The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

dc.contributor.authorMartínez, María Sofía
dc.contributor.authorManzano, Alexander
dc.contributor.authorOlivar, Luis Carlos
dc.contributor.authorNava, Manuel
dc.contributor.authorSalazar, Juan
dc.contributor.authorD'Marco, Luis
dc.contributor.authorOrtiz, Rina
dc.contributor.authorChacín, Maricarmen
dc.contributor.authorGuerrero-Wyss, Marion
dc.contributor.authorCabrera de Bravo, Mayela
dc.contributor.authorCano, Clímaco
dc.contributor.authorBermúdez, Valmore
dc.contributor.authorAngarita, Lisse
dc.description.abstractType 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.eng
dc.identifier.citationMartínez, 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. 10.3390/ijms22179504eng
dc.identifier.doi 10.3390/ijms22179504
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.sourceInternational Journal of Molecular Scienceseng
dc.sourceVol. 22, No.17 (2021)
dc.subjectLangerhans’ isletseng
dc.subjectType 2 diabeteseng
dc.titleThe Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirroreng
dc.type.spaArtículo científicospa
dcterms.referencesNoncommunicable Diseases Progress Monitor 2017. Available online: 1513029 (accessed on 21 March 2021).eng
dcterms.referencesIDF Diabetes Atlas 9th Edition 2019. Available online: (accessed on 21 March 2021).eng
dcterms.referencesBrown, A.E.; Walker, M. Genetics of Insulin Resistance and the Metabolic Syndrome. Curr. Cardiol. Rep. 2016, 18, 75. [CrossRef] [PubMed]eng
dcterms.referencesPetersen, M.C.; Shulman, G.I. Mechanisms of Insulin Action and Insulin Resistance. Physiol. Rev. 2018, 98, 2133–2223. [CrossRef] [PubMed]eng
dcterms.referencesCantley, J.; Ashcroft, F.M. Q&A: Insulin secretion and type 2 diabetes: Why do β-cells fail? BMC Biol. 2015, 13, 33eng
dcterms.referencesUnger, R.H.; Orci, L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1975, 305, 14–16. [CrossRef]eng
dcterms.referencesReaven, 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]eng
dcterms.referencesLotfy, 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]eng
dcterms.referencesSandoval, 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]eng
dcterms.referencesWendt, A.; Eliasson, L. Pancreatic α-cells—The unsung heroes in islet function. Semin. Cell Dev. Biol. 2020, 103, 41–50. [CrossRef]eng
dcterms.referencesBramswig, N.C.; Kaestner, K.H. Transcriptional regulation of α-cell differentiation. Diabetes Obes. Metab. 2011, 13 (Suppl. S1), 13–20. [CrossRef]eng
dcterms.referencesSinger, 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]eng
dcterms.referencesOrci, L.; Unger, R.H. Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 1975, 2, 1243–1244. [CrossRef]eng
dcterms.referencesBosco, 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]eng
dcterms.referencesArrojo 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]eng
dcterms.referencesOmar-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]eng
dcterms.referencesGromada, 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]eng
dcterms.referencesWatts, 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]eng
dcterms.referencesGylfe, E. Glucose control of glucagon secretion—‘There’s a brand-new gimmick every year’. Ups. J. Med. Sci. 2016, 121, 120–132. [CrossRef]eng
