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Jensen MN, Israelsen IME, Wardman JH, Jensen DB, Andersen DB, Toft-Bertelsen TL, Rath MF, Holst JJ, Rosenkilde MM, MacAulay N. Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats. Fluids Barriers CNS 2025; 22:41. [PMID: 40275284 PMCID: PMC12020230 DOI: 10.1186/s12987-025-00652-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 04/06/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Cerebrospinal fluid (CSF) is produced and absorbed at a balanced rate to maintain a constant intracranial pressure (ICP). The CSF dynamics are, however, disturbed in several pathological conditions, leading to elevated ICP, which may have fatal outcomes if left untreated. Treatment options for these conditions are limited to invasive neurosurgery, and novel pharmacological approaches to manage ICP in pathology are sought. Here, we aimed to demonstrate the potential of the glucagon-like peptide-1 receptor (GLP-1R) as such a target. METHODS We administered male rats with intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) GLP-1R agonist (exendin-4) or antagonist (exendin-9-39) followed by in vivo determination of CSF dynamics. GLP-1R expression in the CSF-secreting choroid plexus was demonstrated with RNAScope in situ hybridization and western blotting and transporter activity with radio-isotope flux assays. RESULTS GLP-1R activation increased the CSF secretion rate with an associated elevation of the ICP, whereas inhibition of the receptor reduced the rate of CSF secretion. These effects were observed with central, but not peripheral, administration of the agonist and antagonist, suggesting receptor expression on the luminal, CSF-facing side of the choroid plexus, which aligned with GLP-1R-mediated modulation of luminally-expressed transporters in excised choroid plexus. Low level GLP-1R expression was demonstrated in the choroid plexus at mRNA and protein levels. CONCLUSION Modulation of GLP-1R affects CSF production, which suggests that GLP-1R-mediated signalling may have the potential to control ICP in pathological conditions with disturbed CSF homeostasis.
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Affiliation(s)
- Mette N Jensen
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark
| | - Ida M E Israelsen
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark
| | - Jonathan H Wardman
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark
| | - Dennis B Jensen
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark
| | - Daniel B Andersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Trine L Toft-Bertelsen
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark
| | - Martin F Rath
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nanna MacAulay
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark.
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Kobayashi N, Okazaki Y, Iwane A, Hara K, Horikoshi M, Awazawa M, Soeda K, Matsushita M, Sasako T, Yoshimura K, Itoh N, Kobayashi K, Seto Y, Yamauchi T, Aburatani H, Blüher M, Kadowaki T, Ueki K. Activin B improves glucose metabolism via induction of Fgf21 and hepatic glucagon resistance. Nat Commun 2025; 16:3678. [PMID: 40246973 PMCID: PMC12006358 DOI: 10.1038/s41467-025-58836-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 04/03/2025] [Indexed: 04/19/2025] Open
Abstract
Orchestrated hormonal interactions in response to feeding and fasting play a pivotal role in regulating glucose homeostasis. Here, we show that in obesity, the production of follistatin-like 3 (FSTL3), an endogenous inhibitor of Activin B, in adipose tissue is increased in both mice and humans. The knockdown of FSTL3 improves insulin sensitivity and glucose tolerance in diabetic obese db/db mice. Notably, the overexpression of Activin B, a member of the TGFβ superfamily that is induced in liver sinusoidal endothelial cells by fasting, exerts multiple metabolically beneficial effects, including improvement of insulin sensitivity, suppression of hepatic glucose production, and enhancement of glucose-stimulated insulin secretion, all of which are attenuated by the overexpression of FSTL3. Activin B increases insulin sensitivity and reduces fat by inducing fibroblast growth factor 21 (FGF21) while suppressing glucagon action in the liver by increasing phosphodiesterase 4 B (PDE4B), leading to hepatic glucagon resistance and resultant hyperglucagonemia. Activin B-induced hyperglucagonemia enhances glucose-stimulated insulin secretion by stimulating glucagon-like peptide-1 (GLP-1) receptor in pancreatic β-cells. Thus, enhancing the action of Activin B which improves multiple components of the pathogenesis of diabetes may be a promising strategy for diabetes treatment.
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Affiliation(s)
- Naoki Kobayashi
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yukiko Okazaki
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Aya Iwane
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuo Hara
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Momoko Horikoshi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoharu Awazawa
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kotaro Soeda
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Maya Matsushita
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takayoshi Sasako
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kotaro Yoshimura
- Department of Plastic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuyuki Itoh
- Department of Genetic Biochemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kenta Kobayashi
- Section of Viral Vector Development, National Institute for Physiological Sciences, Aichi, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Research Center for Advanced Science and Technology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Toranomon Hospital, Tokyo, Japan
| | - Kohjiro Ueki
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan.
- Department of Molecular Diabetology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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3
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Mezza T, Wewer Albrechtsen NJ, Di Giuseppe G, Ferraro PM, Soldovieri L, Ciccarelli G, Brunetti M, Quero G, Alfieri S, Nista EC, Gasbarrini A, Tondolo V, Mari A, Pontecorvi A, Giaccari A, Holst JJ. Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1. Metabolism 2025; 163:156087. [PMID: 39626843 DOI: 10.1016/j.metabol.2024.156087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/08/2024]
Abstract
AIMS A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance. METHODS We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m2) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters. RESULTS Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo. CONCLUSIONS Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.
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Affiliation(s)
- Teresa Mezza
- Pancreas Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Roma, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
| | | | - Gianfranco Di Giuseppe
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Pietro Manuel Ferraro
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Sezione di Nefrologia, Dipartimento di Medicina, Università degli Studi di Verona, Italy
| | - Laura Soldovieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Gea Ciccarelli
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Michela Brunetti
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Giuseppe Quero
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Enrico Celestino Nista
- Pancreas Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Roma, Italy
| | - Antonio Gasbarrini
- Pancreas Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Roma, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Vincenzo Tondolo
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Digestive Surgery Unit, Ospedale Isola Tiberina - Gemelli Isola, Roma, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Council of Research - Padua (IT), Italy
| | - Alfredo Pontecorvi
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Andrea Giaccari
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Endocrinologia e Diabetologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Cilvik SN, Boehmer B, Wesolowski SR, Brown LD, Rozance PJ. Chronic late gestation fetal hyperglucagonaemia results in lower insulin secretion, pancreatic mass, islet area and beta- and α-cell proliferation. J Physiol 2024; 602:6329-6345. [PMID: 39383208 PMCID: PMC11576258 DOI: 10.1113/jp286974] [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: 05/23/2024] [Accepted: 09/09/2024] [Indexed: 10/11/2024] Open
Abstract
Fetal glucagon concentrations are elevated in the presence of a compromised intrauterine environment, as in cases of placental insufficiency and perinatal acidaemia. Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on in vivo insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5 ng/kg/min; GCG-5) or high (50 ng/kg/min; GCG-50) concentrations or a vehicle control (CON) for 8-10 days. Glucose-stimulated fetal insulin secretion (GSIS) was measured following 3 h (acute response) and 8-10 days (chronic response) of experimental infusions. Insulin, glucose and amino acid concentrations were measured longitudinally. The pancreas was collected at the study end for histology and gene expression analysis. Acute exposure (3 h) to GCG-50 induced a 3-fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG-5 and GCG-50 decreased basal insulin concentrations 2-fold by day 8-10. Chronic GCG-50 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24 h of GCG-5 and GCG-50, while there were no differences in fetal glucose. Histologically, GCG-5 and GCG-50 had lower β- and α-cell proliferation, as well as lower α-cell mass and pancreas weight, while GCG-50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs β-cell proliferation and insulin secretion, which has the potential to contribute to later-life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion. KEY POINTS: We have previously demonstrated in a chronically catheterized fetal sheep model that experimentally elevated glucagon in the fetus impairs placental function, reduces fetal protein accretion and lowers fetal weight. In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and β-cell function. We show that experimentally elevated fetal glucagon results in lower β- and α-cell proliferation, as well as decreased insulin secretion after 8-10 days of glucagon infusion. These results have important implications for β-cell reserve and later-life predisposition to diabetes.
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Affiliation(s)
- Sarah N Cilvik
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Brit Boehmer
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Stephanie R Wesolowski
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Laura D Brown
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Paul J Rozance
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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5
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Huang P, Zhu Y, Qin J. Research advances in understanding crosstalk between organs and pancreatic β-cell dysfunction. Diabetes Obes Metab 2024; 26:4147-4164. [PMID: 39044309 DOI: 10.1111/dom.15787] [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: 06/18/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.
