence indicates that Rab1A is essential for amino acids (aas) sensing and signaling to regulate mTORC1 in normal and cancer cells. However, Rab1A's in vivo function in mammals is not known. Here, we report the generation of tamoxifen (TAM)-induced whole body Rab1A knockout (Rab1A-/-) in adult mice. Rab1A-/- mice are viable but become hyperglycemic and glucose intolerant due to impaired insulin transcription and β-cell proliferation and maintenance. Mechanistically, Rab1A mediates AA-mTORC1 signaling, particularly branched chain amino acids (BCAA), to regulate the stability and localization of the insulin transcription factor Pdx1. Collectively, these results reveal a physiological role of aa-Rab1A-mTORC1 signaling in the control of whole-body glucose homeostasis in mammals. Intriguingly, Rab1A expression is reduced in β-cells of type 2 diabetes (T2D) patients, which is correlated with loss of insulin expression, suggesting that Rab1A downregulation contributes to T2D progression.
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Affiliation(s)
- Xin Zhang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA
| | - Xiaowen Wang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA
| | - Ziqiang Yuan
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA; Department of Surgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA
| | - Sarah J Radford
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA
| | - Chen Liu
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA
| | - Steven K Libutti
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA; Department of Surgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA
| | - X F Steven Zheng
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
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14
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Engin AB, Engin A. Protein Kinases Signaling in Pancreatic Beta-cells Death and Type 2 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:195-227. [PMID: 33539017 DOI: 10.1007/978-3-030-49844-3_8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes (T2D) is a worldwide serious public health problem. Insulin resistance and β-cell failure are the two major components of T2D pathology. In addition to defective endoplasmic reticulum (ER) stress signaling due to glucolipotoxicity, β-cell dysfunction or β-cell death initiates the deleterious vicious cycle observed in T2D. Although the primary cause is still unknown, overnutrition that contributes to the induction of the state of low-grade inflammation, and the activation of various protein kinases-related metabolic pathways are main factors leading to T2D. In this chapter following subjects, which have critical checkpoints regarding β-cell fate and protein kinases pathways are discussed; hyperglycemia-induced β-cell failure, chronic accumulation of unfolded protein in β-cells, the effect of intracellular reactive oxygen species (ROS) signaling to insulin secretion, excessive saturated free fatty acid-induced β-cell apoptosis, mitophagy dysfunction, proinflammatory responses and insulin resistance, and the reprogramming of β-cell for differentiation or dedifferentiation in T2D. There is much debate about selecting proposed therapeutic strategies to maintain or enhance optimal β-cell viability for adequate insulin secretion in T2D. However, in order to achieve an effective solution in the treatment of T2D, more intensive clinical trials are required on newer therapeutic options based on protein kinases signaling pathways.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
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15
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Lien YC, Won KJ, Simmons RA. Transcriptomic and Quantitative Proteomic Profiling Reveals Signaling Pathways Critical for Pancreatic Islet Maturation. Endocrinology 2020; 161:5923720. [PMID: 33053583 PMCID: PMC7668240 DOI: 10.1210/endocr/bqaa187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic β-cell dysfunction and reduced insulin secretion play a key role in the pathogenesis of diabetes. Fetal and neonatal islets are functionally immature and have blunted glucose responsiveness and decreased insulin secretion in response to stimuli and are far more proliferative. However, the mechanisms underlying functional immaturity are not well understood. Pancreatic islets are composed of a mixture of different cell types, and the microenvironment of islets and interactions between these cell types are critical for β-cell development and maturation. RNA sequencing and quantitative proteomic data from intact islets isolated from fetal (embryonic day 19) and 2-week-old Sprague-Dawley rats were integrated to compare their gene and protein expression profiles. Ingenuity Pathway Analysis (IPA) was also applied to elucidate pathways and upstream regulators modulating functional maturation of islets. By integrating transcriptome and proteomic data, 917 differentially expressed genes/proteins were identified with a false discovery rate of less than 0.05. A total of 411 and 506 of them were upregulated and downregulated in the 2-week-old islets, respectively. IPA revealed novel critical pathways associated with functional maturation of islets, such as AMPK (adenosine monophosphate-activated protein kinase) and aryl hydrocarbon receptor signaling, as well as the importance of lipid homeostasis/signaling and neuronal function. Furthermore, we also identified many proteins enriched either in fetal or 2-week-old islets related to extracellular matrix and cell communication, suggesting that these pathways play critical roles in islet maturation. Our present study identified novel pathways for mature islet function in addition to confirming previously reported mechanisms, and provided new mechanistic insights for future research on diabetes prevention and treatment.
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Affiliation(s)
- Yu-Chin Lien
- Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kyoung-Jae Won
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rebecca A Simmons
- Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Correspondence: Rebecca A. Simmons, MD, Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, the University of Pennsylvania, BRB II/III, 13th Fl, Rm 1308, 421 Curie Blvd, Philadelphia, PA 19104, USA. E-mail:
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16
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Parajuli P, Nguyen TL, Prunier C, Razzaque MS, Xu K, Atfi A. Pancreatic cancer triggers diabetes through TGF-β-mediated selective depletion of islet β-cells. Life Sci Alliance 2020; 3:e201900573. [PMID: 32371554 PMCID: PMC7211975 DOI: 10.26508/lsa.201900573] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 04/21/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfolding. Using a mouse model of KrasG12D-driven PDAC, which faithfully recapitulates the progression of the human disease, we observed a massive and selective depletion of β-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-β) signaling during PDAC progression caused erosion of β-cell mass through apoptosis. Suppressing TGF-β signaling, either pharmacologically through TGF-β immunoneutralization or genetically through deletion of Smad4 or TGF-β type II receptor (TβRII), afforded substantial protection against PDAC-driven β-cell depletion. From a translational perspective, both activation of TGF-β signaling and depletion of β-cells frequently occur in human PDAC, providing a mechanistic explanation for the pathogenesis of diabetes in PDAC patients, and further implicating new-onset diabetes as a potential early prognostic marker for PDAC.
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Affiliation(s)
- Parash Parajuli
- Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Thien Ly Nguyen
- Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Céline Prunier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Paris, France
| | - Mohammed S Razzaque
- Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
| | - Keli Xu
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Azeddine Atfi
- Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Paris, France
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17
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Lammert E, Thorn P. The Role of the Islet Niche on Beta Cell Structure and Function. J Mol Biol 2019; 432:1407-1418. [PMID: 31711959 DOI: 10.1016/j.jmb.2019.10.032] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/25/2019] [Accepted: 10/29/2019] [Indexed: 01/15/2023]
Abstract
The islets of Langerhans or pancreatic islets are pivotal in the control of blood glucose and are complex microorgans embedded within the larger volume of the exocrine pancreas. Humans can have ~3.2 million islets [1] which, to our current knowledge, function in a similar manner to sense circulating blood glucose levels and respond with the secretion of a mix of different hormones that act to maintain glucose concentrations around a specific set point [2]. At a cellular level, the control of hormone secretion by glucose and other secretagogues is well-understood [3]. The key signal cascades have been identified and many details of the secretory process are known. However, if we shift focus from single cells and consider cells within intact islets, we do not have a comprehensive model as to how the islet environment influences cell function and how the islets work as a whole. This is important because there is overwhelming evidence that the structure and function of the individual endocrine cells are dramatically affected by the islet environment [4,5]. Uncovering the influence of this islet niche might drive future progress in treatments for Type 2 diabetes [6] and cell replacement therapies for Type 1 diabetes [7]. In this review, we focus on the insulin secreting beta cells and their interactions with the immediate environment that surrounds them including endocrine-endocrine interactions and contacts with capillaries.