dcterms.referencesRodriguez-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]eng
dcterms.referencesCaicedo, A. Paracrine and autocrine interactions in the human islet: More than meets the eye. Semin. Cell Dev. Biol. 2013, 24, 11–21. [CrossRef]eng
dcterms.referencesKawamori, 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]eng
dcterms.referencesKawamori, 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]eng
dcterms.referencesElliott, 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]eng
dcterms.referencesPatel, 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]eng
dcterms.referencesTian, 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]eng
dcterms.referencesLeung, 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. [CrossRef]eng
dcterms.referencesXu, E.; Kumar, M.; Zhang, Y.; Ju, W.; Obata, T.; Zhang, N.; Liu, S.; Wendt, A.; Deng, S.; Ebina, Y.; et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 2006, 3, 47–58. [CrossRef]eng
dcterms.referencesPurwana, I.; Zheng, J.; Li, X.; Deurloo, M.; Son, D.O.; Zhang, Z.; Liang, C.; Shen, E.; Tadkase, A.; Feng, Z.-P.; et al. GABA promotes human β-cell proliferation and modulates glucose homeostasis. Diabetes 2014, 63, 4197–4205. [CrossRef]eng
dcterms.referencesFeng, A.L.; Xiang, Y.-Y.; Gui, L.; Kaltsidis, G.; Feng, Q.; Lu, W.-Y. Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes. Diabetologia 2017, 60, 1033–1042. [CrossRef]eng
dcterms.referencesKatsura, T.; Kawamori, D.; Aida, E.; Matsuoka, T.-A.; Shimomura, I. Glucotoxicity induces abnormal glucagon secretion through impaired insulin signaling in InR1G cells. PLoS ONE 2017, 12, e0176271. [CrossRef]eng
dcterms.referencesTian, J.; Dang, H.; Chen, Z.; Guan, A.; Jin, Y.; Atkinson, M.A.; Kaufman, D.L. γ-Aminobutyric acid regulates both the survival and replication of human β-cells. Diabetes 2013, 62, 3760–3765. [CrossRef]eng
dcterms.referencesBlodgett, D.M.; Nowosielska, A.; Afik, S.; Pechhold, S.; Cura, A.J.; Kennedy, N.J.; Kim, S.; Kucukural, A.; Davis, R.J.; Kent, S.C.; et al. Novel Observations From Next-Generation RNA Sequencing of Highly Purified Human Adult and Fetal Islet Cell Subsets. Diabetes 2015, 64, 3172–3181. [CrossRef]eng
dcterms.referencesLi, J.; Yu, Q.; Ahooghalandari, P.; Gribble, F.M.; Reimann, F.; Tengholm, A.; Gylfe, E. Submembrane ATP and Ca2+ kinetics in α-cells: Unexpected signaling for glucagon secretion. FASEB J. 2015, 29, 3379–3388. [CrossRef]eng
dcterms.referencesAlmaça, J.; Molina, J.; Menegaz, D.; Pronin, A.N.; Tamayo, A.; Slepak, V.; Berggren, P.-O.; Caicedo, A. Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells. Cell Rep. 2016, 17, 3281–3291. [CrossRef]eng
dcterms.referencesTengholm, A.; Gylfe, E. cAMP signalling in insulin and glucagon secretion. Diabetes Obes. Metab. 2017, 19 (Suppl. S1), 42–53. [CrossRef]eng
dcterms.referencesKailey, B.; van de Bunt, M.; Cheley, S.; Johnson, P.R.; MacDonald, P.E.; Gloyn, A.L.; Rorsman, P.; Braun, M. SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells. Am. J. Physiol. Endocrinol. Metab. 2012, 303, E1107–E1116. [CrossRef]eng
dcterms.referencesBriant, L.J.B.; Reinbothe, T.M.; Spiliotis, I.; Miranda, C.; Rodriguez, B.; Rorsman, P. δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin. J. Physiol. 2018, 596, 197–215. [CrossRef]eng
