The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror
Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, s...
- Autores:
-
Martínez, María Sofía
Manzano, Alexander
Olivar, Luis Carlos
Nava, Manuel
Salazar, Juan
D'Marco, Luis
Ortiz, Rina
Chacín, Maricarmen
Guerrero-Wyss, Marion
Cabrera de Bravo, Mayela
Cano, Clímaco
Bermúdez, Valmore
Angarita, Lisse
- Tipo de recurso:
- Fecha de publicación:
- 2021
- Institución:
- Universidad Simón Bolívar
- Repositorio:
- Repositorio Digital USB
- Idioma:
- eng
- OAI Identifier:
- oai:bonga.unisimon.edu.co:20.500.12442/8642
- Acceso en línea:
- https://hdl.handle.net/20.500.12442/8642
https://doi.org/ 10.3390/ijms22179504
https://www.mdpi.com/1422-0067/22/17/9504/htm
- Palabra clave:
- Glucagon
Langerhans’ islets
Type 2 diabetes
Hyperglycaemia
Hypoglycaemia
- Rights
- openAccess
- License
- Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| title |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| spellingShingle |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror Glucagon Langerhans’ islets Type 2 diabetes Hyperglycaemia Hypoglycaemia |
| title_short |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| title_full |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| title_fullStr |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| title_full_unstemmed |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| title_sort |
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror |
| dc.creator.fl_str_mv |
Martínez, María Sofía Manzano, Alexander Olivar, Luis Carlos Nava, Manuel Salazar, Juan D'Marco, Luis Ortiz, Rina Chacín, Maricarmen Guerrero-Wyss, Marion Cabrera de Bravo, Mayela Cano, Clímaco Bermúdez, Valmore Angarita, Lisse |
| dc.contributor.author.none.fl_str_mv |
Martínez, María Sofía Manzano, Alexander Olivar, Luis Carlos Nava, Manuel Salazar, Juan D'Marco, Luis Ortiz, Rina Chacín, Maricarmen Guerrero-Wyss, Marion Cabrera de Bravo, Mayela Cano, Clímaco Bermúdez, Valmore Angarita, Lisse |
| dc.subject.eng.fl_str_mv |
Glucagon Langerhans’ islets Type 2 diabetes Hyperglycaemia Hypoglycaemia |
| topic |
Glucagon Langerhans’ islets Type 2 diabetes Hyperglycaemia Hypoglycaemia |
| description |
Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy. |
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2021 |
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2021-10-05T16:13:48Z |
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2021-10-05T16:13:48Z |
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2021 |
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info:eu-repo/semantics/article |
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Artículo científico |
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Martínez, M.S.; Manzano, A.; Olivar, L.C.; Nava, M.; Salazar, J.; D’Marco, L.; Ortiz, R.; Chacín, M.; Guerrero-Wyss, M.; Cabrera de Bravo, M.; et al. The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror. Int. J. Mol. Sci. 2021, 22, 9504. https://doi.org/ 10.3390/ijms22179504 |
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14220067 |
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https://hdl.handle.net/20.500.12442/8642 |
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https://doi.org/ 10.3390/ijms22179504 |
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https://www.mdpi.com/1422-0067/22/17/9504/htm |
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Martínez, M.S.; Manzano, A.; Olivar, L.C.; Nava, M.; Salazar, J.; D’Marco, L.; Ortiz, R.; Chacín, M.; Guerrero-Wyss, M.; Cabrera de Bravo, M.; et al. The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror. Int. J. Mol. Sci. 2021, 22, 9504. https://doi.org/ 10.3390/ijms22179504 14220067 |
| url |
https://hdl.handle.net/20.500.12442/8642 https://doi.org/ 10.3390/ijms22179504 https://www.mdpi.com/1422-0067/22/17/9504/htm |
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eng |
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eng |
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Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
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pdf |
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MDPI |
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International Journal of Molecular Sciences |
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Vol. 22, No.17 (2021) |
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Martínez, María Sofía24132de7-a45a-499c-aa91-9dc68c5cbf09Manzano, Alexander0dd1f5fe-19cd-42e0-b698-34b17a178629Olivar, Luis Carlos212e67d1-e669-4a31-9299-d653994d03a6Nava, Manuelcf0ca570-5fc3-4ec7-9913-90be952261e2Salazar, Juanfbd053e7-5aea-424c-812f-92153ecb9181D'Marco, Luis4f289143-892b-43a3-ac1f-6f462224f314Ortiz, Rinab447a86e-9594-4822-8d44-ca0ed740e500Chacín, Maricarmenfdb0f1d1-c963-4360-8d3b-f21d402ee436Guerrero-Wyss, Marion143b8ef8-f0fe-403b-b76c-12d2d9448b2cCabrera de Bravo, Mayelad984e281-e460-420f-9c2a-4af12b674973Cano, Clímacob7d55d6b-f1bf-4136-9b90-54a80ab90ab2Bermúdez, Valmore29f9aa18-16a4-4fd3-8ce5-ed94a0b8663aAngarita, Lisseb43f96d1-8216-41b4-997a-8d011852d8622021-10-05T16:13:48Z2021-10-05T16:13:48Z2021Martínez, M.S.; Manzano, A.; Olivar, L.C.; Nava, M.; Salazar, J.; D’Marco, L.; Ortiz, R.; Chacín, M.; Guerrero-Wyss, M.; Cabrera de Bravo, M.; et al. The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror. Int. J. Mol. Sci. 2021, 22, 9504. https://doi.org/ 10.3390/ijms2217950414220067https://hdl.handle.net/20.500.12442/8642https://doi.org/ 10.3390/ijms22179504https://www.mdpi.com/1422-0067/22/17/9504/htmType 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.pdfengMDPIAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2International Journal of Molecular SciencesVol. 22, No.17 (2021)GlucagonLangerhans’ isletsType 2 diabetesHyperglycaemiaHypoglycaemiaThe Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirrorinfo:eu-repo/semantics/articleArtículo científicohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_2df8fbb1Noncommunicable Diseases Progress Monitor 2017. Available online: https://www.who.int/publications-detail-redirect/978924 1513029 (accessed on 21 March 2021).IDF Diabetes Atlas 9th Edition 2019. Available online: https://www.diabetesatlas.org/en/ (accessed on 21 March 2021).Brown, A.E.; Walker, M. Genetics of Insulin Resistance and the Metabolic Syndrome. Curr. Cardiol. Rep. 2016, 18, 75. [CrossRef] [PubMed]Petersen, M.C.; Shulman, G.I. Mechanisms of Insulin Action and Insulin Resistance. Physiol. Rev. 2018, 98, 2133–2223. [CrossRef] [PubMed]Cantley, J.; Ashcroft, F.M. Q&A: Insulin secretion and type 2 diabetes: Why do β-cells fail? BMC Biol. 2015, 13, 33Unger, R.H.; Orci, L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1975, 305, 14–16. [CrossRef]Reaven, G.M.; Chen, Y.D.; Golay, A.; Swislocki, A.L.; Jaspan, J.B. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 1987, 64, 106–110. [CrossRef]Lotfy, M.; Kalasz, H.; Szalai, G.; Singh, J.; Adeghate, E. Recent Progress in the Use of Glucagon and Glucagon Receptor Antagonists in the Treatment of Diabetes Mellitus. Open Med. Chem. J. 2014, 8, 28–35. [CrossRef]Sandoval, D.A.; D’Alessio, D.A. Physiology of proglucagon peptides: Role of glucagon and GLP-1 in health and disease. Physiol. Rev. 2015, 95, 513–548. [CrossRef]Wendt, A.; Eliasson, L. Pancreatic α-cells—The unsung heroes in islet function. Semin. Cell Dev. Biol. 2020, 103, 41–50. [CrossRef]Bramswig, N.C.; Kaestner, K.H. Transcriptional regulation of α-cell differentiation. Diabetes Obes. Metab. 2011, 13 (Suppl. S1), 13–20. [CrossRef]Singer, R.A.; Arnes, L.; Cui, Y.; Wang, J.; Gao, Y.; Guney, M.A.; Burnum-Johnson, K.E.; Rabadan, R.; Ansong, C.; Orr, G.; et al. The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function. Cell Metab. 2019, 30, 1091–1106.e8. [CrossRef]Orci, L.; Unger, R.H. Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 1975, 2, 1243–1244. [CrossRef]Bosco, D.; Armanet, M.; Morel, P.; Niclauss, N.; Sgroi, A.; Muller, Y.D.; Giovannoni, L.; Parnaud, G.; Berney, T. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 2010, 59, 1202–1210. [CrossRef]Arrojo e Drigo, R.; Ali, Y.; Diez, J.; Srinivasan, D.K.; Berggren, P.-O.; Boehm, B.O. New insights into the architecture of the islet of Langerhans: A focused cross-species assessment. Diabetologia 2015, 58, 2218–2228. [CrossRef]Omar-Hmeadi, M.; Lund, P.-E.; Gandasi, N.R.; Tengholm, A.; Barg, S. Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes. Nat. Commun. 2020, 11, 1896. [CrossRef]Gromada, J.; Franklin, I.; Wollheim, C.B. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr. Rev. 2007, 28, 84–116. [CrossRef]Watts, M.; Ha, J.; Kimchi, O.; Sherman, A. Paracrine regulation of glucagon secretion: The β/α/δ model. Am. J. Physiol. Endocrinol. Metab. 2016, 310, E597–E611. [CrossRef]Gylfe, E. Glucose control of glucagon secretion—‘There’s a brand-new gimmick every year’. Ups. J. Med. Sci. 2016, 121, 120–132. [CrossRef]Rodriguez-Diaz, R.; Molano, R.D.; Weitz, J.R.; Abdulreda, M.H.; Berman, D.M.; Leibiger, B.; Leibiger, I.B.; Kenyon, N.S.; Ricordi, C.; Pileggi, A.; et al. Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point. Cell Metab. 2018, 27, 549–558.e4. [CrossRef]Caicedo, A. Paracrine and autocrine interactions in the human islet: More than meets the eye. Semin. Cell Dev. Biol. 2013, 24, 11–21. [CrossRef]Kawamori, D.; Kurpad, A.J.; Hu, J.; Liew, C.W.; Shih, J.L.; Ford, E.L.; Herrera, P.L.; Polonsky, K.S.; McGuinness, O.P.; Kulkarni, R.N. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab. 2009, 9, 350–361. [CrossRef]Kawamori, D.; Akiyama, M.; Hu, J.; Hambro, B.; Kulkarni, R.N. Growth factor signalling in the regulation of α-cell fate. Diabetes Obes. Metab. 2011, 13 (Suppl. S1), 21–30. [CrossRef] [PubMed]Elliott, A.D.; Ustione, A.; Piston, D.W. Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP. Am. J. Physiol. Endocrinol. Metab. 2015, 308, E130–E143. [CrossRef] [PubMed]Patel, Y.C.; Amherdt, M.; Orci, L. Quantitative electron microscopic autoradiography of insulin, glucagon, and somatostatin binding sites on islets. Science 1982, 217, 1155–1156. [CrossRef] [PubMed]Tian, G.; Sandler, S.; Gylfe, E.; Tengholm, A. Glucose- and hormone-induced cAMP oscillations in α- and β-cells within intact pancreatic islets. Diabetes 2011, 60, 1535–1543. [CrossRef]Leung, Y.M.; Ahmed, I.; Sheu, L.; Gao, X.; Hara, M.; Tsushima, R.G.; Diamant, N.E.; Gaisano, H.Y. Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 50 -triphosphate inhibition. Endocrinology 2006, 147, 2155–2162. 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[CrossRef]Leibiger, B.; Moede, T.; Muhandiramlage, T.P.; Kaiser, D.; Vaca Sanchez, P.; Leibiger, I.B.; Berggren, P.-O. Glucagon regulates its own synthesis by autocrine signaling. Proc. Natl. Acad. Sci. USA 2012, 109, 20925–20930. [CrossRef]Yan, H.; Gu, W.; Yang, J.; Bi, V.; Shen, Y.; Lee, E.; Winters, K.A.; Komorowski, R.; Zhang, C.; Patel, J.J.; et al. Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys. J. Pharmacol. Exp. Ther. 2009, 329, 102–111. [CrossRef]Li, X.C.; Zhuo, J.L. Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in Type 2 diabetes: Theory versus promise. Clin. Sci. 2007, 113, 183–193. [CrossRef]Petersen, K.F.; Sullivan, J.T. Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 2001, 44, 2018–2024. [CrossRef] [PubMed]Ma, X.; Zhang, Y.; Gromada, J.; Sewing, S.; Berggren, P.-O.; Buschard, K.; Salehi, A.; Vikman, J.; Rorsman, P.; Eliasson, L. Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors. Mol. Endocrinol. 2005, 19, 198–212. [CrossRef] [PubMed]Liu, Z.; Kim, W.; Chen, Z.; Shin, Y.-K.; Carlson, O.D.; Fiori, J.L.; Xin, L.; Napora, J.K.; Short, R.; Odetunde, J.O.; et al. Insulin and glucagon regulate pancreatic α-cell proliferation. PLoS ONE 2011, 6, e16096. [CrossRef] [PubMed]Nakashima, K.; Kaneto, H.; Shimoda, M.; Kimura, T.; Kaku, K. Pancreatic alpha cells in diabetic rats express active GLP-1 receptor: Endosomal co-localization of GLP-1/GLP-1R complex functioning through intra-islet paracrine mechanism. Sci. Rep. 2018, 8, 3725. [CrossRef]Cabrera, O.; Jacques-Silva, M.C.; Speier, S.; Yang, S.-N.; Köhler, M.; Fachado, A.; Vieira, E.; Zierath, J.R.; Kibbey, R.; Berman, D.M.; et al. 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