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Affiliation(s)
- Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, Germany; Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Peter Thorn
- Charles Perkins Centre, School of Medical Sciences, University of Sydney, Camperdown, NSW 2006, Australia.
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Allosteric modulation of β-cell M 3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc Natl Acad Sci U S A 2019; 116:18684-18690. [PMID: 31451647 DOI: 10.1073/pnas.1904943116] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.
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19
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Dai C, Wang X, Wu Y, Xu Y, Zhuo S, Qi M, Ji W, Zhan L. Polarity Protein AF6 Controls Hepatic Glucose Homeostasis and Insulin Sensitivity by Modulating IRS1/AKT Insulin Pathway in an SHP2-Dependent Manner. Diabetes 2019; 68:1577-1590. [PMID: 31127058 DOI: 10.2337/db18-0695] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 05/21/2019] [Indexed: 11/13/2022]
Abstract
Insulin resistance is a major contributing factor in the development of metabolic disease. Although numerous functions of the polarity protein AF6 (afadin and MLLT4) have been identified, a direct effect on insulin sensitivity has not been previously described. We show that AF6 is elevated in the liver tissues of dietary and genetic mouse models of diabetes. We generated liver-specific AF6 knockout mice and show that these animals exhibit enhanced insulin sensitivity and liver glycogen storage, whereas overexpression of AF6 in wild-type mice by adenovirus-expressing AF6 led to the opposite phenotype. Similar observations were obtained from in vitro studies. In addition, we discovered that AF6 directly regulates IRS1/AKT kinase-mediated insulin signaling through its interaction with Src homology 2 domain-containing phosphatase 2 (SHP2) and its regulation of SHP2's tyrosine phosphatase activity. Finally, we show that knockdown of hepatic AF6 ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or db/db diabetic mice. These results demonstrate a novel function for hepatic AF6 in the regulation of insulin sensitivity, providing important insights about the metabolic role of AF6.
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Affiliation(s)
- Cheng Dai
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xinyu Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yanjun Wu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yi Xu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shu Zhuo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Meiyan Qi
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Weiwei Ji
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lixing Zhan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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20
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Jaafar R, Tran S, Shah AN, Sun G, Valdearcos M, Marchetti P, Masini M, Swisa A, Giacometti S, Bernal-Mizrachi E, Matveyenko A, Hebrok M, Dor Y, Rutter GA, Koliwad SK, Bhushan A. mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes. J Clin Invest 2019; 129:4124-4137. [PMID: 31265435 PMCID: PMC6763225 DOI: 10.1172/jci127021] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 06/24/2019] [Indexed: 12/28/2022] Open
Abstract
Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.
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Affiliation(s)
- Rami Jaafar
- The Diabetes Center, UCSF, San Francisco, California, USA
| | - Stella Tran
- The Diabetes Center, UCSF, San Francisco, California, USA
| | - Ajit N. Shah
- The Diabetes Center, UCSF, San Francisco, California, USA
| | - Gao Sun
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital London, United Kingdom
| | | | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matilde Masini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Avital Swisa
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | | | - Ernesto Bernal-Mizrachi
- Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Aleksey Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Yuval Dor
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital London, United Kingdom
| | | | - Anil Bhushan
- The Diabetes Center, UCSF, San Francisco, California, USA
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21
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Barella LF, Rossi M, Zhu L, Cui Y, Mei FC, Cheng X, Chen W, Gurevich VV, Wess J. β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion. J Clin Invest 2019; 129:3732-3737. [PMID: 31184597 PMCID: PMC6715363 DOI: 10.1172/jci126309] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 06/04/2019] [Indexed: 12/27/2022] Open
Abstract
Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta-cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and co-immunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta-cells may prove useful for the development of efficacious antidiabetic drugs.
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Affiliation(s)
- Luiz F. Barella
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Mario Rossi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Lu Zhu
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Yinghong Cui
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Fang C. Mei
- Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Xiaodong Cheng
- Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Wei Chen
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | | | - Jürgen Wess
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
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22
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Zhou S, Li Y, Qiao L, Ge Y, Huang X, Gao X, Ju H, Wang W, Zhang J, Yan J, Teng H, Jiang Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation. FASEB J 2019; 33:9476-9488. [PMID: 31091421 DOI: 10.1096/fj.201900294rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Liver serine-threonine kinase B1 (LKB1) is a tumor suppressor that has been linked to many types of tumors. However, the role of LKB1 in cartilaginous tumorigenesis is still poorly understood. In this study, we find that cartilage-specific, tamoxifen-inducible Lkb1 knockout results in multiple enchondroma-like lesions adjacent to the disorganized growth plates. We showed that chondrocytes retain an immature status caused by loss of Lkb1, which may lead to the dramatic expansion of growth-plate cartilage and the formation of enchondroma-like lesions. Additionally, increased mammalian target of rapamycin complex 1 (mTORC1) activity is observed in the Lkb1 conditional knockout (cKO) chondrocytes, and rapamycin (mTORC1 inhibitor) treatment significantly alleviates the expansion of growth-plate cartilage and eliminates the enchondroma-like lesions in Lkb1 cKO mice. Thus, our findings indicate that loss of Lkb1 leads to the expansion of chondrocytes and the formation of enchondroma-like lesions during postnatal cartilage development, and that the up-regulated mTORC1-signaling pathway is implicated in this process. Our findings suggest that modulation of LKB1 and related signaling is a potential therapy in cartilaginous tumorigenesis.-Zhou, S., Li, Y., Qiao, L., Ge, Y., Huang, X., Gao, X., Ju, H., Wang, W., Zhang, J., Yan, J., Teng, H., Jiang, Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.
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Affiliation(s)
- Sheng Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yixuan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Qiao
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuxiang Ge
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | | | - Xiang Gao
- Model Animal Research Center (MARC), Nanjing, China
| | | | - Wei Wang
- Nanjing University, Nanjing, China
| | | | - Jun Yan
- Model Animal Research Center (MARC), Nanjing, China
| | - Huajian Teng
- Model Animal Research Center (MARC), Nanjing, China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Model Animal Research Center (MARC), Nanjing, China
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23
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Ye R, Onodera T, Scherer PE. Lipotoxicity and β Cell Maintenance in Obesity and Type 2 Diabetes. J Endocr Soc 2019; 3:617-631. [PMID: 30834357 PMCID: PMC6391718 DOI: 10.1210/js.2018-00372] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 01/30/2019] [Indexed: 12/11/2022] Open
Abstract
Obesity and diabetes are often associated with lipotoxic conditions in multiple tissues. The insulin-producing β cells are susceptible to elevated lipid levels and the ensuing lipotoxicity. The preservation of β cell mass and function is one of the main goals of diabetes management under these metabolically stressful conditions. However, the adverse effects from the adaptive signaling pathways that β cells use to counteract lipotoxic stress have secondary negative effects in their own right. Antilipotoxic signaling cascades in β cells can contribute to their eventual failure. Such dual roles are seen for many other biological adaptive processes as well.
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Affiliation(s)
- Risheng Ye
- Department of Medical Education, Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, El Paso, Texas
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas
| | - Toshiharu Onodera
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, Texas
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24
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Sakamoto K, Bultot L, Göransson O. The Salt-Inducible Kinases: Emerging Metabolic Regulators. Trends Endocrinol Metab 2018; 29:827-840. [PMID: 30385008 DOI: 10.1016/j.tem.2018.09.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/18/2018] [Accepted: 09/27/2018] [Indexed: 01/08/2023]
Abstract
The discovery of liver kinase B1 (LKB1) as an upstream kinase for AMP-activated protein kinase (AMPK) led to the identification of several related kinases that also rely on LKB1 for their catalytic activity. Among these, the salt-inducible kinases (SIKs) have emerged as key regulators of metabolism. Unlike AMPK, SIKs do not respond to nucleotides, but their function is regulated by extracellular signals, such as hormones, through complex LKB1-independent mechanisms. While AMPK acts on multiple targets, including metabolic enzymes, to maintain cellular ATP levels, SIKs primarily regulate gene expression, by acting on transcriptional regulators, such as the cAMP response element-binding protein-regulated transcription coactivators and class IIa histone deacetylases. This review describes the development of research on SIKs, from their discovery to the most recent findings on metabolic regulation.