dcterms.referencesVierra, N.C.; Dickerson, M.T.; Jordan, K.L.; Dadi, P.K.; Katdare, K.A.; Altman, M.K.; Milian, S.C.; Jacobson, D.A. TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion. Mol. Metab. 2018, 9, 84–97. [CrossRef]eng
dcterms.referencesLeibiger, 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]eng
dcterms.referencesYan, 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]eng
dcterms.referencesLi, 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]eng
dcterms.referencesPetersen, 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]eng
dcterms.referencesMa, 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]eng
dcterms.referencesLiu, 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]eng
dcterms.referencesNakashima, 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]eng
dcterms.referencesCabrera, 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. Glutamate is a positive autocrine signal for glucagon release. Cell Metab. 2008, 7, 545–554. [CrossRef]eng
dcterms.referencesWang, Q.; Liang, X.; Wang, S. Intra-islet glucagon secretion and action in the regulation of glucose homeostasis. Front. Physiol. 2012, 3, 485. [CrossRef]eng
dcterms.referencesJiao, Z.-Y.; Wu, J.; Liu, C.; Wen, B.; Zhao, W.-Z.; Du, X.-L. Type 3 muscarinic acetylcholine receptor stimulation is a determinant of endothelial barrier function and adherens junctions integrity: Role of protein-tyrosine phosphatase 1B. BMB Rep. 2014, 47, 552–557. [CrossRef]eng
dcterms.referencesRodriguez-Diaz, R.; Menegaz, D.; Caicedo, A. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet. J. Physiol. 2014, 592, 3413–3417. [CrossRef]eng
dcterms.referencesHutchens, T.; Piston, D.W. EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From α-Cells. Diabetes 2015, 64, 3839–3851. [CrossRef]eng
dcterms.referencesLiu, W.; Kin, T.; Ho, S.; Dorrell, C.; Campbell, S.R.; Luo, P.; Chen, X. Abnormal regulation of glucagon secretion by human islet alpha cells in the absence of beta cells. EBioMedicine 2019, 50, 306–316. [CrossRef]eng
dcterms.referencesReissaus, C.A.; Piston, D.W. Reestablishment of Glucose Inhibition of Glucagon Secretion in Small Pseudoislets. Diabetes 2017, 66, 960–969. [CrossRef]eng
dcterms.referencesKania, A.; Klein, R. Mechanisms of ephrin–Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol. 2016, 17, 240–256. [CrossRef]eng
dcterms.referencesDarling, T.K.; Lamb, T.J. Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity. Front. Immunol. 2019, 10, 1473. [CrossRef]eng
dcterms.referencesGilon, P. The Role of α-Cells in Islet Function and Glucose Homeostasis in Health and Type 2 Diabetes. J. Mol. Biol. 2020, 432, 1367–1394. [CrossRef]eng
dcterms.referencesHughes, J.W.; Ustione, A.; Lavagnino, Z.; Piston, D.W. Regulation of islet glucagon secretion: Beyond calcium. Diabetes Obes. Metab. 2018, 20 (Suppl. S2), 127–136. [CrossRef]eng
dcterms.referencesChung, Y.H.; Piston, D.W. RhoA Mediated Juxtacrine Regulation of Glucagon Secretion. Biophys. J. 2020, 118, 248a. [CrossRef]eng
dcterms.referencesDiIorio, P.; Rittenhouse, A.R.; Bortell, R.; Jurczyk, A. Role of cilia in normal pancreas function and in diseased states. Birth Defects Res. C Embryo Today 2014, 102, 126–138. [CrossRef]eng
dcterms.referencesLodh, S.; O’Hare, E.A.; Zaghloul, N.A. Primary cilia in pancreatic development and disease. Birth Defects Res. C Embryo Today 2014, 102, 139–158. [CrossRef]eng
dcterms.referencesGerdes, J.M.; Christou-Savina, S.; Xiong, Y.; Moede, T.; Moruzzi, N.; Karlsson-Edlund, P.; Leibiger, B.; Leibiger, I.B.; Östenson, C.-G.; Beales, P.L.; et al. Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents. Nat. Commun. 2014, 5, 5308. [CrossRef]eng
dcterms.referencesRojas, J.; Bermudez, V.; Palmar, J.; Martínez, M.S.; Olivar, L.C.; Nava, M.; Tomey, D.; Rojas, M.; Salazar, J.; Garicano, C.; et al. Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy. J. Diabetes Res. 2018, 2018, 9601801. [CrossRef]eng
dcterms.referencesMizukami, H.; Takahashi, K.; Inaba, W.; Tsuboi, K.; Osonoi, S.; Yoshida, T.; Yagihashi, S. Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of β-cell mass in Japanese type 2 diabetic patients. Diabetes Care 2014, 37, 1966–1974. [CrossRef]eng
dcterms.referencesEllingsgaard, H.; Ehses, J.A.; Hammar, E.B.; Van Lommel, L.; Quintens, R.; Martens, G.; Kerr-Conte, J.; Pattou, F.; Berney, T.; Pipeleers, D.; et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc. Natl. Acad. Sci. USA 2008, 105, 13163–13168. [CrossRef]eng
dcterms.referencesOlofsson, C.S.; Håkansson, J.; Salehi, A.; Bengtsson, M.; Galvanovskis, J.; Partridge, C.; SörhedeWinzell, M.; Xian, X.; Eliasson, L.; Lundquist, I.; et al. Impaired insulin exocytosis in neural cell adhesion molecule−/− mice due to defective reorganization of the submembrane F-actin network. Endocrinology 2009, 150, 3067–3075. [CrossRef]eng
dcterms.referencesBagger, J.I.; Knop, F.K.; Lund, A.; Vestergaard, H.; Holst, J.J.; Vilsbøll, T. Impaired regulation of the incretin effect in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 2011, 96, 737–745. [CrossRef] [PubMed]eng
dcterms.referencesPiro, S.; Mascali, L.G.; Urbano, F.; Filippello, A.; Malaguarnera, R.; Calanna, S.; Rabuazzo, A.M.; Purrello, F. Chronic exposure to GLP-1 increases GLP-1 synthesis and release in a pancreatic alpha cell line (α-TC1): Evidence of a direct effect of GLP-1 on pancreatic alpha cells. PLoS ONE 2014, 9, e90093. [CrossRef] [PubMed]eng
dcterms.referencesHolst, J.J.; Christensen, M.; Lund, A.; de Heer, J.; Svendsen, B.; Kielgast, U.; Knop, F.K. Regulation of glucagon secretion by incretins. Diabetes Obes. Metab. 2011, 13 (Suppl. S1), 89–94. [CrossRef] [PubMed]eng
dcterms.referencesKirk, R.K.; Pyke, C.; von Herrath, M.G.; Hasselby, J.P.; Pedersen, L.; Mortensen, P.G.; Knudsen, L.B.; Coppieters, K. Immunohistochemical assessment of glucagon-like peptide 1 receptor (GLP-1R) expression in the pancreas of patients with type 2 diabetes. Diabetes Obes. Metab. 2017, 19, 705–712. [CrossRef] [PubMed]eng
dcterms.referencesØrgaard, A.; Holst, J.J. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice. Diabetologia 2017, 60, 1731–1739. [CrossRef]eng
dcterms.referencesRamracheya, R.; Chapman, C.; Chibalina, M.; Dou, H.; Miranda, C.; González, A.; Moritoh, Y.; Shigeto, M.; Zhang, Q.; Braun, M.; et al. GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels. Physiol. Rep. 2018, 6, e13852. [CrossRef]eng