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Affiliation(s)
- Peng Huang
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yunling Zhu
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian Qin
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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6
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Lasher AT, Sun LY. Distinct physiological characteristics and altered glucagon signaling in GHRH knockout mice: Implications for longevity. Aging Cell 2023; 22:e13985. [PMID: 37667562 PMCID: PMC10726877 DOI: 10.1111/acel.13985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 09/06/2023] Open
Abstract
Our previous research has demonstrated that mice lacking functional growth hormone-releasing hormone (GHRH) exhibit distinct physiological characteristics, including an extended lifespan, a preference for lipid utilization during rest, mild hypoglycemia, and heightened insulin sensitivity. They also show a further increase in lifespan when subjected to caloric restriction. These findings suggest a unique response to fasting, which motivated our current study on the response to glucagon, a key hormone released from the pancreas during fasting that regulates glucose levels, energy expenditure, and metabolism. Our study investigated the effects of an acute glucagon challenge on female GHRH knockout mice and revealed that they exhibit reduced glucose production, likely due to suppressed gluconeogenesis. However, these mice showed an increase in energy expenditure. We also observed alterations in pancreatic islet architecture, with smaller islets and a reduction of insulin-producing beta cells but no changes in glucagon-producing alpha cells. Additionally, the analysis of hepatic glucagon signaling showed a decrease in glucagon receptor expression and phosphorylated CREB. In conclusion, our findings suggest that the unique metabolic phenotype observed in these long-lived mice may be partly explained by changes in glucagon signaling. Further exploration of this pathway may lead to new insights into the regulation of longevity in mammals.
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Affiliation(s)
- A. Tate Lasher
- Department of BiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Liou Y. Sun
- Department of BiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
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7
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Aldous N, Moin ASM, Abdelalim EM. Pancreatic β-cell heterogeneity in adult human islets and stem cell-derived islets. Cell Mol Life Sci 2023; 80:176. [PMID: 37270452 DOI: 10.1007/s00018-023-04815-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/27/2023] [Accepted: 05/19/2023] [Indexed: 06/05/2023]
Abstract
Recent studies reported that pancreatic β-cells are heterogeneous in terms of their transcriptional profiles and their abilities for insulin secretion. Sub-populations of pancreatic β-cells have been identified based on the functionality and expression of specific surface markers. Under diabetes condition, β-cell identity is altered leading to different β-cell sub-populations. Furthermore, cell-cell contact between β-cells and other endocrine cells within the islet play an important role in regulating insulin secretion. This highlights the significance of generating a cell product derived from stem cells containing β-cells along with other major islet cells for treating patients with diabetes, instead of transplanting a purified population of β-cells. Another key question is how close in terms of heterogeneity are the islet cells derived from stem cells? In this review, we summarize the heterogeneity in islet cells of the adult pancreas and those generated from stem cells. In addition, we highlight the significance of this heterogeneity in health and disease conditions and how this can be used to design a stem cell-derived product for diabetes cell therapy.
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Affiliation(s)
- Noura Aldous
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar
| | - Abu Saleh Md Moin
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Kingdom of Bahrain
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar.
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar.
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Abstract
The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find novel mechanisms and targets that could be utilized in potential treatment strategies and, as such, intracellular membrane trafficking has re-emerged as a regulatory tool for controlling metabolic homeostasis. Membrane trafficking is an essential physiological process that is responsible for the sorting and distribution of signalling receptors, membrane transporters and hormones or other ligands between different intracellular compartments and the plasma membrane. Dysregulation of intracellular transport is associated with many human diseases, including cancer, neurodegeneration, immune deficiencies and metabolic diseases, such as type 2 diabetes mellitus and its associated complications. This Review focuses on the latest advances on the role of endosomal membrane trafficking in metabolic physiology and pathology in vivo, highlighting the importance of this research field in targeting metabolic diseases.
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Affiliation(s)
- Jerome Gilleron
- Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1065 C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France.
| | - Anja Zeigerer
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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9
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Habegger KM. Cross Talk Between Insulin and Glucagon Receptor Signaling in the Hepatocyte. Diabetes 2022; 71:1842-1851. [PMID: 35657690 PMCID: PMC9450567 DOI: 10.2337/dbi22-0002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/19/2022] [Indexed: 11/13/2022]
Abstract
While the consumption of external energy (i.e., feeding) is essential to life, this action induces a temporary disturbance of homeostasis in an animal. A primary example of this effect is found in the regulation of glycemia. In the fasted state, stored energy is released to maintain physiological glycemic levels. Liver glycogen is liberated to glucose, glycerol and (glucogenic) amino acids are used to build new glucose molecules (i.e., gluconeogenesis), and fatty acids are oxidized to fuel long-term energetic demands. This regulation is driven primarily by the counterregulatory hormones epinephrine, growth hormone, cortisol, and glucagon. Conversely, feeding induces a rapid influx of diverse nutrients, including glucose, that disrupt homeostasis. Consistently, a host of hormonal and neural systems under the coordination of insulin are engaged in the transition from fasting to prandial states to reduce this disruption. The ultimate action of these systems is to appropriately store the newly acquired energy and to return to the homeostatic norm. Thus, at first glance it is tempting to assume that glucagon is solely antagonistic regarding the anabolic effects of insulin. We have been intrigued by the role of glucagon in the prandial transition and have attempted to delineate its role as beneficial or inhibitory to glycemic control. The following review highlights this long-known yet poorly understood hormone.
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Affiliation(s)
- Kirk M. Habegger
- Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
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10
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Insights into the Role of Glucagon Receptor Signaling in Metabolic Regulation from Pharmacological Inhibition and Tissue-Specific Knockout Models. Biomedicines 2022; 10:biomedicines10081907. [PMID: 36009454 PMCID: PMC9405517 DOI: 10.3390/biomedicines10081907] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
While glucagon has long been recognized as the primary counter hormone to insulin’s actions, it has recently gained recognition as a metabolic regulator with its effects extending beyond control of glycemia. Recently developed models of tissue-specific glucagon receptor knockouts have advanced our understanding of this hormone, providing novel insight into the role it plays within organs as well as its systemic effects. Studies where the pharmacological blockade of the glucagon receptor has been employed have proved similarly valuable in the study of organ-specific and systemic roles of glucagon signaling. Studies carried out employing these tools demonstrate that glucagon indeed plays a role in regulating glycemia, but also in amino acid and lipid metabolism, systemic endocrine, and paracrine function, and in the response to cardiovascular injury. Here, we briefly review recent progress in our understanding of glucagon’s role made through inhibition of glucagon receptor signaling utilizing glucagon receptor antagonists and tissue specific genetic knockout models.
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11
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Wendt A, Eliasson L. Pancreatic alpha cells and glucagon secretion: Novel functions and targets in glucose homeostasis. Curr Opin Pharmacol 2022; 63:102199. [PMID: 35245797 DOI: 10.1016/j.coph.2022.102199] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 11/16/2022]
Abstract
Diabetes is the result of dysregulation of both insulin and glucagon. Still, insulin has attracted much more attention than glucagon. Glucagon is released from alpha cells in the islets of Langerhans in response to low glucose and certain amino acids. Drugs with the primary aim of targeting glucagon signalling are scarce. However, glucagon is often administered to counteract severe hypoglycaemia, and commonly used diabetes medications such as GLP-1 analogues, sulfonylureas and SGLT2-inhibitors also affect alpha cells. Indeed, there are physiological and developmental similarities between the alpha cell and the insulin-secreting beta cell and new data confirm that alpha cells can be converted into insulin-secreting cells. These aspects and attributes, the need to find novel therapies targeting the alpha cell and more are considered in this review.
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Affiliation(s)
- Anna Wendt
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Clinical Research Centre, SUS, Malmö, Sweden
| | - Lena Eliasson
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Clinical Research Centre, SUS, Malmö, Sweden.
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12
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Cabrera O, Ficorilli J, Shaw J, Echeverri F, Schwede F, Chepurny OG, Leech CA, Holz GG. Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon. J Biol Chem 2022; 298:101484. [PMID: 34896391 PMCID: PMC8789663 DOI: 10.1016/j.jbc.2021.101484] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
We report that intra-islet glucagon secreted from α-cells signals through β-cell glucagon and GLP-1 receptors (GcgR and GLP-1R), thereby conferring to rat islets their competence to exhibit first-phase glucose-stimulated insulin secretion (GSIS). Thus, in islets not treated with exogenous glucagon or GLP-1, first-phase GSIS is abolished by a GcgR antagonist (LY2786890) or a GLP-1R antagonist (Ex[9-39]). Mechanistically, glucose competence in response to intra-islet glucagon is conditional on β-cell cAMP signaling because it is blocked by the cAMP antagonist prodrug Rp-8-Br-cAMPS-pAB. In its role as a paracrine hormone, intra-islet glucagon binds with high affinity to the GcgR, while also exerting a "spillover" effect to bind with low affinity to the GLP-1R. This produces a right shift of the concentration-response relationship for the potentiation of GSIS by exogenous glucagon. Thus, 0.3 nM glucagon fails to potentiate GSIS, as expected if similar concentrations of intra-islet glucagon already occupy the GcgR. However, 10 to 30 nM glucagon effectively engages the β-cell GLP-1R to potentiate GSIS, an action blocked by Ex[9-39] but not LY2786890. Finally, we report that the action of intra-islet glucagon to support insulin secretion requires a step-wise increase of glucose concentration to trigger first-phase GSIS. It is not measurable when GSIS is stimulated by a gradient of increasing glucose concentrations, as occurs during an oral glucose tolerance test in vivo. Collectively, such findings are understandable if defective intra-islet glucagon action contributes to the characteristic loss of first-phase GSIS in an intravenous glucose tolerance test that is diagnostic of type 2 diabetes in the clinical setting.