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Affiliation(s)
- Kei Sakamoto
- Nestlé Research, EPFL Innovation Park, Bâtiment G, 1015 Lausanne, Switzerland.
| | - Laurent Bultot
- Nestlé Research, EPFL Innovation Park, Bâtiment G, 1015 Lausanne, Switzerland; Current address: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pole of Cardiovascular Research, Brussels, Belgium
| | - Olga Göransson
- Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden.
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25
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Nie J, Sun C, Chang Z, Musi N, Shi Y. SAD-A Promotes Glucose-Stimulated Insulin Secretion Through Phosphorylation and Inhibition of GDIα in Male Islet β Cells. Endocrinology 2018; 159:3036-3047. [PMID: 29873699 PMCID: PMC6693047 DOI: 10.1210/en.2017-03243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/26/2018] [Indexed: 02/06/2023]
Abstract
Rho GDP-dissociation inhibitor (GDIα) inhibits glucose-stimulated insulin secretion (GSIS) in part by locking Rho GTPases in an inactive GDP-bound form. The onset of GSIS causes phosphorylation of GDIα at Ser174, a critical inhibitory site for GDIα, leading to the release of Rho GTPases and their subsequent activation. However, the kinase regulator(s) that catalyzes the phosphorylation of GDIα in islet β cells remains elusive. We propose that SAD-A, a member of AMP-activated protein kinase-related kinases that promotes GSIS as an effector kinase for incretin signaling, interacts with and inhibits GDIα through phosphorylation of Ser174 during the onset GSIS from islet β cells. Coimmunoprecipitation and phosphorylation analyses were carried out to identify the physical interaction and phosphorylation site of GDIα by SAD-A in the context of GSIS from INS-1 β cells and primary islets. We identified GDIα directly binds to SAD-A kinase domain and phosphorylated by SAD-A on Ser174, leading to dissociation of Rho GTPases from GDIα complexes. Accordingly, overexpression of SAD-A significantly stimulated GDIα phosphorylation at Ser174 in response to GSIS, which is dramatically potentiated by glucagonlike peptide-1, an incretin hormone. Conversely, SAD-A deficiency, which is mediated by short hairpin RNA transfection in INS-1 cells, significantly attenuated endogenous GDIα phosphorylation at Ser174. Consequently, coexpression of SAD-A completely prevented the inhibitory effect of GDIα on insulin secretion in islets. In summary, glucose and incretin stimulate insulin secretion through the phosphorylation of GDIα at Ser174 by SAD-A, which leads to the activation of Rho GTPases, culminating in insulin exocytosis.
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Affiliation(s)
- Jia Nie
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas
- Correspondence: Jia Nie, PhD, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245. E-mail:
| | - Chao Sun
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Zhijie Chang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing, China
| | - Nicolas Musi
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Yuguang Shi
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas
- School of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
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26
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Nguyen-Tu MS, da Silva Xavier G, Leclerc I, Rutter GA. Transcription factor-7-like 2 ( TCF7L2) gene acts downstream of the Lkb1/ Stk11 kinase to control mTOR signaling, β cell growth, and insulin secretion. J Biol Chem 2018; 293:14178-14189. [PMID: 29967064 PMCID: PMC6130960 DOI: 10.1074/jbc.ra118.003613] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/15/2018] [Indexed: 12/25/2022] Open
Abstract
Variants in the transcription factor-7–like 2 (TCF7L2/TCF4) gene, involved in Wnt signaling, are associated with type 2 diabetes. Loss of Tcf7l2 selectively from the β cell in mice has previously been shown to cause glucose intolerance and to lower β cell mass. Deletion of the tumor suppressor liver kinase B1 (LKB1/STK11) leads to β cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased β cell growth and function. The aim of this study was to explore the possibility that Tcf7l2 may be required for the effects of Lkb1 deletion on insulin secretion in the mouse β cell. Mice bearing floxed Lkb1 and/or Tcf7l2 alleles were bred with knockin mice bearing Cre recombinase inserted at the Ins1 locus (Ins1Cre), allowing highly β cell–selective deletion of either or both genes. Oral glucose tolerance was unchanged by the further deletion of a single Tcf7l2 allele in these cells. By contrast, mice lacking both Tcf7l2 alleles on this background showed improved oral glucose tolerance and insulin secretion in vivo and in vitro compared with mice lacking a single Tcf7l2 allele. Biallelic Tcf7l2 deletion also enhanced β cell proliferation, increased β cell mass, and caused changes in polarity as revealed by the “rosette-like” arrangement of β cells. Tcf7l2 deletion also increased signaling by mammalian target of rapamycin (mTOR), augmenting phospho-ribosomal S6 levels. We identified a novel signaling mechanism through which a modifier gene, Tcf7l2, lies on a pathway through which LKB1 acts in the β cell to restrict insulin secretion.
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Affiliation(s)
- Marie-Sophie Nguyen-Tu
- From the Section of Cell Biology and Functional Genomics and Pancreatic Islet and Diabetes Consortium, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Gabriela da Silva Xavier
- From the Section of Cell Biology and Functional Genomics and Pancreatic Islet and Diabetes Consortium, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Isabelle Leclerc
- From the Section of Cell Biology and Functional Genomics and Pancreatic Islet and Diabetes Consortium, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
| | - Guy A Rutter
- From the Section of Cell Biology and Functional Genomics and Pancreatic Islet and Diabetes Consortium, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
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27
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Rourke JL, Hu Q, Screaton RA. AMPK and Friends: Central Regulators of β Cell Biology. Trends Endocrinol Metab 2018; 29:111-122. [PMID: 29289437 DOI: 10.1016/j.tem.2017.11.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 11/20/2017] [Accepted: 11/29/2017] [Indexed: 02/08/2023]
Abstract
If left unchecked, prediabetic hyperglycemia can progress to diabetes and often life-threatening attendant secondary complications. Central to the process of glucose homeostasis are pancreatic β cells, which sense elevations in plasma glucose and additional dietary components and respond by releasing the appropriate quantity of insulin, ensuring the arrest of hepatic glucose output and glucose uptake in peripheral tissues. Given that β cell failure is associated with the transition from prediabetes to diabetes, improved β cell function ('compensation') has a central role in preventing type 2 diabetes mellitus (T2DM). Recent data have shown that both insulin secretion and β cell mass dynamics are regulated by the liver kinase B1-AMP-activated kinase (LKB1-AMPK) pathway and related kinases of the AMPK family; thus, an improved understanding of the biological roles of AMPK in the β cell is now of considerable interest.
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Affiliation(s)
- Jillian L Rourke
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ONT, M4N 3M5, Canada
| | - Queenie Hu
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ONT, M4N 3M5, Canada
| | - Robert A Screaton
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ONT, M4N 3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ONT, M5S 1A8, Canada.
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28
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Bergeron V, Ghislain J, Vivot K, Tamarina N, Philipson LH, Fielitz J, Poitout V. Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice. Diabetes 2018; 67:71-77. [PMID: 29038309 PMCID: PMC5741145 DOI: 10.2337/db17-0982] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 10/09/2017] [Indexed: 12/29/2022]
Abstract
Ββ-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using β-cell-specific, inducible PKD1 knockout mice (βPKD1KO), we examined the role of β-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in β-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet-fed βPKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice.