dcterms.referencesNakashima, K.; Hamamoto, S.; Kimura, Y.; Shimoda, M.; Tawaramoto, K.; Hirukawa, H.; Kimura, T.; Okauchi, S.; Kaku, K. Pulsatile Secretion of Glucagon-Like Peptide-1(GLP-1) from Pancreatic Alpha Cells: Evidence for Independent Mechanism from Intestinal GLP-1 Secretion in Rodents. Diabetologia 2013, 56, 45. [CrossRef]eng
dcterms.referencesHabener, J.F.; Stanojevic, V. α-cell role in β-cell generation and regeneration. Islets 2012, 4, 188–198. [CrossRef]eng
dcterms.referencesPatarrão, R.S.; Lautt, W.W.; Macedo, M.P. Acute glucagon induces postprandial peripheral insulin resistance. PLoS ONE 2015, 10, e0127221. [CrossRef]eng
dcterms.referencesMoon, J.S.; Won, K.C. Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block. Diabetes Metab. J. 2015, 39, 1–9. [CrossRef]eng
dcterms.referencesD’Alessio, D. The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes. Metab. 2011, 13, 126–132. [CrossRef]eng
dcterms.referencesCampbell-Thompson, M.; Tang, S.-C. Pancreas Optical Clearing and 3-D Microscopy in Health and Diabetes. Front. Endocrinol. 2021, 12, 644826. [CrossRef]eng
dcterms.referencesMasini, M.; Martino, L.; Marselli, L.; Bugliani, M.; Boggi, U.; Filipponi, F.; Marchetti, P.; De Tata, V. Ultrastructural alterations of pancreatic beta cells in human diabetes mellitus. Diabetes Metab. Res. Rev. 2017, 33, e2894. [CrossRef]eng
dcterms.referencesWillcox, A.; Gillespie, K.M. Histology of Type 1 Diabetes Pancreas. In Type-1 Diabetes; Gillespie, K.M., Ed.; Methods in Molecular Biology; Springer: New York, NY, USA, 2015; Volume 1433, pp. 105–117. ISBN 978-1-4939-3641-0.eng
dcterms.referencesMateus Gonçalves, L.; Almaça, J. Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices. Front. Endocrinol. 2021, 11, 602519. [CrossRef]eng
dcterms.referencesCai, Y.; Yuchi, Y.; De Groef, S.; Coppens, V.; Leuckx, G.; Baeyens, L.; Van de Casteele, M.; Heimberg, H. IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation. Diabetologia 2014, 57, 1420–1427. [CrossRef]eng
dcterms.referencesLam, C.J.; Cox, A.R.; Jacobson, D.R.; Rankin, M.M.; Kushner, J.A. Highly Proliferative α-Cell-Related Islet Endocrine Cells in Human Pancreata. Diabetes 2018, 67, 674–686. [CrossRef]eng
dcterms.referencesKawamori, D.; Katakami, N.; Takahara, M.; Miyashita, K.; Sakamoto, F.; Yasuda, T.; Matsuoka, T.-A.; Shimomura, I. Dysregulated plasma glucagon levels in Japanese young adult type 1 diabetes patients. J. Diabetes Investig. 2019, 10, 62–66. [CrossRef]eng
dcterms.referencesHughes, D.S.; Narendran, P. Alpha cell function in type 1 diabetes. Br. J. Diabetes 2014, 14, 45. [CrossRef]eng
dcterms.referencesZhang, Y.; Thai, K.; Jin, T.; Woo, M.; Gilbert, R.E. SIRT1 activation attenuates α cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice. Sci. Rep. 2018, 8, 13972. [CrossRef]eng
dcterms.referencesCodella, R.; Lanzoni, G.; Zoso, A.; Caumo, A.; Montesano, A.; Terruzzi, I.M.; Ricordi, C.; Luzi, L.; Inverardi, L. Moderate Intensity Training Impact on the Inflammatory Status and Glycemic Profiles in NOD Mice. J. Diabetes Res. 2015, 2015, 737586. [CrossRef]eng
dcterms.referencesBrereton, M.F.; Iberl, M.; Shimomura, K.; Zhang, Q.; Adriaenssens, A.E.; Proks, P.; Spiliotis, I.I.; Dace, W.; Mattis, K.K.; Ramracheya, R.; et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat. Commun. 2014, 5, 4639. [CrossRef]eng
dcterms.referencesPuri, S.; Folias, A.E.; Hebrok, M. Plasticity and dedifferentiation within the pancreas: Development, homeostasis, and disease. Cell Stem Cell 2015, 16, 18–31. [CrossRef]eng
dcterms.referencesCai, Q.; Bonfanti, P.; Sambathkumar, R.; Vanuytsel, K.; Vanhove, J.; Gysemans, C.; Debiec-Rychter, M.; Raitano, S.; Heimberg, H.; Ordovas, L.; et al. Prospectively isolated NGN3-expressing progenitors from human embryonic stem cells give rise to pancreatic endocrine cells. Stem Cells Transl. Med. 2014, 3, 489–499. [CrossRef]eng
dcterms.referencesRiedel, M.J.; Asadi, A.; Wang, R.; Ao, Z.; Warnock, G.L.; Kieffer, T.J. Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetologia 2012, 55, 372–381. [CrossRef]eng
dcterms.referencesSpijker, H.S.; Ravelli, R.B.G.; Mommaas-Kienhuis, A.M.; van Apeldoorn, A.A.; Engelse, M.A.; Zaldumbide, A.; Bonner-Weir, S.; Rabelink, T.J.; Hoeben, R.C.; Clevers, H.; et al. Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes 2013, 62, 2471–2480. [CrossRef]eng
dcterms.referencesSpijker, H.S.; Song, H.; Ellenbroek, J.H.; Roefs, M.M.; Engelse, M.A.; Bos, E.; Koster, A.J.; Rabelink, T.J.; Hansen, B.C.; Clark, A.; et al. Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated with Islet Amyloid Deposits. Diabetes 2015, 64, 2928–2938. [CrossRef]eng
dcterms.referencesFujita, Y.; Kozawa, J.; Iwahashi, H.; Yoneda, S.; Uno, S.; Eguchi, H.; Nagano, H.; Imagawa, A.; Shimomura, I. Human pancreatic αto β-cell area ratio increases after type 2 diabetes onset. J. Diabetes Investig. 2018, 9, 1270–1282. [CrossRef]eng
dcterms.referencesTalchai, C.; Xuan, S.; Lin, H.V.; Sussel, L.; Accili, D. Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure. Cell 2012, 150, 1223–1234. [CrossRef] [PubMed]eng
dcterms.referencesWang, Z.; York, N.W.; Nichols, C.G.; Remedi, M.S. Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 2014, 19, 872–882. [CrossRef] [PubMed]eng
dcterms.referencesNordmann, T.M.; Dror, E.; Schulze, F.; Traub, S.; Berishvili, E.; Barbieux, C.; Böni-Schnetzler, M.; Donath, M.Y. The Role of Inflammation in β-cell Dedifferentiation. Sci. Rep. 2017, 7, 6285. [CrossRef] [PubMed]eng
dcterms.referencesZhu, Y.; Liu, Q.; Zhou, Z.; Ikeda, Y. PDX1, Neurogenin-3, and MAFA: Critical transcription regulators for beta cell development and regeneration. Stem Cell Res. Ther. 2017, 8, 240. [CrossRef] [PubMed]eng
dcterms.referencesCinti, F.; Bouchi, R.; Kim-Muller, J.Y.; Ohmura, Y.; Sandoval, P.R.; Masini, M.; Marselli, L.; Suleiman, M.; Ratner, L.E.; Marchetti, P.; et al. Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2016, 101, 1044–1054. [CrossRef]eng
dcterms.referencesKim-Muller, J.Y.; Fan, J.; Kim, Y.J.R.; Lee, S.-A.; Ishida, E.; Blaner, W.S.; Accili, D. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice. Nat. Commun. 2016, 7, 12631. [CrossRef]eng
dcterms.referencesGao, T.; McKenna, B.; Li, C.; Reichert, M.; Nguyen, J.; Singh, T.; Yang, C.; Pannikar, A.; Doliba, N.; Zhang, T.; et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab. 2014, 19, 259–271. [CrossRef]eng
dcterms.referencesMalenczyk, K.; Szodorai, E.; Schnell, R.; Lubec, G.; Szabó, G.; Hökfelt, T.; Harkany, T. Secretagogin protects Pdx1 from proteasomal degradation to control a transcriptional program required for β cell specification. Mol. Metab. 2018, 14, 108–120. [CrossRef]eng
dcterms.referencesSwisa, A.; Glaser, B.; Dor, Y. Metabolic Stress and Compromised Identity of Pancreatic Beta Cells. Front. Genet. 2017, 8, 21. [CrossRef]eng
dcterms.referencesInaishi, J.; Saisho, Y.; Sato, S.; Kou, K.; Murakami, R.; Watanabe, Y.; Kitago, M.; Kitagawa, Y.; Yamada, T.; Itoh, H. Effects of Obesity and Diabetes on α- and β-Cell Mass in Surgically Resected Human Pancreas. J. Clin. Endocrinol. Metab. 2016, 101, 2874–2882. [CrossRef]eng
dcterms.referencesTakahashi, K.; Nakamura, A.; Miyoshi, H.; Nomoto, H.; Kitao, N.; Omori, K.; Yamamoto, K.; Cho, K.Y.; Terauchi, Y.; Atsumi, T. Effect of the sodium-glucose cotransporter 2 inhibitor luseogliflozin on pancreatic beta cell mass in db/db mice of different ages. Sci. Rep. 2018, 8, 6864. [CrossRef]eng
dcterms.referencesIshida, E.; Kim-Muller, J.Y.; Accili, D. Pair Feeding, but Not Insulin, Phloridzin, or Rosiglitazone Treatment, Curtails Markers of β-Cell Dedifferentiation in db/db Mice. Diabetes 2017, 66, 2092–2101. [CrossRef]eng
dcterms.referencesHamilton, A.; Zhang, Q.; Salehi, A.; Willems, M.; Knudsen, J.G.; Ringgaard, A.K.; Chapman, C.E.; Gonzalez-Alvarez, A.; Surdo, N.C.; Zaccolo, M.; et al. Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization from Acidic Stores in Pancreatic α-Cells. Diabetes 2018, 67, 1128–1139. [CrossRef]eng
dcterms.referencesZhang, Q.; Ramracheya, R.; Lahmann, C.; Tarasov, A.; Bengtsson, M.; Braha, O.; Braun, M.; Brereton, M.; Collins, S.; Galvanovskis, J.; et al. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 2013, 18, 871–882. [CrossRef]eng
dcterms.referencesKnudsen, J.G.; Hamilton, A.; Ramracheya, R.; Tarasov, A.I.; Brereton, M.; Haythorne, E.; Chibalina, M.V.; Spégel, P.; Mulder, H.; Zhang, Q.; et al. Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production. Cell Metab. 2019, 29, 430–442.e4. [CrossRef]eng
dcterms.referencesAdam, J.; Ramracheya, R.; Chibalina, M.V.; Ternette, N.; Hamilton, A.; Tarasov, A.I.; Zhang, Q.; Rebelato, E.; Rorsman, N.J.G.; Martín-Del-Río, R.; et al. Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes. Cell Rep. 2017, 20, 3135–3148. [CrossRef]eng
dcterms.referencesPareek, A.; Chandurkar, N.; Naidu, K. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 1800.eng
dcterms.referencesZinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [CrossRef]eng
dcterms.referencesBasco, D.; Zhang, Q.; Salehi, A.; Tarasov, A.; Dolci, W.; Herrera, P.; Spiliotis, I.; Berney, X.; Tarussio, D.; Rorsman, P.; et al. α-cell glucokinase suppresses glucose-regulated glucagon secretion. Nat. Commun. 2018, 9, 546. [CrossRef]eng
dcterms.referencesWang, P.; Liu, H.; Chen, L.; Duan, Y.; Chen, Q.; Xi, S. Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus. J. Diabetes Res. 2017, 2017, 1–9. [CrossRef]eng
dcterms.referencesScheen, A.J.; Paquot, N.; Lefèbvre, P.J. Investigational glucagon receptor antagonists in Phase I and II clinical trials for diabetes. Expert Opin. Investig. Drugs 2017, 26, 1373–1389. [CrossRef] [PubMed]eng
dcterms.referencesGuan, H.-P.; Yang, X.; Lu, K.; Wang, S.-P.; Castro-Perez, J.M.; Previs, S.; Wright, M.; Shah, V.; Herath, K.; Xie, D.; et al. Glucagon receptor antagonism induces increased cholesterol absorption. J. Lipid Res. 2015, 56, 2183–2195. [CrossRef] [PubMed]eng
dcterms.referencesGuzman, C.B.; Zhang, X.M.; Liu, R.; Regev, A.; Shankar, S.; Garhyan, P.; Pillai, S.G.; Kazda, C.; Chalasani, N.; Hardy, T.A. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes: Guzman et al. Diabetes Obes. Metab. 2017, 19, 1521–1528. [CrossRef] [PubMed]eng
dcterms.referencesPearson, M.J.; Unger, R.H.; Holland, W.L. Clinical Trials, Triumphs, and Tribulations of Glucagon Receptor Antagonists. Dia Care 2016, 39, 1075–1077. [CrossRef] [PubMed]eng
dcterms.referencesMorgan, E.S.; Tai, L.-J.; Pham, N.C.; Overman, J.K.; Watts, L.M.; Smith, A.; Jung, S.W.; Gajdošík, M.; Krššák, M.; Krebs, M.; et al. Antisense Inhibition of Glucagon Receptor by IONIS-GCGRRx Improves Type 2 Diabetes without Increase in Hepatic Glycogen Content in Patients with Type 2 Diabetes on Stable Metformin Therapy. Diabetes Care 2019, 42, 585–593. [CrossRef] [PubMed]eng
dcterms.referencesYu, R.; Ren, S.-G.; Mirocha, J. Glucagon receptor is required for long-term survival: A natural history study of the Mahvash disease in a murine model. Endocrinol. Nutr. 2012, 59, 523–530. [CrossRef] [PubMed]eng
dcterms.referencesLi, H.; Zhao, L.; Singh, R.; Ham, J.N.; Fadoju, D.O.; Bean, L.J.H.; Zhang, Y.; Xu, Y.; Xu, H.E.; Gambello, M.J. The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine. Mol. Genet. Metab. Rep. 2018, 17, 46–52. [CrossRef]eng
dcterms.referencesGild, M.L.; Tsang, V.; Samra, J.; Clifton-Bligh, R.J.; Tacon, L.; Gill, A.J. Hypercalcemia in Glucagon Cell Hyperplasia and Neoplasia (Mahvash Syndrome): A New Association. J. Clin. Endocrinol. Metab. 2018, 103, 3119–3123. [CrossRef]eng
dcterms.referencesMatsumoto, S.; Yamazaki, M.; Kadono, M.; Iwase, H.; Kobayashi, K.; Okada, H.; Fukui, M.; Hasegawa, G.; Nakamura, N. Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes. J. Clin. Biochem. Nutr. 2013, 53, 68–72. [CrossRef]eng
dcterms.referencesSun, X.F.; Wang, Y.; Zhao, W.J.; Wang, L.; Bao, D.Q.; Qu, G.R.; Yao, M.X.; Luan, J.; Wang, Y.G.; Yan, S.L. Effect of liraglutide on glucagon secretion in obese type 2 diabetic patients. Zhonghua Nei Ke Za Zhi 2019, 58, 33–38.eng
dcterms.referencesHalden, T.A.S.; Egeland, E.J.; Åsberg, A.; Hartmann, A.; Midtvedt, K.; Khiabani, H.Z.; Holst, J.J.; Knop, F.K.; Hornum, M.; Feldt-Rasmussen, B.; et al. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes. Diabetes Care 2016, 39, 617–624. [CrossRef]eng
dcterms.referencesSeghieri, M.; Rebelos, E.; Gastaldelli, A.; Astiarraga, B.D.; Casolaro, A.; Barsotti, E.; Pocai, A.; Nauck, M.; Muscelli, E.; Ferrannini, E. Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia 2013, 56, 156–161. [CrossRef]eng
dcterms.referencesHare, K.J.; Vilsboll, T.; Asmar, M.; Deacon, C.F.; Knop, F.K.; Holst, J.J. The Glucagonostatic and Insulinotropic Effects of Glucagon-Like Peptide 1 Contribute Equally to Its Glucose-Lowering Action. Diabetes 2010, 59, 1765–1770. [CrossRef]eng
dcterms.referencesKuhadiya, N.D.; Dhindsa, S.; Ghanim, H.; