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Sihan Lv Department of Endocrinology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

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Xinchen Qiu Department of Endocrinology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Jian Li Department of Endocrinology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Jinye Liang Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Weida Li Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Chao Zhang Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Zhen-Ning Zhang Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Bing Luan Department of Endocrinology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

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glucose and lipid metabolism in response to hormonal signals. Dedicated transcription regulatory network is involved in the hepatic response to fasting. During the fasted state, one of the major circulating hormones required for liver function is glucagon

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Daniella B R Insuela Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Julio B Daleprane Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Luciana P Coelho Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Adriana R Silva Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Patrícia M R e Silva Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Marco A Martins Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Vinicius F Carvalho Laboratório de Inflamação, Instituto de Nutrição, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, n° 4365, Manguinhos, CEP 21040‐360 Rio de Janeiro, Brazil

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Introduction Glucagon is a 29-amino-acid peptide hormone secreted during fasting periods by the pancreatic islet α-cells into hepatic portal venous circulation in response to falling glucose levels ( Conarello et al . 2007 , Cryer 2012 ). Glucagon

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Daniella Bianchi Reis Insuela Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Maximiliano Ruben Ferrero Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Amanda da Silva Chaves Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Diego de Sá Coutinho Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Nathalia dos Santos Magalhães Laboratório de Pesquisa em Infecção Hospitalar, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Ana Carolina Santos de Arantes Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Adriana Ribeiro Silva Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil
Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação (INCT-NIM), Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Patrícia Machado Rodrigues e Silva Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Marco Aurélio Martins Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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Vinicius Frias Carvalho Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil
Instituto Nacional de Ciência e Tecnologia em Neuroimunomodulação (INCT-NIM), Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil

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. 2018 , Cartwright et al. 2019 ). Glucagon is secreted by pancreatic alpha cells, responsible for mobilizing glucose stored in the liver, promoting an increase in blood glucose levels ( Jo et al. 2021 ). We previously demonstrated that pre

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Ryan A Lafferty Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Laura M McShane Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Zara J Franklin Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Peter R Flatt Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Finbarr P M O’Harte Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Nigel Irwin Biomedical Sciences Research Institute, Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK

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Introduction It has been well established that abnormal elevation in circulating glucagon leads to an increase in hepatic glucose production and glycogen metabolism that contribute to hyperglycaemia in diabetes ( Unger 1978 ). For this reason

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Toya M Albury-Warren Burnett School of Biomedical Sciences, Department of Head and Neck Surgery, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, Florida 32827, USA

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Veethika Pandey Burnett School of Biomedical Sciences, Department of Head and Neck Surgery, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, Florida 32827, USA

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Lina P Spinel Burnett School of Biomedical Sciences, Department of Head and Neck Surgery, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, Florida 32827, USA

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Michal M Masternak Burnett School of Biomedical Sciences, Department of Head and Neck Surgery, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, Florida 32827, USA
Burnett School of Biomedical Sciences, Department of Head and Neck Surgery, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, Florida 32827, USA

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Deborah A Altomare Burnett School of Biomedical Sciences, Department of Head and Neck Surgery, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, Florida 32827, USA

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downregulation of the Akt1 Myr transgene reduced the non-fasted and fasted hyperglycemia to WT levels. Collectively, metabolic characterization of the AKT1 Myr mice revealed a novel glucagon-mediated mechanism by which AKT1 hyperactivation affects glucose

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L M McShane SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK


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N Irwin SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK

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D O’Flynn Conway Institute of Biomolecular and Biomedical Research, UCD, Belfield, Dublin 4, Ireland

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Z J Franklin SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK


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C M Hewage Conway Institute of Biomolecular and Biomedical Research, UCD, Belfield, Dublin 4, Ireland

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F P M O’Harte SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK

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DM are present in the setting of glucagon excess ( Unger & Cherrington 2012 ). Thus, improved control of glucagon signaling represents a rational therapeutic target for T2DM. In agreement with this, early proof-of-concept studies using the orally

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Lyle Wiemerslage Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Priya A Gohel Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Giulia Maestri Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Torfi G Hilmarsson Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Michel Mickael Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Robert Fredriksson Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Michael J Williams Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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Helgi B Schiöth Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden

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for studying a variety of molecular pathways, as well as behavior. Specifically for obesity, they have organs that function similar to the human pancreas with corresponding orthologs of insulin and glucagon: insulin-like protein 2 (Ilp2) and

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Courtney A Deck Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA
Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA

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Jamie L Mankiewicz Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA
United States Department of Agriculture, Agricultural Research Service, National Center for Cool and Cold Water Aquaculture, Kearneysville, West Virginia, USA

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Russell J Borski Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA

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as glucagon, in non-mammalian vertebrates. Zebrafish larvae lacking a functional leptin receptor exhibited increased beta-cell numbers and insulin a ( insa ) mRNA levels ( Michel et al. 2016 ). Further, an increase in lep levels in response to

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Bernard Khoo Endocrinology, Division of Medicine, University College London, Royal Free Campus, London, UK

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Tricia Mei-Mei Tan Department of Digestion, Metabolism and Reproduction, Imperial College London, Hammersmith Campus, London, UK

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gut hormone path-finder Glucagon-like peptide 1 (GLP-1) is the most extensively studied gut hormone with translational and clinical evidence for its efficacy ( Holst 2007 ). It is an alternatively processed product of the proglucagon peptide

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Zhongxiuzi Gao Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Li Zhang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Wenting Xie Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Siqi Wang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Xiaorui Bao Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Yuli Guo Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Houjian Zhang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Qingzhong Hu Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Yi Chen Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Zeen Wang Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Maoqiang Xue Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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Guanghui Jin Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China

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resulted in impairment of glucose metabolism in 12-month-old male mice; however, it did not induce insulin resistance. Instead, it promoted glucagon production and increased hepatic glucose output (HGO), which together contributed to increased glucose

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