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Affiliation(s)
- Valérie Bergeron
- Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - Julien Ghislain
- Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
| | - Kevin Vivot
- Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
| | | | | | - Jens Fielitz
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Greifswald, Germany
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
| | - Vincent Poitout
- Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
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Differential regulation of spermatogenic process by Lkb1 isoforms in mouse testis. Cell Death Dis 2017; 8:e3121. [PMID: 29022902 PMCID: PMC5682689 DOI: 10.1038/cddis.2017.527] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 07/28/2017] [Accepted: 09/04/2017] [Indexed: 01/27/2023]
Abstract
Liver serine/threonine kinase B1 (LKB1) is a tumor suppressor associated with the pathogenesis of Peutz-Jeghers syndrome. Affected males are at increased risk of developing Sertoli cell tumors and display defective spermatogenesis. Male mice lacking the short isoform (Lkb1S) of Lkb1 were sterile and exhibited abnormal spermiogenesis. In addition to the short isoform, the long isoform of Lkb1 (Lkb1L) is also expressed in testis; however, the requirement of the long isoform for fertility and the functional difference between the isoforms remain unknown. Herein, different from the spermiation failure reported in Lkb1S knockout mice, conditional deletion (cKO) of both isoforms of Lkb1 in germ cells resulted in male sterility stemming from defects in acrosome formation, as well as nuclear elongation and condensation during spermatid differentiation. Additionally, cKO mice showed a progressive germ cell loss that was never reported in mice with Lkb1S deletion. Further experiments revealed that the defect resulted from the failure of spermatogonial stem/progenitor cells (SPCs) maintenance. Although increased mTORC1 activity in postnatal cKO testes was consistent with a tendency toward germline stem cell differentiation, in vivo inhibition of the pathway by rapamycin treatment failed to rescue the phenotype. Concurrently, we detected a significant reduction of mitochondrial activity in Lkb1deficient SPCs. The results suggest that the regulation of LKB1 on SPCs' maintenance is associated with mitochondrial functions but not through the mTOR signaling pathway. In summary, our study supports different roles of Lkb1 isoforms in spermatogenesis with Lkb1L directing SPCs maintenance, and Lkb1L and Lkb1S coordinately regulating spermatid differentiation.
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Moullé VS, Ghislain J, Poitout V. Nutrient regulation of pancreatic β-cell proliferation. Biochimie 2017; 143:10-17. [PMID: 28987628 DOI: 10.1016/j.biochi.2017.09.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/28/2017] [Indexed: 12/17/2022]
Abstract
Excess consumption of energy-dense foods combined with a sedentary lifestyle is driving an obesity epidemic. Although obesity is closely associated with insulin resistance, most individuals meet the insulin demand by increasing their functional β-cell mass. Those who eventually develop type 2 diabetes are distinguished by a failure in this compensatory process. Although a causal role of insulin resistance in compensatory β-cell responses has received considerable experimental support, precisely how the β cell senses changes in the metabolic environment is still unknown. As metabolism of glucose, lipids and amino acids is profoundly altered in obesity, it is not surprising that these nutrients are conspicuous among the factors proposed to contribute. In this review we summarise our understanding of the role of nutrients, in particular glucose, fatty acids and amino acids in β-cell compensation with a particular emphasis on their relation to insulin resistance-induced factors and their underlying mechanism of action. Finally, we describe the concept of epigenetic programming and review recent studies illustrating how the status of the β cell epigenome is a product of its nutrient environment, and how metabolic programming of the β cell contributes to diabetes risk.
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Affiliation(s)
- Valentine S Moullé
- Montreal Diabetes Research Center, University of Montreal, QC, Canada; CRCHUM, University of Montreal, QC, Canada.
| | - Julien Ghislain
- Montreal Diabetes Research Center, University of Montreal, QC, Canada; CRCHUM, University of Montreal, QC, Canada.
| | - Vincent Poitout
- Montreal Diabetes Research Center, University of Montreal, QC, Canada; CRCHUM, University of Montreal, QC, Canada; Department of Medicine, University of Montreal, QC, Canada; Department of Biochemistry and Molecular Medicine, University of Montreal, QC, Canada.
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A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK. Pharm Res 2017; 34:2873-2890. [DOI: 10.1007/s11095-017-2271-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/24/2017] [Indexed: 01/04/2023]
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Li H, Li Y, Xiang L, Zhang J, Zhu B, Xiang L, Dong J, Liu M, Xiang G. GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet β-Cell Function and Survival. Diabetes 2017; 66:1914-1927. [PMID: 28450417 DOI: 10.2337/db17-0086] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 04/18/2017] [Indexed: 11/13/2022]
Abstract
Growth differentiation factor 11 (GDF11) has been implicated in the regulation of islet development and a variety of aging conditions, but little is known about the physiological functions of GDF11 in adult pancreatic islets. Here, we showed that systematic replenishment of GDF11 not only preserved insulin secretion but also improved the survival and morphology of β-cells and improved glucose metabolism in both nongenetic and genetic mouse models of type 2 diabetes (T2D). Conversely, anti-GDF11 monoclonal antibody treatment caused β-cell failure and lethal T2D. In vitro treatment of isolated murine islets and MIN6 cells with recombinant GDF11 attenuated glucotoxicity-induced β-cell dysfunction and apoptosis. Mechanistically, the GDF11-mediated protective effects could be attributed to the activation of transforming growth factor-β/Smad2 and phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-FoxO1 signaling. These findings suggest that GDF11 repletion may improve β-cell function and mass and thus may lead to a new therapeutic approach for T2D.
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Affiliation(s)
- Huan Li
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
| | - Yixiang Li
- Radiation-Diagnostic/Oncology School of Medicine, Emory University, Atlanta, GA
| | - Lingwei Xiang
- Mathematics and Statistics Department, Georgia State University, Atlanta, GA
| | - JiaJia Zhang
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
| | - Biao Zhu
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
| | - Lin Xiang
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
| | - Jing Dong
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
| | - Min Liu
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
| | - Guangda Xiang
- Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei Province, China
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Sinagoga KL, Stone WJ, Schiesser JV, Schweitzer JI, Sampson L, Zheng Y, Wells JM. Distinct roles for the mTOR pathway in postnatal morphogenesis, maturation and function of pancreatic islets. Development 2017; 144:2402-2414. [PMID: 28576773 DOI: 10.1242/dev.146316] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 05/26/2017] [Indexed: 02/03/2023]
Abstract
While much is known about the molecular pathways that regulate embryonic development and adult homeostasis of the endocrine pancreas, little is known about what regulates early postnatal development and maturation of islets. Given that birth marks the first exposure to enteral nutrition, we investigated how nutrient-regulated signaling pathways influence postnatal islet development in mice. We performed loss-of-function studies of mechanistic target of rapamycin (mTOR), a highly conserved kinase within a nutrient-sensing pathway known to regulate cellular growth, morphogenesis and metabolism. Deletion of Mtor in pancreatic endocrine cells had no significant effect on their embryonic development. However, within the first 2 weeks after birth, mTOR-deficient islets became dysmorphic, β-cell maturation and function were impaired, and animals lost islet mass. Moreover, we discovered that these distinct functions of mTOR are mediated by separate downstream branches of the pathway, in that mTORC1 (with adaptor protein Raptor) is the main complex mediating the maturation and function of islets, whereas mTORC2 (with adaptor protein Rictor) impacts islet mass and architecture. Taken together, these findings suggest that nutrient sensing may be an essential trigger for postnatal β-cell maturation and islet development.
