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Franca S Angeli Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania, 3400 Spruce Street, Centrex 100, Philadelphia, Pennsylvania 19104, USA

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Richard P Shannon Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania, 3400 Spruce Street, Centrex 100, Philadelphia, Pennsylvania 19104, USA

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worldwide epidemic, there is a growing demand for new treatments that not only control plasma glucose but also reduce macrovascular complications. Glucagon-like peptide 1 (GLP-1) is a peptide hormone synthesized in and secreted by enteroendocrine L cells in

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Antonella Amato Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Palermo, Italy

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Sara Baldassano Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Palermo, Italy

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Flavia Mulè Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Palermo, Italy

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Introduction Glucagon-like peptide 2 (GLP2) is a 33 amino acid proglucagon-derived peptide produced by a subset of enteroendocrine cells (L-cells) residing within the epithelium of the small and large intestine ( Yusta et al . 2000 ). GLP2 is

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Tao Xie Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

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Min Chen Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

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Lee S Weinstein Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

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. 2003 ). In addition, type 2 diabetics also have increased glucagon (GCG) secretion from pancreatic α-cells and inappropriately increased serum levels of GCG ( Goke 2008 ). Glucagon-like peptide 1 (GLP1) and other incretin hormones promote glucose

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Bethany P Cummings Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA
Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA

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Andrew A Bremer Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA

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Timothy J Kieffer Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA

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David D'Alessio Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA

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Peter J Havel Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA
Department of Molecular Biosciences, Department of Nutrition, Department of Pediatrics, Department of Physiology, Division of Endocrinology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, California 95616, USA

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hypothesized that dexamethasone may enhance postprandial insulin secretion by increasing meal-stimulated incretin hormone secretion and/or by increasing parasympathetic input to the pancreas. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose

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Sayaka Akieda-Asai Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan

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Paul-Emile Poleni Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan

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Kazuya Hasegawa Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan

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Yukari Date Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan

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( Bjorbaek & Kahn 2004 ). Leptin also inhibits AMP-activated protein kinase (AMPK) activity in the arcuate nucleus and in the paraventricular nucleus of the hypothalamus ( Minokoshi et al . 2004 ). Glucagon-like peptide-1 (GLP1), a gastrointestinal hormone

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Jordan S F Chan Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada

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Tanin Shafaati Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada

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John R Ussher Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada

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approval of three new drug classes available for the treatment of T2D, including the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, the dipeptidyl peptidase-4 (DPP-4) inhibitors, and the sodium–glucose co-transporter 2 inhibitors. Although

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Shin-ya Ueda Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

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Takahiro Yoshikawa Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

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Yoshihiro Katsura Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

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Tatsuya Usui Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

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Hayato Nakao Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

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Shigeo Fujimoto Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

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endocrine organs, including ghrelin, peptide YY (PYY), pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), and oxyntomodulin ( Huda et al . 2006 , Näslund & Hellstrom 2007 , Wren & Bloom 2007 ). While of these, ghrelin is

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Paige V Bauer Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON, Canada
Department of Physiology, University of Toronto, Toronto, ON, Canada

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Frank A Duca Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON, Canada

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. 2015 , Buse et al . 2016 ). Interestingly, this is not the only evidence for a therapeutic role of the gut in diabetes treatment. Over the past decade, incretin-based therapies including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl

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Lars P Klieverik Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Ewout Foppen Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of
Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Mariëtte T Ackermans Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Mireille J Serlie Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Hans P Sauerwein Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Thomas S Scanlan Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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David K Grandy Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Eric Fliers Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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Andries Kalsbeek Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of
Laboratory of Endocrinology, Clinical Chemistry, Netherlands Institute for Neuroscience, Department of Physiology and Pharmacology, Departments of

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.c.v. bolus infusion, isotope dilution and blood sampling were conducted to permit measurement of endogenous glucose production (EGP), and the concentration of plasma glucose, insulin, glucagon, corticosterone, thyroid stimulating hormone (TSH), T 3 and T 4

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Joshua A Kulas Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA

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Kendra L Puig Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA

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Colin K Combs Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA

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chemiluminescent visualization. Antibodies Antibodies against full-length APP (ab32136), BACE2 (ab8025), glucagon (ab10988), IDE (ab32216) and the insulin receptor (ab69508) were purchased from Abcam. Antibodies against insulin (L6B10), p-GSK3β (D3A4), GSK3

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