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Affiliation(s)
- Over Cabrera
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
| | - James Ficorilli
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Janice Shaw
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | | | - Frank Schwede
- Biolog Life Science Institute GmbH & Co KG, Bremen, Germany
| | - Oleg G Chepurny
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA
| | - Colin A Leech
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA
| | - George G Holz
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA; Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA.
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13
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Göbl C, Morettini M, Salvatori B, Alsalim W, Kahleova H, Ahrén B, Tura A. Temporal Patterns of Glucagon and Its Relationships with Glucose and Insulin following Ingestion of Different Classes of Macronutrients. Nutrients 2022; 14:nu14020376. [PMID: 35057557 PMCID: PMC8780023 DOI: 10.3390/nu14020376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
Background: glucagon secretion and inhibition should be mainly determined by glucose and insulin levels, but the relative relevance of each factor is not clarified, especially following ingestion of different macronutrients. We aimed to investigate the associations between plasma glucagon, glucose, and insulin after ingestion of single macronutrients or mixed-meal. Methods: thirty-six participants underwent four metabolic tests, based on administration of glucose, protein, fat, or mixed-meal. Glucagon, glucose, insulin, and C-peptide were measured at fasting and for 300 min following food ingestion. We analyzed relationships between time samples of glucagon, glucose, and insulin in each individual, as well as between suprabasal area-under-the-curve of the same variables (ΔAUCGLUCA, ΔAUCGLU, ΔAUCINS) over the whole participants’ cohort. Results: in individuals, time samples of glucagon and glucose were related in only 26 cases (18 direct, 8 inverse relationships), whereas relationship with insulin was more frequent (60 and 5, p < 0.0001). The frequency of significant relationships was different among tests, especially for direct relationships (p ≤ 0.006). In the whole cohort, ΔAUCGLUCA was weakly related to ΔAUCGLU (p ≤ 0.02), but not to ΔAUCINS, though basal insulin secretion emerged as possible covariate. Conclusions: glucose and insulin are not general and exclusive determinants of glucagon secretion/inhibition after mixed-meal or macronutrients ingestion.
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Affiliation(s)
- Christian Göbl
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, 60131 Ancona, Italy;
| | | | - Wathik Alsalim
- Department of Clinical Sciences, Faculty of Medicine, Lund University, 22184 Lund, Sweden; (W.A.); (B.A.)
| | - Hana Kahleova
- Physicians Committee for Responsible Medicine, Washington, DC 20016, USA;
| | - Bo Ahrén
- Department of Clinical Sciences, Faculty of Medicine, Lund University, 22184 Lund, Sweden; (W.A.); (B.A.)
| | - Andrea Tura
- CNR Institute of Neuroscience, 35127 Padova, Italy;
- Correspondence: ; Tel.: +39-049-829-5786
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14
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Liu T, Ji RL, Tao YX. Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus. Pharmacol Ther 2021; 234:108044. [PMID: 34822948 DOI: 10.1016/j.pharmthera.2021.108044] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/15/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022]
Abstract
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors involved in the regulation of almost all known physiological processes. Dysfunctions of GPCR-mediated signaling have been shown to cause various diseases. The prevalence of obesity and type 2 diabetes mellitus (T2DM), two strongly associated disorders, is increasing worldwide, with tremendous economical and health burden. New safer and more efficacious drugs are required for successful weight reduction and T2DM treatment. Multiple GPCRs are involved in the regulation of energy and glucose homeostasis. Mutations in these GPCRs contribute to the development and progression of obesity and T2DM. Therefore, these receptors can be therapeutic targets for obesity and T2DM. Indeed some of these receptors, such as melanocortin-4 receptor and glucagon-like peptide 1 receptor, have provided important new drugs for treating obesity and T2DM. This review will focus on the naturally occurring mutations of several GPCRs associated with obesity and T2DM, especially incorporating recent large genomic data and insights from structure-function studies, providing leads for future investigations.
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Affiliation(s)
- Ting Liu
- Department of Anatomy, Physiology and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, AL 36849, United States
| | - Ren-Lei Ji
- Department of Anatomy, Physiology and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, AL 36849, United States
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, AL 36849, United States.
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15
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Zhang Y, Han C, Zhu W, Yang G, Peng X, Mehta S, Zhang J, Chen L, Liu Y. Glucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose. Cells 2021; 10:cells10092495. [PMID: 34572144 PMCID: PMC8471175 DOI: 10.3390/cells10092495] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/21/2022] Open
Abstract
Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.
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Affiliation(s)
- Yulin Zhang
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; (Y.Z.); (C.H.); (W.Z.); (G.Y.); (X.P.)
| | - Chengsheng Han
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; (Y.Z.); (C.H.); (W.Z.); (G.Y.); (X.P.)
| | - Wenzhen Zhu
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; (Y.Z.); (C.H.); (W.Z.); (G.Y.); (X.P.)
| | - Guoyi Yang
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; (Y.Z.); (C.H.); (W.Z.); (G.Y.); (X.P.)
| | - Xiaohong Peng
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; (Y.Z.); (C.H.); (W.Z.); (G.Y.); (X.P.)
| | - Sohum Mehta
- Department of Pharmacology, University of California San Diego, La Jolla, CA 92093-0702, USA; (S.M.); (J.Z.)
| | - Jin Zhang
- Department of Pharmacology, University of California San Diego, La Jolla, CA 92093-0702, USA; (S.M.); (J.Z.)
| | - Liangyi Chen
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; (Y.Z.); (C.H.); (W.Z.); (G.Y.); (X.P.)
- PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
- Beijing Academy of Artificial Intelligence, Beijing 100871, China
- Correspondence: (L.C.); (Y.L.)
| | - Yanmei Liu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
- Correspondence: (L.C.); (Y.L.)
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16
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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17
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Laurenti MC, Matveyenko A, Vella A. Measurement of Pulsatile Insulin Secretion: Rationale and Methodology. Metabolites 2021; 11:409. [PMID: 34206296 PMCID: PMC8305896 DOI: 10.3390/metabo11070409] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 12/29/2022] Open
Abstract
Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, and secretory parameters, such as pulse amplitude, time interval and frequency distribution, are impaired in obesity, aging and type 2 diabetes. In this review, we detail the mechanisms of insulin production and β-cell synchronization that regulate pulsatile insulin secretion, and we discuss the challenges to consider when measuring fast oscillatory secretion in vivo. These include the anatomical difficulties of measuring portal vein insulin noninvasively in humans before the hormone is extracted by the liver and quickly removed from the circulation. Peripheral concentrations of insulin or C-peptide, a peptide cosecreted with insulin, can be used to estimate their secretion profile, but mathematical deconvolution is required. Parametric and nonparametric approaches to the deconvolution problem are evaluated, alongside the assumptions and trade-offs required for their application in the quantification of unknown insulin secretory rates from known peripheral concentrations. Finally, we discuss the therapeutical implication of targeting impaired pulsatile secretion and its diagnostic value as an early indicator of β-cell stress.
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Affiliation(s)
- Marcello C. Laurenti
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, Rochester, MN 55905, USA; (M.C.L.); (A.M.)
- Biomedical Engineering and Physiology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA
| | - Aleksey Matveyenko
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, Rochester, MN 55905, USA; (M.C.L.); (A.M.)
| | - Adrian Vella
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, Rochester, MN 55905, USA; (M.C.L.); (A.M.)
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18
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Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, Fasciani I, Annibale P, Maggio R, Scarselli M. Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences. Pharmaceuticals (Basel) 2021; 14:238. [PMID: 33800403 PMCID: PMC8001502 DOI: 10.3390/ph14030238] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5'AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP's higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.
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Affiliation(s)
- Marco Carli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Shivakumar Kolachalam
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Biancamaria Longoni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Anna Pintaudi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Marco Baldini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Stefano Aringhieri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Irene Fasciani
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (I.F.); (R.M.)
| | - Paolo Annibale
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
| | - Roberto Maggio
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (I.F.); (R.M.)
| | - Marco Scarselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
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19
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Ahrén B, Yamada Y, Seino Y. The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice. Peptides 2021; 135:170434. [PMID: 33172827 DOI: 10.1016/j.peptides.2020.170434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/20/2020] [Accepted: 10/20/2020] [Indexed: 12/28/2022]
Abstract
To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, C11 BMC, Sölvegatan 19, 221 84 Lund, Sweden.
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
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Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders. Biochem J 2020; 477:2581-2594. [PMID: 32677665 DOI: 10.1042/bcj20200235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/01/2020] [Accepted: 06/16/2020] [Indexed: 01/19/2023]
Abstract
Glucagon is a peptide hormone secreted by islet α cells. It plays crucial roles in glucose homeostasis and metabolism by activating its cognate glucagon receptor (GCGR). A naturally occurring deleterious mutation V368M in the human GCGR leads to reduced ligand binding and down-regulation of glucagon signaling. To examine the association between this mutation and metabolic disorders, a knock-in mouse model bearing homozygous V369M substitution (equivalent to human V368M) in GCGR was made using CRISPR-Cas9 technology. These GcgrV369M+/+ mice displayed lower fasting blood glucose levels with improved glucose tolerance compared with wild-type controls. They also exhibited hyperglucagonemia, pancreas enlargement and α cell hyperplasia with a lean phenotype. Additionally, V369M mutation resulted in a reduction in adiposity with normal body weight and food intake. Our findings suggest a key role of V369M/V368M mutation in GCGR-mediated glucose homeostasis and pancreatic functions, thereby pointing to a possible interplay between GCGR defect and metabolic disorders.
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21
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Rodriguez-Diaz R, Tamayo A, Hara M, Caicedo A. The Local Paracrine Actions of the Pancreatic α-Cell. Diabetes 2020; 69:550-558. [PMID: 31882565 PMCID: PMC7085245 DOI: 10.2337/dbi19-0002] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022]
Abstract
Secretion of glucagon from the pancreatic α-cells is conventionally seen as the first and most important defense against hypoglycemia. Recent findings, however, show that α-cell signals stimulate insulin secretion from the neighboring β-cell. This article focuses on these seemingly counterintuitive local actions of α-cells and describes how they impact islet biology and glucose metabolism. It is mostly based on studies published in the last decade on the physiology of α-cells in human islets and incorporates results from rodents where appropriate. As this and the accompanying articles show, the emerging picture of α-cell function is one of increased complexity that needs to be considered when developing new therapies aimed at promoting islet function in the context of diabetes.
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Affiliation(s)
- Rayner Rodriguez-Diaz
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro Tamayo
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - Manami Hara
- Department of Medicine, University of Chicago, Chicago, IL
| | - Alejandro Caicedo
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL
- Program in Neuroscience, University of Miami Miller School of Medicine, Miami, FL
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Thakur G, Lee HJ, Jeon RH, Lee SL, Rho GJ. Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies. Int J Mol Sci 2020; 21:E2388. [PMID: 32235681 PMCID: PMC7178115 DOI: 10.3390/ijms21072388] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/26/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes is a metabolic disease which affects not only glucose metabolism but also lipid and protein metabolism. It encompasses two major types: type 1 and 2 diabetes. Despite the different etiologies of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively), the defining features of the two forms are insulin deficiency and resistance, respectively. Stem cell therapy is an efficient method for the treatment of diabetes, which can be achieved by differentiating pancreatic β-like cells. The consistent generation of glucose-responsive insulin releasing cells remains challenging. In this review article, we present basic concepts of pancreatic organogenesis, which intermittently provides a basis for engineering differentiation procedures, mainly based on the use of small molecules. Small molecules are more auspicious than any other growth factors, as they have unique, valuable properties like cell-permeability, as well as a nonimmunogenic nature; furthermore, they offer immense benefits in terms of generating efficient functional beta-like cells. We also summarize advances in the generation of stem cell-derived pancreatic cell lineages, especially endocrine β-like cells or islet organoids. The successful induction of stem cells depends on the quantity and quality of available stem cells and the efficient use of small molecules.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (H.-J.L.); (S.-L.L.)
| | - Hyeon-Jeong Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (H.-J.L.); (S.-L.L.)
| | - Ryoung-Hoon Jeon
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA;
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (H.-J.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (H.-J.L.); (S.-L.L.)
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Wendt A, Eliasson L. Pancreatic α-cells - The unsung heroes in islet function. Semin Cell Dev Biol 2020; 103:41-50. [PMID: 31983511 DOI: 10.1016/j.semcdb.2020.01.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 01/15/2023]
Abstract
The pancreatic islets of Langerhans consist of several hormone-secreting cell types important for blood glucose control. The insulin secreting β-cells are the best studied of these cell types, but less is known about the glucagon secreting α-cells. The α-cells secrete glucagon as a response to low blood glucose. The major function of glucagon is to release glucose from the glycogen stores in the liver. In both type 1 and type 2 diabetes, glucagon secretion is dysregulated further exaggerating the hyperglycaemia, and in type 1 diabetes α-cells fail to counter regulate hypoglycaemia. Although glucagon has been recognized for almost 100 years, the understanding of how glucagon secretion is regulated and how glucagon act within the islet is far from complete. However, α-cell research has taken off lately which is promising for future knowledge. In this review we aim to highlight α-cell regulation and glucagon secretion with a special focus on recent discoveries from human islets. We will present some novel aspects of glucagon function and effects of selected glucose lowering agents on glucagon secretion.
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Affiliation(s)
- Anna Wendt
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Clinical Research Centre, SUS, Malmö, Sweden
| | - Lena Eliasson
- Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Clinical Research Centre, SUS, Malmö, Sweden.
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Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network. Int J Mol Sci 2020; 21:ijms21030724. [PMID: 31979106 PMCID: PMC7037442 DOI: 10.3390/ijms21030724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/23/2019] [Accepted: 01/20/2020] [Indexed: 12/18/2022] Open
Abstract
The glucagon receptor (GCGR) is a G-protein-coupled receptor (GPCR) that mediates the activity of glucagon. Disruption of GCGR results in many metabolic alterations, including increased glucose tolerance, decreased adiposity, hypoglycemia, and pancreatic α-cell hyperplasia. To better understand the global transcriptomic changes resulting from GCGR deficiency, we performed whole-organism RNA sequencing analysis in wild type and gcgr-deficient zebrafish. We found that the expression of 1645 genes changes more than two-fold among mutants. Most of these genes are related to metabolism of carbohydrates, lipids, and amino acids. Genes related to fatty acid β-oxidation, amino acid catabolism, and ureagenesis are often downregulated. Among gcrgr-deficient zebrafish, we experimentally confirmed increases in lipid accumulation in the liver and whole-body glucose uptake, as well as a modest decrease in total amino acid content. These results provide new information about the global metabolic network that GCGR signaling regulates in addition to a better understanding of the receptor’s physiological functions.
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Insulin Secretion Depends on Intra-islet Glucagon Signaling. Cell Rep 2019; 25:1127-1134.e2. [PMID: 30380405 DOI: 10.1016/j.celrep.2018.10.018] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 06/11/2018] [Accepted: 10/02/2018] [Indexed: 12/20/2022] Open
Abstract
The intra-islet theory states that glucagon secretion is suppressed when insulin secretion is stimulated, but glucagon's role in intra-islet paracrine regulation is controversial. This study investigated intra-islet functions of glucagon in mice. We examined glucagon-induced insulin secretion using isolated perfused pancreata from wild-type, GLP-1 receptor (GLP-1R) knockout, diphtheria toxin-induced proglucagon knockdown, β cell-specific glucagon receptor (Gcgr) knockout, and global Gcgr knockout (Gcgr-/-) mice. We found that glucagon stimulates insulin secretion through both Gcgr and GLP-1R. Moreover, loss of either Gcgr or GLP-1R does not change insulin responses, whereas combined blockage of both receptors significantly reduces insulin secretion. Active GLP-1 is identified in pancreatic perfusate from Gcgr-/- but not wild-type mice, suggesting that β cell GLP-1R activation results predominantly from glucagon action. Our results suggest that combined activity of glucagon and GLP-1 receptors is essential for β cell secretory responses, emphasizing a role for paracrine intra-islet glucagon actions to maintain appropriate insulin secretion.
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26
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Janah L, Kjeldsen S, Galsgaard KD, Winther-Sørensen M, Stojanovska E, Pedersen J, Knop FK, Holst JJ, Wewer Albrechtsen NJ. Glucagon Receptor Signaling and Glucagon Resistance. Int J Mol Sci 2019; 20:E3314. [PMID: 31284506 PMCID: PMC6651628 DOI: 10.3390/ijms20133314] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 02/08/2023] Open
Abstract
Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon's potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.
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Affiliation(s)
- Lina Janah
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Sasha Kjeldsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Katrine D Galsgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Marie Winther-Sørensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Elena Stojanovska
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens Pedersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital Hillerød, University of Copenhagen, 3400 Hillerød, Denmark
| | - Filip K Knop
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
- Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark.
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
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27
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Tura A, Pacini G, Yamada Y, Seino Y, Ahrén B. Glucagon and insulin secretion, insulin clearance, and fasting glucose in GIP receptor and GLP-1 receptor knockout mice. Am J Physiol Regul Integr Comp Physiol 2019; 316:R27-R37. [DOI: 10.1152/ajpregu.00288.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
It is not known whether GIP receptor and GLP-1 receptor knockout (KO) mice have perturbations in glucagon secretion or insulin clearance, and studies on impact on fasting glycemia have previously been inconsistent in these mice. We therefore studied glucagon secretion after oral whey protein (60 mg) and intravenous arginine (6.25 mg), insulin clearance after intravenous glucose (0.35 g/kg) and fasting glucose, insulin, and glucagon levels after standardized 5-h fasting in female GIP receptor and GLP-1 receptor KO mice and their wild-type (WT) littermates. Compared with WT controls, GIP receptor KO mice had normal glucagon responses to oral protein and intravenous arginine, except for an enhanced 1-min response to arginine, whereas glucagon levels after oral protein and intravenous arginine were enhanced in GLP-1 receptor KO mice. Furthermore, the intravenous glucose test revealed normal insulin clearance in both GIP receptor and GLP-1 receptor KO mice, whereas β-cell glucose sensitivity was enhanced in GIP receptor KO mice and reduced in GLP-1 receptor KO mice. Finally, GIP receptor KO mice had reduced fasting glucose (6.7 ± 0.1, n = 56, vs. 7.4 ± 0.1 mmol/l, n = 59, P = 0.001), whereas GLP-1 receptor KO mice had increased fasting glucose (9.1 ± 0.2, n = 44, vs. 7.7 ± 0.1 mmol/l, n = 41, P < 0.001). We therefore suggest that GIP has a limited role for glucagon secretion in mice, whereas GLP-1 is of importance for glucagon regulation, that GIP and GLP-1 are of importance for the regulation of β-cell function beyond their role as incretin hormones, and that they are both of importance for fasting glucose.