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Affiliation(s)
- Katie L Sinagoga
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
| | - William J Stone
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
| | - Jacqueline V Schiesser
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
| | - Jamie I Schweitzer
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
| | - Leesa Sampson
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
| | - Yi Zheng
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
| | - James M Wells
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA .,Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA
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Li J, Zhong L, Wang F, Zhu H. Dissecting the role of AMP-activated protein kinase in human diseases. Acta Pharm Sin B 2017; 7:249-259. [PMID: 28540163 PMCID: PMC5430814 DOI: 10.1016/j.apsb.2016.12.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/12/2016] [Accepted: 11/17/2016] [Indexed: 12/18/2022] Open
Abstract
AMP-activated protein kinase (AMPK), known as a sensor and a master of cellular energy balance, integrates various regulatory signals including anabolic and catabolic metabolic processes. Accompanying the application of genetic methods and a plethora of AMPK agonists, rapid progress has identified AMPK as an attractive therapeutic target for several human diseases, such as cancer, type 2 diabetes, atherosclerosis, myocardial ischemia/reperfusion injury and neurodegenerative disease. The role of AMPK in metabolic and energetic modulation both at the intracellular and whole body levels has been reviewed elsewhere. In the present review, we summarize and update the paradoxical role of AMPK implicated in the diseases mentioned above and put forward the challenge encountered. Thus it will be expected to provide important clues for exploring rational methods of intervention in human diseases.
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Affiliation(s)
- Jin Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Liping Zhong
- Life Science College of Tarim University, Xinjiang 843300, China
| | - Fengzhong Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
- Corresponding author. Tel./fax: +86 10 62810295.
| | - Haibo Zhu
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing 100050, China
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Beijing 100050, China
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Corresponding author at: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Tel./fax: +86 10 63188106.
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Shan T, Xu Z, Liu J, Wu W, Wang Y. Lkb1 regulation of skeletal muscle development, metabolism and muscle progenitor cell homeostasis. J Cell Physiol 2017; 232:2653-2656. [DOI: 10.1002/jcp.25786] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 01/06/2017] [Indexed: 12/25/2022]
Affiliation(s)
- Tizhong Shan
- College of Animal Sciences; Zhejiang University; Hangzhou Zhejiang P. R. China
- The Key Laboratory of Molecular Animal Nutrition; Ministry of Education; Zhejiang University; Hangzhou Zhejiang P. R. China
- Zhejiang Provincial Laboratory of Feed and Animal Nutrition; Zhejiang University; Hangzhou Zhejiang P. R. China
| | - Ziye Xu
- College of Animal Sciences; Zhejiang University; Hangzhou Zhejiang P. R. China
- The Key Laboratory of Molecular Animal Nutrition; Ministry of Education; Zhejiang University; Hangzhou Zhejiang P. R. China
- Zhejiang Provincial Laboratory of Feed and Animal Nutrition; Zhejiang University; Hangzhou Zhejiang P. R. China
| | - Jiaqi Liu
- College of Animal Sciences; Zhejiang University; Hangzhou Zhejiang P. R. China
- The Key Laboratory of Molecular Animal Nutrition; Ministry of Education; Zhejiang University; Hangzhou Zhejiang P. R. China
- Zhejiang Provincial Laboratory of Feed and Animal Nutrition; Zhejiang University; Hangzhou Zhejiang P. R. China
| | - Weiche Wu
- College of Animal Sciences; Zhejiang University; Hangzhou Zhejiang P. R. China
- The Key Laboratory of Molecular Animal Nutrition; Ministry of Education; Zhejiang University; Hangzhou Zhejiang P. R. China
- Zhejiang Provincial Laboratory of Feed and Animal Nutrition; Zhejiang University; Hangzhou Zhejiang P. R. China
| | - Yizhen Wang
- College of Animal Sciences; Zhejiang University; Hangzhou Zhejiang P. R. China
- The Key Laboratory of Molecular Animal Nutrition; Ministry of Education; Zhejiang University; Hangzhou Zhejiang P. R. China
- Zhejiang Provincial Laboratory of Feed and Animal Nutrition; Zhejiang University; Hangzhou Zhejiang P. R. China
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36
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Xu Z, Liu J, Shan T. New Roles of Lkb1 in Regulating Adipose Tissue Development and Thermogenesis. J Cell Physiol 2017; 232:2296-2298. [PMID: 27731500 DOI: 10.1002/jcp.25643] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 10/10/2016] [Indexed: 12/19/2022]
Abstract
Adipose tissues regulate energy metabolism and reproduction. There are three types of adipocytes (brown, white, and beige adipocytes) in mammals. White adipocytes store energy and are closely associated with obesity and other metabolic diseases. The beige and brown adipocytes have numerous mitochondria and high levels of UCP1 that dissipates lipid to generate heat and defend against obesity. The global epidemic of obesity and its associated metabolic diseases urge an imperative need for understating the regulation of adipogenesis. Liver kinase B1 (Lkb1), also called STK11, is a master kinase of the AMPK subfamily and plays crucial roles in regulating glucose and energy homeostasis in various metabolic tissues. In this review, we focus on the regulatory roles of Lkb1 in regulating preadipocyte differentiation, adipose tissue development, and thermogenesis. J. Cell. Physiol. 232: 2296-2298, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ziye Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Jiaqi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Tizhong Shan
- College of Animal Sciences, Zhejiang University, Hangzhou, China
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37
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Zhu L, Almaça J, Dadi PK, Hong H, Sakamoto W, Rossi M, Lee RJ, Vierra NC, Lu H, Cui Y, McMillin SM, Perry NA, Gurevich VV, Lee A, Kuo B, Leapman RD, Matschinsky FM, Doliba NM, Urs NM, Caron MG, Jacobson DA, Caicedo A, Wess J. β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. Nat Commun 2017; 8:14295. [PMID: 28145434 PMCID: PMC5296650 DOI: 10.1038/ncomms14295] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 12/15/2016] [Indexed: 01/06/2023] Open
Abstract
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.
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Affiliation(s)
- Lu Zhu
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Joana Almaça
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Prasanna K. Dadi
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Hao Hong
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wataru Sakamoto
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Mario Rossi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Regina J. Lee
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Nicholas C. Vierra
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Huiyan Lu
- Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Yinghong Cui
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Sara M. McMillin
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
| | - Nicole A. Perry
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Vsevolod V. Gurevich
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Amy Lee
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA
| | - Bryan Kuo
- Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland 20892, USA
| | - Richard D. Leapman
- Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland 20892, USA
| | - Franz M. Matschinsky
- Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennslvania 19104, USA
| | - Nicolai M. Doliba
- Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennslvania 19104, USA
| | - Nikhil M. Urs
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
| | - Marc G. Caron
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
| | - David A. Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Alejandro Caicedo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Jürgen Wess
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA
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Cheng J, Zhang T, Ji H, Tao K, Guo J, Wei W. Functional characterization of AMP-activated protein kinase signaling in tumorigenesis. Biochim Biophys Acta Rev Cancer 2016; 1866:232-251. [PMID: 27681874 DOI: 10.1016/j.bbcan.2016.09.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 09/22/2016] [Accepted: 09/23/2016] [Indexed: 12/13/2022]
Abstract
AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.
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Affiliation(s)
- Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Tao Zhang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Hongbin Ji
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 200031, People's Republic of China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China.
| | - Jianping Guo
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Shan T, Xiong Y, Zhang P, Li Z, Jiang Q, Bi P, Yue F, Yang G, Wang Y, Liu X, Kuang S. Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3. Nat Commun 2016; 7:12205. [PMID: 27461402 PMCID: PMC4974456 DOI: 10.1038/ncomms12205] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/09/2016] [Indexed: 12/20/2022] Open
Abstract
Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Here we show that Lkb1 controls BAT expansion and UCP1 expression in mice. We generate adipocyte-specific Lkb1 knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. Consequently, KO mice have improved glucose tolerance and insulin sensitivity, and are more resistant to high-fat diet (HFD)-induced obesity. Deletion of Lkb1 results in a cytoplasm to nuclear translocation of CRTC3 in brown adipocytes, where it recruits C/EBPβ to enhance Ucp1 transcription. In parallel, the absence of Lkb1 also suppresses AMPK activity, leading to activation of the mTOR signalling pathway and subsequent BAT expansion. These data suggest that inhibition of Lkb1 or its downstream signalling in adipocytes could be a novel strategy to increase energy expenditure in the context of obesity, diabetes and other metabolic diseases. The kinase Lkb1 is expressed in various metabolic tissues and is known to regulate cellular and systemic energy homeostasis. Here, the authors delete Lkb1 specifically in mature adipocytes of mice to show that Lkb1 regulates brown adipose tissue expansion and expression of UCP1.
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Affiliation(s)
- Tizhong Shan
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.,College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yan Xiong
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.,Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Pengpeng Zhang
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA
| | - Zhiguo Li
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA
| | - Qingyang Jiang
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA
| | - Pengpeng Bi
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA
| | - Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA
| | - Gongshe Yang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Yizhen Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Xiaoqi Liu
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.,Purdue University Center for Cancer Research, West Lafayette, Indiana 47907, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.,Purdue University Center for Cancer Research, West Lafayette, Indiana 47907, USA
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Shan T, Zhang P, Xiong Y, Wang Y, Kuang S. Lkb1 deletion upregulates Pax7 expression through activating Notch signaling pathway in myoblasts. Int J Biochem Cell Biol 2016; 76:31-8. [PMID: 27131604 DOI: 10.1016/j.biocel.2016.04.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 03/19/2016] [Accepted: 04/26/2016] [Indexed: 11/28/2022]
Abstract
Satellite cells play crucial roles in mediating the growth, maintenance, and repair of postnatal skeletal muscle. Activated satellite cells (myoblasts) can divide symmetrically or asymmetrically to generate progenies that self-renewal, proliferate or differentiate. Pax7 is a defining marker of quiescent and activated satellite cells, but not differentiated myoblast. We demonstrate here that deletion of Lkb1 upregulates Pax7 expression in myoblasts and inhibits asymmetric divisions that generate differentiating progenies. Furthermore, we find that Lkb1 activates the Notch signaling pathway, which subsequently increases Pax7 expression and promotes self-renewal and proliferation while inhibiting differentiation. Mechanistic studies reveal that Lkb1 regulates Notch activation through AMPK-mTOR pathway in myoblasts. Together, these results establish a key role of Lkb1 in regulating myoblast division and cell fates choices.
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Affiliation(s)
- Tizhong Shan
- Department of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of Animal Science, Purdue University, West Lafayette, IN 47907, USA.
| | - Pengpeng Zhang
- Department of Animal Science, Purdue University, West Lafayette, IN 47907, USA
| | - Yan Xiong
- Department of Animal Science, Purdue University, West Lafayette, IN 47907, USA
| | - Yizhen Wang
- Department of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Shihuan Kuang
- Department of Animal Science, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA.
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Pepin É, Al-Mass A, Attané C, Zhang K, Lamontagne J, Lussier R, Madiraju SRM, Joly E, Ruderman NB, Sladek R, Prentki M, Peyot ML. Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression. PLoS One 2016; 11:e0153017. [PMID: 27043434 PMCID: PMC4820227 DOI: 10.1371/journal.pone.0153017] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 03/22/2016] [Indexed: 12/27/2022] Open
Abstract
Diet induced obese (DIO) mice can be stratified according to their weight gain in response to high fat diet as low responders (LDR) and high responders (HDR). This allows the study of β-cell failure and the transitions to prediabetes (LDR) and early diabetes (HDR). C57BL/6N mice were fed for 8 weeks with a normal chow diet (ND) or a high fat diet and stratified as LDR and HDR. Freshly isolated islets from ND, LDR and HDR mice were studied ex-vivo for mitochondrial metabolism, AMPK activity and signalling, the expression and activity of key enzymes of energy metabolism, cholesterol synthesis, and mRNA profiling. Severely compromised glucose-induced insulin secretion in HDR islets, as compared to ND and LDR islets, was associated with suppressed AMP-kinase activity. HDR islets also showed reduced acetyl-CoA carboxylase activity and enhanced activity of 3-hydroxy-3-methylglutaryl-CoA reductase, which led respectively to elevated fatty acid oxidation and increased cholesterol biosynthesis. HDR islets also displayed mitochondrial membrane hyperpolarization and reduced ATP turnover in the presence of elevated glucose. Expression of protein kinase Cε, which reduces both lipolysis and production of signals for insulin secretion, was elevated in DIO islets. Genes whose expression increased or decreased by more than 1.2-fold were minor between LDR and ND islets (17 differentially expressed), but were prominent between HDR and ND islets (1508 differentially expressed). In HDR islets, particularly affected genes were related to cell cycle and proliferation, AMPK signaling, mitochondrial metabolism and cholesterol metabolism. In conclusion, chronically reduced AMPK activity, mitochondrial dysfunction, elevated cholesterol biosynthesis in islets, and substantial alterations in gene expression accompany β-cell failure in HDR islets. The β-cell compensation process in the prediabetic state (LDR) is largely independent of transcriptional adaptive changes, whereas the transition to early diabetes (HDR) is associated with major alterations in gene expression.
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Affiliation(s)
- Émilie Pepin
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
| | - Anfal Al-Mass
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
- Departments of Medicine and Human Genetics, McGill University, Montreal, Québec, Canada
| | - Camille Attané
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
| | - Kezhuo Zhang
- Departments of Medicine and Human Genetics, McGill University, Montreal, Québec, Canada
| | - Julien Lamontagne
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
| | - Roxane Lussier
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
| | - S. R. Murthy Madiraju
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
| | - Erik Joly
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
| | - Neil B. Ruderman
- Departments of Medicine and Physiology and Biophysics, Boston University School of Medicine and Diabetes Unit, Boston Medical Center, Boston, MA, United States of America
| | - Robert Sladek
- Departments of Medicine and Human Genetics, McGill University, Montreal, Québec, Canada
| | - Marc Prentki
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
- Departments of Nutrition, Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montréal, Montreal, Québec, Canada
- * E-mail: (MP); (MLP)
| | - Marie-Line Peyot
- Montreal Diabetes Research Center and Centre de Recherche du CHUM, Montréal, Québec, Canada
- * E-mail: (MP); (MLP)
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Sayers SR, Reimann F, Gribble FM, Parker H, Zac-Varghese S, Bloom SR, Foretz M, Viollet B, Rutter GA. Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance. PLoS One 2016; 11:e0149549. [PMID: 27010458 PMCID: PMC4806996 DOI: 10.1371/journal.pone.0149549] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 02/02/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Enteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1 (GLP-1) in response to food transit. Deletion of the tumour suppressor kinase LKB1 from proglucagon-expressing cells leads to the generation of intestinal polyps but no change in circulating GLP-1 levels. Here, we explore the role of the downstream kinase AMP-activated protein kinase (AMPK) in these cells. METHOD Loss of AMPK from proglucagon-expressing cells was achieved using a preproglucagon promoter-driven Cre (iGluCre) to catalyse recombination of floxed alleles of AMPKα1 and α2. Oral and intraperitoneal glucose tolerance were measured using standard protocols. L-cell mass was measured by immunocytochemistry. Hormone and peptide levels were measured by electrochemical-based luminescence detection or radioimmunoassay. RESULTS Recombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreatic alpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, mice deleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01) in L-cell mass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01) and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01) GLP-1 levels. Oral, but not intraperitoneal, glucose tolerance was significantly improved by AMPK deletion, whilst insulin and glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT: 0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01). CONCLUSION AMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targeted inhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms of type 2 diabetes.
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Affiliation(s)
- Sophie R. Sayers
- Department of Cell Biology and Functional Genomics, Imperial College London, London, W12 ONN, United Kingdom
| | - Frank Reimann
- Wellcome Trust - MRC Institute of Metabolic Science, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, United Kingdom
| | - Fiona M. Gribble
- Wellcome Trust - MRC Institute of Metabolic Science, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, United Kingdom
| | - Helen Parker
- Wellcome Trust - MRC Institute of Metabolic Science, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, United Kingdom
| | - Sagen Zac-Varghese
- Department of Investigative Medicine, Imperial College London, London, W12 ONN, United Kingdom
| | - Stephen R. Bloom
- Department of Investigative Medicine, Imperial College London, London, W12 ONN, United Kingdom
| | - Marc Foretz
- INSERM, U1016, Institut Cochin, 75014 Paris, France
- CNRS, UMR8104, 75014 Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
| | - Benoit Viollet
- INSERM, U1016, Institut Cochin, 75014 Paris, France
- CNRS, UMR8104, 75014 Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
| | - Guy A. Rutter
- Department of Cell Biology and Functional Genomics, Imperial College London, London, W12 ONN, United Kingdom
- * E-mail:
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Gan WJ, Zavortink M, Ludick C, Templin R, Webb R, Webb R, Ma W, Poronnik P, Parton RG, Gaisano HY, Shewan AM, Thorn P. Cell polarity defines three distinct domains in pancreatic β-cells. J Cell Sci 2016; 130:143-151. [PMID: 26919978 PMCID: PMC5394774 DOI: 10.1242/jcs.185116] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 02/08/2016] [Indexed: 12/15/2022] Open
Abstract
The structural organisation of pancreatic β-cells in the islets of Langerhans is relatively unknown. Here, using three-dimensional (3D) two-photon, 3D confocal and 3D block-face serial electron microscopy, we demonstrate a consistent in situ polarisation of β-cells and define three distinct cell surface domains. An apical domain located at the vascular apogee of β-cells, defined by the location of PAR-3 (also known as PARD3) and ZO-1 (also known as TJP1), delineates an extracellular space into which adjacent β-cells project their primary cilia. A separate lateral domain, is enriched in scribble and Dlg, and colocalises with E-cadherin and GLUT2 (also known as SLC2A2). Finally, a distinct basal domain, where the β-cells contact the islet vasculature, is enriched in synaptic scaffold proteins such as liprin. This 3D analysis of β-cells within intact islets, and the definition of distinct domains, provides new insights into understanding β-cell structure and function. Summary: 3D imaging methods identify three structural and functional domains within β-cells in islets: apical, lateral and basal.
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Affiliation(s)
- Wan J Gan
- School of Biomedical Sciences, University of Queensland, St Lucia, Queensland 4072, Australia.,Charles Perkins Centre, John Hopkins Drive, University of Sydney, Camperdown, New South Wales, 2050, Australia
| | - Michael Zavortink
- School of Biomedical Sciences, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Christine Ludick
- School of Biomedical Sciences, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Rachel Templin
- Centre for Microscopy and Microanalysis, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Robyn Webb
- Centre for Microscopy and Microanalysis, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Richard Webb
- Centre for Microscopy and Microanalysis, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Wei Ma
- Charles Perkins Centre, John Hopkins Drive, University of Sydney, Camperdown, New South Wales, 2050, Australia
| | - Philip Poronnik
- Department of Physiology, School of Medical Sciences, The University of Sydney, Camperdown, New South Wales, 2006, Australia
| | - Robert G Parton
- Centre for Microscopy and Microanalysis, University of Queensland, St Lucia, Queensland 4072, Australia.,Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Herbert Y Gaisano
- Department of Medicine, University of Toronto, Toronto, Ontario, M5S1A8, Canada
| | - Annette M Shewan
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Peter Thorn
- School of Biomedical Sciences, University of Queensland, St Lucia, Queensland 4072, Australia .,Charles Perkins Centre, John Hopkins Drive, University of Sydney, Camperdown, New South Wales, 2050, Australia
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Shan T, Zhang P, Liang X, Bi P, Yue F, Kuang S. Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis. Stem Cells 2015; 32:2893-907. [PMID: 25069613 DOI: 10.1002/stem.1788] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 06/14/2014] [Accepted: 06/19/2014] [Indexed: 12/17/2022]
Abstract
Serine/threonine kinase 11, commonly known as liver kinase b1 (Lkb1), is a tumor suppressor that regulates cellular energy metabolism and stem cell function. Satellite cells are skeletal muscle resident stem cells that maintain postnatal muscle growth and repair. Here, we used MyoD(Cre)/Lkb1(flox/flox) mice (called MyoD-Lkb1) to delete Lkb1 in embryonic myogenic progenitors and their descendant satellite cells and myofibers. The MyoD-Lkb1 mice exhibit a severe myopathy characterized by central nucleated myofibers, reduced mobility, growth retardation, and premature death. Although tamoxifen-induced postnatal deletion of Lkb1 in satellite cells using Pax7(CreER) mice bypasses the developmental defects and early death, Lkb1 null satellite cells lose their regenerative capacity cell-autonomously. Strikingly, Lkb1 null satellite cells fail to maintain quiescence in noninjured resting muscles and exhibit accelerated proliferation but reduced differentiation kinetics. At the molecular level, Lkb1 limits satellite cell proliferation through the canonical AMP-activated protein kinase/mammalian target of rapamycin pathway, but facilitates differentiation through phosphorylation of GSK-3β, a key component of the WNT signaling pathway. Together, these results establish a central role of Lkb1 in muscle stem cell homeostasis, muscle development, and regeneration.
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Affiliation(s)
- Tizhong Shan
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA
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45
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Swisa A, Granot Z, Tamarina N, Sayers S, Bardeesy N, Philipson L, Hodson DJ, Wikstrom JD, Rutter GA, Leibowitz G, Glaser B, Dor Y. Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects. J Biol Chem 2015; 290:20934-20946. [PMID: 26139601 PMCID: PMC4543653 DOI: 10.1074/jbc.m115.639237] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Indexed: 12/25/2022] Open
Abstract
The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper β cell polarity and restricts β cell size, total β cell mass, and glucose-stimulated insulin secretion (GSIS). However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro and cannot be explained by altered cell polarity, increased β cell number, or increased insulin content. Increased secretion does require membrane depolarization and calcium influx but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months.
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Affiliation(s)
- Avital Swisa
- Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
| | - Zvi Granot
- Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
| | - Natalia Tamarina
- Department of Medicine, University of Chicago, Chicago, Illinois 60637
| | - Sophie Sayers
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, SW7 2AZ, London, United Kingdom
| | - Nabeel Bardeesy
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114
| | - Louis Philipson
- Department of Medicine, University of Chicago, Chicago, Illinois 60637
| | - David J Hodson
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, SW7 2AZ, London, United Kingdom
| | - Jakob D Wikstrom
- Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 77 Stockholm, Sweden
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, SW7 2AZ, London, United Kingdom
| | - Gil Leibowitz
- Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Benjamin Glaser
- Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Yuval Dor
- Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
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Fu A, Robitaille K, Faubert B, Reeks C, Dai XQ, Hardy AB, Sankar KS, Ogrel S, Al-Dirbashi OY, Rocheleau JV, Wheeler MB, MacDonald PE, Jones R, Screaton RA. LKB1 couples glucose metabolism to insulin secretion in mice. Diabetologia 2015; 58:1513-22. [PMID: 25874445 DOI: 10.1007/s00125-015-3579-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 03/13/2015] [Indexed: 01/05/2023]
Abstract
AIMS/HYPOTHESIS Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. METHODS To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. RESULTS Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1(-/-) beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. CONCLUSIONS/INTERPRETATION Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.
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Affiliation(s)
- Accalia Fu
- Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, K1H 8L1, Canada
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Matsuda T, Takahashi H, Mieda Y, Shimizu S, Kawamoto T, Matsuura Y, Takai T, Suzuki E, Kanno A, Koyanagi-Kimura M, Asahara SI, Bartolome A, Yokoi N, Inoue H, Ogawa W, Seino S, Kido Y. Regulation of Pancreatic β Cell Mass by Cross-Interaction between CCAAT Enhancer Binding Protein β Induced by Endoplasmic Reticulum Stress and AMP-Activated Protein Kinase Activity. PLoS One 2015; 10:e0130757. [PMID: 26091000 PMCID: PMC4474801 DOI: 10.1371/journal.pone.0130757] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 05/22/2015] [Indexed: 01/05/2023] Open
Abstract
During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to not only insulin resistance but also to pancreatic beta cell failure. Conversely, cell function under various stressed conditions can be restored by reducing ER stress by activating AMP-activated protein kinase (AMPK). However, the details of this mechanism are still obscure. Therefore, the current study aims to elucidate the role of AMPK activity during ER stress-associated pancreatic beta cell failure. MIN6 cells were loaded with 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin to assess the relationship between AMPK activity and CCAAT enhancer binding protein β (C/EBPβ) expression levels. The effect of C/EBPβ phosphorylation on expression levels was also investigated. Vildagliptin and metformin were administered to pancreatic beta cell-specific C/EBPβ transgenic mice to investigate the relationship between C/EBPβ expression levels and AMPK activity in the pancreatic islets. When pancreatic beta cells are exposed to ER stress, the accumulation of the transcription factor C/EBPβ lowers the AMP/ATP ratio, thereby decreasing AMPK activity. In an opposite manner, incubation of MIN6 cells with AICAR or metformin activated AMPK, which suppressed C/EBPβ expression. In addition, administration of the dipeptidyl peptidase-4 inhibitor vildagliptin and metformin to pancreatic beta cell-specific C/EBPβ transgenic mice decreased C/EBPβ expression levels and enhanced pancreatic beta cell mass in proportion to the recovery of AMPK activity. Enhanced C/EBPβ expression and decreased AMPK activity act synergistically to induce ER stress-associated pancreatic beta cell failure.
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Affiliation(s)
- Tomokazu Matsuda
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroaki Takahashi
- Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Yusuke Mieda
- Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Shinobu Shimizu
- Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Takeshi Kawamoto
- Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Yuki Matsuura
- Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Tomoko Takai
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Emi Suzuki
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ayumi Kanno
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Maki Koyanagi-Kimura
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shun-ichiro Asahara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Alberto Bartolome
- Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, United States of America
| | - Norihide Yokoi
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Inoue
- Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Susumu Seino
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshiaki Kido
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
- * E-mail:
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Sun G, da Silva Xavier G, Gorman T, Priest C, Solomou A, Hodson DJ, Foretz M, Viollet B, Herrera PL, Parker H, Reimann F, Gribble FM, Migrenne S, Magnan C, Marley A, Rutter GA. LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia. Mol Metab 2015; 4:277-86. [PMID: 25830091 PMCID: PMC4354920 DOI: 10.1016/j.molmet.2015.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 01/14/2015] [Accepted: 01/17/2015] [Indexed: 10/24/2022] Open
Abstract
AIMS/HYPOTHESIS Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear. METHODS Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre. RESULTS Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. CONCLUSIONS/INTERPRETATION An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
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Affiliation(s)
- Gao Sun
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK
| | - Gabriela da Silva Xavier
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK
| | | | | | - Antonia Solomou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK
| | - David J. Hodson
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK
| | - Marc Foretz
- Inserm, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris cité, Paris, France
| | - Benoit Viollet
- Inserm, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris cité, Paris, France
| | - Pedro-Luis Herrera
- Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Helen Parker
- Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK
| | - Frank Reimann
- Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK
| | - Fiona M. Gribble
- Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK
| | - Stephanie Migrenne
- University Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059C NRS, France
| | - Christophe Magnan
- University Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059C NRS, France
| | | | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK
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Kone M, Pullen TJ, Sun G, Ibberson M, Martinez-Sanchez A, Sayers S, Nguyen-Tu MS, Kantor C, Swisa A, Dor Y, Gorman T, Ferrer J, Thorens B, Reimann F, Gribble F, McGinty JA, Chen L, French PM, Birzele F, Hildebrandt T, Uphues I, Rutter GA. LKB1 and AMPK differentially regulate pancreatic β-cell identity. FASEB J 2014; 28:4972-85. [PMID: 25070369 PMCID: PMC4377859 DOI: 10.1096/fj.14-257667] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 07/14/2014] [Indexed: 12/15/2022]
Abstract
Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E < 0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P = 1.3 × 10(-33)) and hypoxia-regulated (HIF1; P = 2.5 × 10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Avital Swisa
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Yuval Dor
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Tracy Gorman
- AstraZeneca Diabetes and Obesity Drug Discovery, Alderley Edge, UK
| | - Jorge Ferrer
- Section of β-Cell Development, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Frank Reimann
- Metabolic Research Laboratories, University of Cambridge, Cambridge, UK and
| | - Fiona Gribble
- Metabolic Research Laboratories, University of Cambridge, Cambridge, UK and
| | - James A McGinty
- Photonics Group, Department of Physics, Imperial College London, London, UK
| | - Lingling Chen
- Photonics Group, Department of Physics, Imperial College London, London, UK
| | - Paul M French
- Photonics Group, Department of Physics, Imperial College London, London, UK
| | | | | | - Ingo Uphues
- Boehringer Ingelheim Pharma, Ingelheim, Germany
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50
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Haissaguerre M, Saucisse N, Cota D. Influence of mTOR in energy and metabolic homeostasis. Mol Cell Endocrinol 2014; 397:67-77. [PMID: 25109278 DOI: 10.1016/j.mce.2014.07.015] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/23/2014] [Accepted: 07/24/2014] [Indexed: 01/01/2023]
Abstract
The mechanistic (or mammalian) target of rapamycin couples a variety of different environmental signals, including nutrients and hormones, with the regulation of several energy-demanding cellular functions, spanning from protein and lipid synthesis to mitochondrial activity and cytoskeleton dynamics. mTOR forms two distinct protein complexes in cells, mTORC1 and mTORC2. This review focuses on recent advances made in understanding the roles played by these two complexes in the regulation of whole body metabolic homeostasis. Studies carried out in the past few years have shown that mTORC1 activity in the hypothalamus varies by cell and stimulus type, and that this complex is critically implicated in the regulation of food intake and body weight and in the central actions of both nutrients and hormones, such as leptin, ghrelin and triiodothyronine. As a regulator of cellular anabolic processes, mTORC1 activity in the periphery favors adipogenesis, lipogenesis, glucose uptake and beta-cell mass expansion. Much less is known about the function of mTORC2 in the hypothalamus, while in peripheral organs this second complex exerts roles strikingly similar to those described for mTORC1. Deregulation of mTORC1 and mTORC2 is associated with obesity, type 2 diabetes, cancer and neurodegenerative disorders. Insights on the exact relationship between mTORC1 and mTORC2 in the context of the regulation of metabolic homeostasis and on the specific molecular mechanisms engaged by these two complexes in such regulation may provide new avenues for therapy.
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Affiliation(s)
- Magalie Haissaguerre
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France
| | - Nicolas Saucisse
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France
| | - Daniela Cota
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
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