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Affiliation(s)
- Andrea Tura
- Metabolic Unit, National Research Council Institute of Neuroscience, Padua, Italy
| | - Giovanni Pacini
- Metabolic Unit, National Research Council Institute of Neuroscience, Padua, Italy
| | - Yuchiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Graduate School of Medicine, Akita University, Akita, Japan
| | | | - Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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28
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Rivero-Gutierrez B, Haller A, Holland J, Yates E, Khrisna R, Habegger K, Dimarchi R, D'Alessio D, Perez-Tilve D. Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia. Mol Metab 2018; 17:28-38. [PMID: 30170980 PMCID: PMC6197675 DOI: 10.1016/j.molmet.2018.07.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 07/26/2018] [Accepted: 07/31/2018] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Mice with congenital loss of the glucagon receptor gene (Gcgr-/- mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with hypoglycemic activity. We combined temporally-controlled GCGR deletion with pharmacological treatments to dissect the direct contribution of GCGR signaling to glucose control in a common mouse model of T1DM. METHODS We induced experimental T1DM by injecting the beta-cell cytotoxin streptozotocin (STZ) in mice with congenital or temporally-controlled Gcgr loss-of-function using tamoxifen (TMX). RESULTS Disruption of Gcgr expression, using either an inducible approach in adult mice or animals with congenital knockout, abolished the response to a long-acting Gcgr agonist. Mice with either developmental Gcgr disruption or inducible deletion several weeks before STZ treatment maintained normoglycemia. However, mice with inducible knockout of the Gcgr one week after the onset of STZ diabetes had only partial correction of hyperglycemia, an effect that was reversed by GLP-1 receptor blockade. Mice with Gcgr deletion for either 2 or 6 weeks had similar patterns of gene expression, although the changes were generally larger with longer GCGR knockout. CONCLUSIONS These findings demonstrate that the effects of glucagon to mitigate diabetic hyperglycemia are not through acute signaling but require compensations that take weeks to develop.
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Affiliation(s)
- Belen Rivero-Gutierrez
- Department of Internal Medicine, University of Cincinnati, 2180 E. Galbraith Rd, Cincinnati, OH, USA
| | - April Haller
- Department of Internal Medicine, University of Cincinnati, 2180 E. Galbraith Rd, Cincinnati, OH, USA
| | - Jenna Holland
- Department of Internal Medicine, University of Cincinnati, 2180 E. Galbraith Rd, Cincinnati, OH, USA
| | - Emily Yates
- Department of Internal Medicine, University of Cincinnati, 2180 E. Galbraith Rd, Cincinnati, OH, USA
| | - Radha Khrisna
- Department of Medicine, Duke University School of Medicine, NC, USA
| | - Kirk Habegger
- Comprehensive Diabetes Center and Department of Medicine - Endocrinology, Diabetes & and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Richard Dimarchi
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
| | - David D'Alessio
- Department of Medicine, Duke University School of Medicine, NC, USA
| | - Diego Perez-Tilve
- Department of Internal Medicine, University of Cincinnati, 2180 E. Galbraith Rd, Cincinnati, OH, USA.
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Design principles of the paradoxical feedback between pancreatic alpha and beta cells. Sci Rep 2018; 8:10694. [PMID: 30013127 PMCID: PMC6048053 DOI: 10.1038/s41598-018-29084-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/05/2018] [Indexed: 01/11/2023] Open
Abstract
Mammalian glucose homeostasis is controlled by the antagonistic hormones insulin and glucagon, secreted by pancreatic beta and alpha cells respectively. These two cell types are adjacently located in the islets of Langerhans and affect each others’ secretions in a paradoxical manner: while insulin inhibits glucagon secretion from alpha cells, glucagon seems to stimulate insulin secretion from beta cells. Here we ask what are the design principles of this negative feedback loop. We systematically simulate the dynamics of all possible islet inter-cellular connectivity patterns and analyze different performance criteria. We find that the observed circuit dampens overshoots of blood glucose levels after reversion of glucose drops. This feature is related to the temporal delay in the rise of insulin concentrations in peripheral tissues, compared to the immediate hormone action on the liver. In addition, we find that the circuit facilitates coordinate secretion of both hormones in response to protein meals. Our study highlights the advantages of a paradoxical paracrine feedback loop in maintaining metabolic homeostasis.
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30
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Karanth S, Adams JD, Serrano MDLA, Quittner-Strom EB, Simcox J, Villanueva CJ, Ozcan L, Holland WL, Yost HJ, Vella A, Schlegel A. A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose. Cell Rep 2018; 24:312-319. [PMID: 29996093 DOI: 10.1016/j.celrep.2018.06.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/07/2018] [Accepted: 06/08/2018] [Indexed: 01/26/2023] Open
Abstract
The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non-diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and α cell mass. Conversely, liver-limited overexpression of foxn3 increases α cell mass. Supporting these genetic findings in model organisms, non-diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose.
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Affiliation(s)
- Santhosh Karanth
- University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - J D Adams
- Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Maria de Los Angeles Serrano
- University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Ezekiel B Quittner-Strom
- University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA
| | - Judith Simcox
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Claudio J Villanueva
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Lale Ozcan
- Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, NY, USA
| | - William L Holland
- University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - H Joseph Yost
- University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Adrian Vella
- Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Amnon Schlegel
- University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
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GLP-2 receptor signaling controls circulating bile acid levels but not glucose homeostasis in Gcgr -/- mice and is dispensable for the metabolic benefits ensuing after vertical sleeve gastrectomy. Mol Metab 2018; 16:45-54. [PMID: 29937214 PMCID: PMC6157461 DOI: 10.1016/j.molmet.2018.06.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 02/06/2023] Open
Abstract
Objective Therapeutic interventions that improve glucose homeostasis such as attenuation of glucagon receptor (Gcgr) signaling and bariatric surgery share common metabolic features conserved in mice and humans. These include increased circulating levels of bile acids (BA) and the proglucagon-derived peptides (PGDPs), GLP-1 and GLP-2. Whether BA acting through TGR5 (Gpbar1) increases PGDP levels in these scenarios has not been examined. Furthermore, although the importance of GLP-1 action has been interrogated in Gcgr−/− mice and after bariatric surgery, whether GLP-2 contributes to the metabolic benefits of these interventions is not known. Methods To assess whether BA acting through Gpbar1 mediates improved glucose homeostasis in Gcgr−/− mice we generated and characterized Gcgr−/−:Gpbar1−/− mice. The contribution of GLP-2 receptor (GLP-2R) signaling to intestinal and metabolic adaptation arising following loss of the Gcgr was studied in Gcgr−/−:Glp2r−/− mice. The role of the GLP-2R in the metabolic improvements evident after bariatric surgery was studied in high fat-fed Glp2r−/− mice subjected to vertical sleeve gastrectomy (VSG). Results Circulating levels of BA were markedly elevated yet similar in Gcgr−/−:Gpbar1+/+ vs. Gcgr−/−:Gpbar1−/− mice. Loss of GLP-2R lowered levels of BA in Gcgr−/− mice. Gcgr−/−:Glp2r−/− mice also exhibited shifts in the proportion of circulating BA species. Loss of Gpbar1 did not impact body weight, intestinal mass, or glucose homeostasis in Gcgr−/− mice. In contrast, small bowel growth was attenuated in Gcgr−/−:Glp2r−/− mice. The improvement in glucose tolerance, elevated circulating levels of GLP-1, and glucose-stimulated insulin levels were not different in Gcgr−/−:Glp2r+/+ vs. Gcgr−/−:Glp2r−/− mice. Similarly, loss of the GLP-2R did not attenuate the extent of weight loss and improvement in glucose control after VSG. Conclusions These findings reveal that GLP-2R controls BA levels and relative proportions of BA species in Gcgr−/− mice. Nevertheless, the GLP-2R is not essential for i) control of body weight or glucose homeostasis in Gcgr−/− mice or ii) metabolic improvements arising after VSG in high fat-fed mice. Furthermore, despite elevations of circulating levels of BA, Gpbar1 does not mediate elevated levels of PGDPs or major metabolic phenotypes in Gcgr−/− mice. Collectively these findings refine our understanding of the relationship between Gpbar1, elevated levels of BA, PGDPs, and the GLP-2R in amelioration of metabolic derangements arising following loss of Gcgr signaling or after vertical sleeve gastrectomy.
GLP-2 receptor controls bile acid levels in Gcgr−/− mice. Gpbar1 is not required for the metabolic benefits or elevated levels of PGDPs in Gcgr−/− mice. GLP-2 regulates gut adaptation in Gcgr−/− mice. Bile acid profiles are altered in Gcgr−/− mice following loss of GLP-2R. GLP-2R is not required for improvements in glucose homeostasis or weight loss after VSG in mice.
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1,25-Dihydroxyvitamin D3 protects obese rats from metabolic syndrome via promoting regulatory T cell-mediated resolution of inflammation. Acta Pharm Sin B 2018; 8:178-187. [PMID: 29719778 PMCID: PMC5925395 DOI: 10.1016/j.apsb.2018.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/06/2017] [Accepted: 12/15/2018] [Indexed: 12/20/2022] Open
Abstract
Vitamin D3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity, but the precise immunomodulatory mechanism remains poorly understood. In the present study we found that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, significantly attenuated monosodium glutamate (MSG)-induced obesity and insulin resistance as indicated by body weight reduction, oral glucose tolerance improvement, and a glucose infusion rate increase as detected with hyperinsulinemic-euglycemic clamp. Moreover, 1,25(OH)2D3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues. The protective effects of 1,25(OH)2D3 on glycolipid metabolism were attributed to its ability to inhibit an obesity-activated inflammatory response in insulin secretory and targeted tissues, as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-β1 in liver tissue, which was accompanied by increased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulin-targeted tissues such as liver, adipose, and muscle. Together, our findings suggest that 1,25(OH)2D3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects.
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Martinez-Sanchez A, Nguyen-Tu MS, Cebola I, Yavari A, Marchetti P, Piemonti L, de Koning E, Shapiro AMJ, Johnson P, Sakamoto K, Smith DM, Leclerc I, Ashrafian H, Ferrer J, Rutter GA. MiR-184 expression is regulated by AMPK in pancreatic islets. FASEB J 2018; 32:2587-2600. [PMID: 29269398 PMCID: PMC6207280 DOI: 10.1096/fj.201701100r] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits [β-cell–specific AMPK double-knockout (βAMPKdKO) mice] impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β cells.—Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.
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Affiliation(s)
- Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Marie-Sophie Nguyen-Tu
- Section of Cell Biology and Functional Genomics Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Ines Cebola
- Beta Cell Genome Regulation Laboratory, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Arash Yavari
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Piero Marchetti
- Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute (SR-DRI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Eelco de Koning
- Hubrecht Institute, Utrecht, The Netherlands.,Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - A M James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
| | - Paul Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Kei Sakamoto
- Nestle Institute of Health Sciences, Lausanne, Switzerland
| | - David M Smith
- AstraZeneca Research and Development, Innovative Medicines and Early Development, Discovery Sciences, Cambridge, United Kingdom
| | - Isabelle Leclerc
- Section of Cell Biology and Functional Genomics Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Houman Ashrafian
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Jorge Ferrer
- Beta Cell Genome Regulation Laboratory, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
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Müller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH. The New Biology and Pharmacology of Glucagon. Physiol Rev 2017; 97:721-766. [PMID: 28275047 DOI: 10.1152/physrev.00025.2016] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis. Specifically, the molecular basis of the huge metabolic benefits in bariatric surgery is emerging while novel incretin-based medicines based on endogenous hormones such as glucagon-like peptide 1 and pancreas-derived amylin are improving diabetes management. These and related developments have fostered the discovery of novel insights into endocrine control of systemic metabolism, and in particular a deeper understanding of the importance of communication across vital organs, and specifically the gut-brain-pancreas-liver network. Paradoxically, the pancreatic peptide glucagon has reemerged in this period among a plethora of newly identified metabolic macromolecules, and new data complement and challenge its historical position as a gut hormone involved in metabolic control. The synthesis of glucagon analogs that are biophysically stable and soluble in aqueous solutions has promoted biological study that has enriched our understanding of glucagon biology and ironically recruited glucagon agonism as a central element to lower body weight in the treatment of metabolic disease. This review summarizes the extensive historical record and the more recent provocative direction that integrates the prominent role of glucagon in glucose elevation with its under-acknowledged effects on lipids, body weight, and vascular health that have implications for the pathophysiology of metabolic diseases, and the emergence of precision medicines to treat metabolic diseases.
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Affiliation(s)
- T D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Department of Chemistry, Indiana University, Bloomington, Indiana; Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - B Finan
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Department of Chemistry, Indiana University, Bloomington, Indiana; Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - C Clemmensen
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Department of Chemistry, Indiana University, Bloomington, Indiana; Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - R D DiMarchi
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Department of Chemistry, Indiana University, Bloomington, Indiana; Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - M H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Department of Chemistry, Indiana University, Bloomington, Indiana; Division of Metabolic Diseases, Technische Universität München, Munich, Germany
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35
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Song G, Pacini G, Ahrén B, D'Argenio DZ. Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice. Peptides 2017; 88:74-79. [PMID: 28012858 PMCID: PMC5272823 DOI: 10.1016/j.peptides.2016.12.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 11/28/2016] [Accepted: 12/20/2016] [Indexed: 11/24/2022]
Abstract
Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35g/kg i.v.) and following glucose plus glucagon (10μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC0-20) compared to that with glucose alone (p<0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4±0.34mL/min for glucose alone and 5.8±1.5mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion.
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Affiliation(s)
- Gina Song
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | | | - Bo Ahrén
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - David Z D'Argenio
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
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36
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Zhang D, Wang F, Lal N, Chiu APL, Wan A, Jia J, Bierende D, Flibotte S, Sinha S, Asadi A, Hu X, Taghizadeh F, Pulinilkunnil T, Nislow C, Vlodavsky I, Johnson JD, Kieffer TJ, Hussein B, Rodrigues B. Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes. Diabetes 2017; 66:45-57. [PMID: 27999107 DOI: 10.2337/db16-0761] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 10/01/2016] [Indexed: 11/13/2022]
Abstract
Heparanase, a protein with enzymatic and nonenzymatic properties, contributes toward disease progression and prevention. In the current study, a fortuitous observation in transgenic mice globally overexpressing heparanase (hep-tg) was the discovery of improved glucose homeostasis. We examined the mechanisms that contribute toward this improved glucose metabolism. Heparanase overexpression was associated with enhanced glucose-stimulated insulin secretion and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in hep-tg mice, with >2,000 genes differentially expressed versus control. The upregulated genes were enriched for diverse functions including cell death regulation, extracellular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple low-dose streptozotocin (STZ), hep-tg animals developed less severe hyperglycemia compared with wild-type, an effect likely related to their β-cells being more functionally efficient. In animals given a single high dose of STZ causing severe and rapid development of hyperglycemia related to the catastrophic loss of insulin, hep-tg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of fibroblast growth factor 21 and glucagon-like peptide 1. This study uncovers the opportunity to use properties of heparanase in management of diabetes.
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Affiliation(s)
- Dahai Zhang
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Fulong Wang
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Nathaniel Lal
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Amy Pei-Ling Chiu
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrea Wan
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Jocelyn Jia
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Denise Bierende
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Stephane Flibotte
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Sunita Sinha
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Ali Asadi
- Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Xiaoke Hu
- Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Farnaz Taghizadeh
- Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Thomas Pulinilkunnil
- Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick, Canada
| | - Corey Nislow
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Israel Vlodavsky
- Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Technion, Haifa, Israel
| | - James D Johnson
- Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Timothy J Kieffer
- Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
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37
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Bankir L, Bouby N, Blondeau B, Crambert G. Glucagon actions on the kidney revisited: possible role in potassium homeostasis. Am J Physiol Renal Physiol 2016; 311:F469-86. [DOI: 10.1152/ajprenal.00560.2015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/31/2016] [Indexed: 12/25/2022] Open
Abstract
It is now recognized that the metabolic disorders observed in diabetes are not, or not only due to the lack of insulin or insulin resistance, but also to elevated glucagon secretion. Accordingly, selective glucagon receptor antagonists are now proposed as a novel strategy for the treatment of diabetes. However, besides its metabolic actions, glucagon also influences kidney function. The glucagon receptor is expressed in the thick ascending limb, distal tubule, and collecting duct, and glucagon regulates the transepithelial transport of several solutes in these nephron segments. Moreover, it also influences solute transport in the proximal tubule, possibly by an indirect mechanism. This review summarizes the knowledge accumulated over the last 30 years about the influence of glucagon on the renal handling of electrolytes and urea. It also describes a possible novel role of glucagon in the short-term regulation of potassium homeostasis. Several original findings suggest that pancreatic α-cells may express a “potassium sensor” sensitive to changes in plasma K concentration and could respond by adapting glucagon secretion that, in turn, would regulate urinary K excretion. By their combined actions, glucagon and insulin, working in a combinatory mode, could ensure an independent regulation of both plasma glucose and plasma K concentrations. The results and hypotheses reviewed here suggest that the use of glucagon receptor antagonists for the treatment of diabetes should take into account their potential consequences on electrolyte handling by the kidney.
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Affiliation(s)
- Lise Bankir
- INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- Université Pierre et Marie Curie, Paris, France; and
| | - Nadine Bouby
- INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- Université Pierre et Marie Curie, Paris, France; and
- Université Paris-Descartes, Paris, France
| | - Bertrand Blondeau
- INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- Université Pierre et Marie Curie, Paris, France; and
| | - Gilles Crambert
- INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
- Université Pierre et Marie Curie, Paris, France; and
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38
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Iida A, Seino Y, Fukami A, Maekawa R, Yabe D, Shimizu S, Kinoshita K, Takagi Y, Izumoto T, Ogata H, Ishikawa K, Ozaki N, Tsunekawa S, Hamada Y, Oiso Y, Arima H, Hayashi Y. Endogenous GIP ameliorates impairment of insulin secretion in proglucagon-deficient mice under moderate beta cell damage induced by streptozotocin. Diabetologia 2016; 59:1533-1541. [PMID: 27053237 PMCID: PMC4901104 DOI: 10.1007/s00125-016-3935-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/02/2016] [Indexed: 01/06/2023]
Abstract
AIMS/HYPOTHESIS The action of incretin hormones including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is potentiated in animal models defective in glucagon action. It has been reported that such animal models maintain normoglycaemia under streptozotocin (STZ)-induced beta cell damage. However, the role of GIP in regulation of glucose metabolism under a combination of glucagon deficiency and STZ-induced beta cell damage has not been fully explored. METHODS In this study, we investigated glucose metabolism in mice deficient in proglucagon-derived peptides (PGDPs)-namely glucagon gene knockout (GcgKO) mice-administered with STZ. Single high-dose STZ (200 mg/kg, hSTZ) or moderate-dose STZ for five consecutive days (50 mg/kg × 5, mSTZ) was administered to GcgKO mice. The contribution of GIP to glucose metabolism in GcgKO mice was also investigated by experiments employing dipeptidyl peptidase IV (DPP4) inhibitor (DPP4i) or Gcg-Gipr double knockout (DKO) mice. RESULTS GcgKO mice developed severe diabetes by hSTZ administration despite the absence of glucagon. Administration of mSTZ decreased pancreatic insulin content to 18.8 ± 3.4 (%) in GcgKO mice, but ad libitum-fed blood glucose levels did not significantly increase. Glucose-induced insulin secretion was marginally impaired in mSTZ-treated GcgKO mice but was abolished in mSTZ-treated DKO mice. Although GcgKO mice lack GLP-1, treatment with DPP4i potentiated glucose-induced insulin secretion and ameliorated glucose intolerance in mSTZ-treated GcgKO mice, but did not increase beta cell area or significantly reduce apoptotic cells in islets. CONCLUSIONS/INTERPRETATION These results indicate that GIP has the potential to ameliorate glucose intolerance even under STZ-induced beta cell damage by increasing insulin secretion rather than by promoting beta cell survival.
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Affiliation(s)
- Atsushi Iida
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Yusuke Seino
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
- Department of Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Ayako Fukami
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Ryuya Maekawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Daisuke Yabe
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan
- Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shinobu Shimizu
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan
| | - Keita Kinoshita
- Research Center of Health, Physical Fitness and Sports, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 4648601, Japan
| | - Yusuke Takagi
- Research Center of Health, Physical Fitness and Sports, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
- Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 4648601, Japan
| | - Takako Izumoto
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidetada Ogata
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Kota Ishikawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Nobuaki Ozaki
- Research Center of Health, Physical Fitness and Sports, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Shin Tsunekawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Yoji Hamada
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
- Department of Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yutaka Oiso
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Yoshitaka Hayashi
- Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 4648601, Japan.
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Green AD, Vasu S, Moffett RC, Flatt PR. Co-culture of clonal beta cells with GLP-1 and glucagon-secreting cell line impacts on beta cell insulin secretion, proliferation and susceptibility to cytotoxins. Biochimie 2016; 125:119-25. [DOI: 10.1016/j.biochi.2016.03.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 03/21/2016] [Indexed: 12/22/2022]
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40
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Wang Y, Han C, Zhu W, Wu Z, Liu Y, Chen L. An optical method to evaluate both mass and functional competence of pancreatic α- and β-cells. J Cell Sci 2016; 129:2462-71. [PMID: 27173492 DOI: 10.1242/jcs.184523] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/28/2016] [Indexed: 01/09/2023] Open
Abstract
Imbalanced glucagon and insulin release leads to the onset of type 2 diabetes. To pinpoint the underlying primary driving force, here we have developed a fast, non-biased optical method to measure ratios of pancreatic α- and β-cell mass and function simultaneously. We firstly label both primary α- and β-cells with the red fluorescent probe ZinRhodaLactam-1 (ZRL1), and then highlight α-cells by selectively quenching the ZRL1 signal from β-cells. Based on the signals before and after quenching, we calculate the ratio of the α-cell to β-cell mass within live islets, which we found matched the results from immunohistochemistry. From the same islets, glucagon and insulin release capability can be concomitantly measured. Thus, we were able to measure the ratio of α-cell to β-cell mass and their function in wild-type and diabetic Lepr(db)/Lepr(db) (denoted db/db) mice at different ages. We find that the initial glucose intolerance that appears in 10-week-old db/db mice is associated with further expansion of α-cell mass prior to deterioration in functional β-cell mass. Our method is extendable to studies of islet mass and function in other type 2 diabetes animal models, which shall benefit mechanistic studies of imbalanced hormone secretion during type 2 diabetes progression.
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Affiliation(s)
- Yi Wang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Chengsheng Han
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Wenzhen Zhu
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Zhengxing Wu
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yanmei Liu
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Liangyi Chen
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
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Malmgren S, Ahrén B. Evidence for time dependent variation of glucagon secretion in mice. Peptides 2016; 76:102-7. [PMID: 26774585 DOI: 10.1016/j.peptides.2016.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 01/05/2016] [Accepted: 01/09/2016] [Indexed: 12/15/2022]
Abstract
Glucose metabolism is subjected to diurnal variation, which might be mediated by alterations in the transcription pattern of clock genes and regulated by hormonal factors, as has been demonstrated for insulin. However, whether also glucagon is involved in the diurnal variation of glucose homeostasis is not known. We therefore examined glucagon secretion after meal ingestion (meal tolerance test) and during hypoglycemia (hyperinsulinemic hypoglycemic clamp at 2.5mmol/L glucose) and in vitro from isolated islets at ZT3 versus ZT15 in normal C57BL/6J mice and, furthermore, glucose levels and the insulin response to meal ingestion were also examined at these time points in glucagon receptor knockout mice (GCGR-/-) and their wildtype (wt) littermates. We found in normal mice that whereas the glucagon response to meal ingestion was not different between ZT3 and ZT15, the glucagon response to hypoglycemia was lower at ZT3 than at ZT15 and glucagon secretion from isolated islets was higher at ZT3 than at ZT15. GCGR-/- mice displayed lower basal glucose, a lower insulin response to meal and a higher insulin sensitivity than wt mice at ZT3 but not at ZT15. We conclude that there is a time dependent variation in glucagon secretion in normal mice, which is dependent both on intraislet and extraislet regulatory mechanisms and that the phenotype characteristics of a lower glucose and reduced insulin response to meal in GCGR-/- mice are evident only during the light phase. These findings suggest that glucagon signaling is a plausible contributor to the diurnal variation in glucose homeostasis which may explain that the phenotype of the GCGR-/- mice is dependent on the time of the day when it is examined.
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Affiliation(s)
- Siri Malmgren
- Department of Clinical Sciences in Lund, Section of Medicine, Lund University, Lund, Sweden
| | - Bo Ahrén
- Department of Clinical Sciences in Lund, Section of Medicine, Lund University, Lund, Sweden.
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Arrojo e Drigo R, Ali Y, Diez J, Srinivasan DK, Berggren PO, Boehm BO. New insights into the architecture of the islet of Langerhans: a focused cross-species assessment. Diabetologia 2015. [PMID: 26215305 DOI: 10.1007/s00125-015-3699-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The human genome project and its search for factors underlying human diseases has fostered a major human research effort. Therefore, unsurprisingly, in recent years we have observed an increasing number of studies on human islet cells, including disease approaches focusing on type 1 and type 2 diabetes. Yet, the field of islet and diabetes research relies on the legacy of rodent-based investigations, which have proven difficult to translate to humans, particularly in type 1 diabetes. Whole islet physiology and pathology may differ between rodents and humans, and thus a comprehensive cross-species as well as species-specific view on islet research is much needed. In this review we summarise the current knowledge of interspecies islet cytoarchitecture, and discuss its potential impact on islet function and future perspectives in islet pathophysiology research.
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Affiliation(s)
- Rafael Arrojo e Drigo
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Research Techno Plaza, Level 4, 637 553, Singapore, Singapore
| | - Yusuf Ali
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Research Techno Plaza, Level 4, 637 553, Singapore, Singapore
| | - Juan Diez
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Research Techno Plaza, Level 4, 637 553, Singapore, Singapore
| | - Dinesh Kumar Srinivasan
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Research Techno Plaza, Level 4, 637 553, Singapore, Singapore
| | - Per-Olof Berggren
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Research Techno Plaza, Level 4, 637 553, Singapore, Singapore.
- Imperial College London, London, UK.
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital L1, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
| | - Bernhard O Boehm
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Research Techno Plaza, Level 4, 637 553, Singapore, Singapore.
- Imperial College London, London, UK.
- Department of Internal Medicine 1, Ulm University Medical Centre, Ulm, Germany.
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Sandoval DA, D'Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev 2015; 95:513-48. [PMID: 25834231 DOI: 10.1152/physrev.00013.2014] [Citation(s) in RCA: 342] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.
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Affiliation(s)
- Darleen A Sandoval
- Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David A D'Alessio
- Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio
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44
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Ahrén B. Glucagon--Early breakthroughs and recent discoveries. Peptides 2015; 67:74-81. [PMID: 25814364 DOI: 10.1016/j.peptides.2015.03.011] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/14/2015] [Accepted: 03/16/2015] [Indexed: 12/12/2022]
Abstract
Glucagon was discovered in 1922 as a hyperglycemic factor in the pancreas. During its early history up to 1970, glucagon was shown to increase circulating glucose through stimulating glycogenolysis in the liver. It was also shown to be a constituent of islet non-β cells and to signal through G protein coupled receptors and cyclic AMP. Furthermore, its chemical characteristics, including amino acid sequence, and its processing from the preproglucagon gene had been established. During the modern research during the last 40 years, glucagon has been established as a key hormone in the regulation of glucose homeostasis, including a key role for the glucose counterregulation to hypoglycemia and for development of type 2 diabetes, and today glucagon is a potential target for treatment of the disease. Glucagon has also been shown to be a key factor beyond glucose control and involved in many processes. For the coming, future research, studies will be focused on α-cell biology beyond glucagon, hyperglucagonemia in other conditions than diabetes, its involvement in the regulation of body weight and energy expenditure and the potential of glucagon as a target for other diseases than type 2 diabetes, such as type 1 diabetes and obesity. This review summarizes the more than 90 years history of this important hormone as well as discusses potential future research regarding glucagon.
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Affiliation(s)
- Bo Ahrén
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
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45
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Filipski KJ. Small molecule glucagon receptor antagonists: a patent review (2011 – 2014). Expert Opin Ther Pat 2015; 25:819-30. [DOI: 10.1517/13543776.2015.1032250] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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Kaiser D, Oetjen E. Something old, something new and something very old: drugs for treating type 2 diabetes. Br J Pharmacol 2015; 171:2940-50. [PMID: 24641580 DOI: 10.1111/bph.12624] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/13/2014] [Accepted: 01/30/2014] [Indexed: 12/28/2022] Open
Abstract
Diabetes mellitus belongs to the most rapidly increasing diseases worldwide. Approximately 90-95% of these patients suffer from type 2 diabetes mellitus, which is characterized by peripheral insulin resistance and the progressive loss of beta-cell function and mass. Considering the complications of this chronic disease, a reliable anti-diabetic treatment is indispensable. An ideal oral anti-diabetic drug should not only correct glucose homeostasis but also preserve or even augment beta-cell function and mass, ameliorate the subclinical inflammation present under insulin-resistant conditions and prevent the macro- and microvascular consequences of diabetes in order to reduce the mortality. Despite the many anti-diabetic drugs already in use, there is an ongoing research for additional drugs, guided by different concepts of the pathogenesis of type 2 diabetes. This review will briefly summarize current oral anti-diabetic drugs. In addition, emerging strategies for the treatment of diabetes will be described, among them the inhibition of glucagon action and anti-inflammatory drugs. Their suitability as 'ideal anti-diabetic drugs' will be discussed.
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Affiliation(s)
- D Kaiser
- Department of Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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47
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Abstract
The short chain fatty acid (SCFA) receptor (free fatty acid receptor-3; FFAR3) is expressed in pancreatic β cells; however, its role in insulin secretion is not clearly defined. Here, we examined the role of FFAR3 in insulin secretion. Using islets from global knockout FFAR3 (Ffar3(-/-)) mice, we explored the role of FFAR3 and ligand-induced FFAR3 signaling on glucose stimulated insulin secretion. RNA sequencing was also performed to gain greater insight into the impact of FFAR3 deletion on the islet transcriptome. First exploring insulin secretion, it was determined that Ffar3(-/-) islets secrete more insulin in a glucose-dependent manner as compared to wildtype (WT) islets. Next, exploring its primary endogenous ligand, propionate, and a specific agonist for FFAR3, signaling by FFAR3 inhibited glucose-dependent insulin secretion, which occurred through a Gαi/o pathway. To help understand these results, transcriptome analyses by RNA-sequencing of Ffar3(-/-) and WT islets observed multiple genes with well-known roles in islet biology to be altered by genetic knockout of FFAR3. Our data shows that FFAR3 signaling mediates glucose stimulated insulin secretion through Gαi/o sensitive pathway. Future studies are needed to more rigorously define the role of FFAR3 by in vivo approaches.
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Affiliation(s)
- Medha Priyadarshini
- Division of Endocrinology, Metabolism and Molecular Medicine; Northwestern University Feinberg School of Medicine; Chicago, IL USA
| | - Brian T Layden
- Division of Endocrinology, Metabolism and Molecular Medicine; Northwestern University Feinberg School of Medicine; Chicago, IL USA
- Jesse Brown Veterans Affairs Medical Center; Chicago, IL USA
- Correspondence to: Brian T Layden;
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48
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Wang L, Luk CT, Cai EP, Schroer SA, Allister EM, Shi SY, Wheeler MB, Gaisano HY, Woo M. PTEN deletion in pancreatic α-cells protects against high-fat diet-induced hyperglucagonemia and insulin resistance. Diabetes 2015; 64:147-57. [PMID: 25092678 DOI: 10.2337/db13-1715] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
An aberrant increase in circulating catabolic hormone glucagon contributes to type 2 diabetes pathogenesis. However, mechanisms regulating glucagon secretion and α-cell mass are not well understood. In this study, we aimed to demonstrate that phosphatidylinositol 3-kinase (PI3K) signaling is an important regulator of α-cell function. Mice with deletion of PTEN, a negative regulator of this pathway, in α-cells show reduced circulating glucagon levels and attenuated l-arginine-stimulated glucagon secretion both in vivo and in vitro. This hypoglucagonemic state is maintained after high-fat-diet feeding, leading to reduced expression of hepatic glycogenolytic and gluconeogenic genes. These beneficial effects protected high-fat diet-fed mice against hyperglycemia and insulin resistance. The data demonstrate an inhibitory role of PI3K signaling on α-cell function and provide experimental evidence for enhancing α-cell PI3K signaling for diabetes treatment.
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Affiliation(s)
- Linyuan Wang
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Cynthia T Luk
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Erica P Cai
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Stephanie A Schroer
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada
| | - Emma M Allister
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Sally Y Shi
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Michael B Wheeler
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Herbert Y Gaisano
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Minna Woo
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada Division of Endocrinology & Metabolism, Department of Medicine, University Health Network, Toronto, ON, Canada
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Lu J, Jaafer R, Bonnavion R, Bertolino P, Zhang CX. Transdifferentiation of pancreatic α-cells into insulin-secreting cells: From experimental models to underlying mechanisms. World J Diabetes 2014; 5:847-853. [PMID: 25512786 PMCID: PMC4265870 DOI: 10.4239/wjd.v5.i6.847] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 04/10/2014] [Accepted: 07/29/2014] [Indexed: 02/05/2023] Open
Abstract
Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are currently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.
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50
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Karambataki M, Malousi A, Kouidou S. Risk-associated coding synonymous SNPs in type 2 diabetes and neurodegenerative diseases: genetic silence and the underrated association with splicing regulation and epigenetics. Mutat Res 2014; 770:85-93. [PMID: 25771874 DOI: 10.1016/j.mrfmmm.2014.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 09/15/2014] [Accepted: 09/16/2014] [Indexed: 06/04/2023]
Abstract
Single nucleotide polymorphisms (SNPs) are tentatively critical with regard to disease predisposition, but coding synonymous SNPs (sSNPs) are generally considered "neutral". Nevertheless, sSNPs in serine/arginine-rich (SR) and splice-site (SS) exonic splicing enhancers (ESEs) or in exonic CpG methylation targets, could be decisive for splicing, particularly in aging-related conditions, where mis-splicing is frequently observed. We presently identified 33 genes T2D-related and 28 related to neurodegenerative diseases, by investigating the impact of the corresponding coding sSNPs on splicing and using gene ontology data and computational tools. Potentially critical (prominent) sSNPs comply with the following criteria: changing the splicing potential of prominent SR-ESEs or of significant SS-ESEs by >1.5 units (Δscore), or formation/deletion of ESEs with maximum splicing score. We also noted the formation/disruption of CpGs (tentative methylation sites of epigenetic sSNPs). All disease association studies involving sSNPs are also reported. Only 21/670 coding SNPs, mostly epigenetic, reported in 33 T2D-related genes, were found to be prominent coding synonymous. No prominent sSNPs have been recorded in three key T2D-related genes (GCGR, PPARGC1A, IGF1). Similarly, 20/366 coding synonymous were identified in ND related genes, mostly epigenetic. Meta-analysis showed that 17 of the above prominent sSNPs were previously investigated in association with various pathological conditions. Three out of four sSNPs (all epigenetic) were associated with T2D and one with NDs (branch site sSNP). Five were associated with other or related pathological conditions. None of the four sSNPs introducing new ESEs was found to be disease-associated. sSNPs introducing smaller Δscore changes (<1.5) in key proteins (INSR, IRS1, DISC1) were also correlated to pathological conditions. This data reveals that genetic variation in splicing-regulatory and particularly CpG sites might be related to disease predisposition and that in-silico analysis is useful for identifying sSNPs, which might be falsely identified as silent or synonymous.
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Affiliation(s)
- M Karambataki
- Lab of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - A Malousi
- Lab of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - S Kouidou
- Lab of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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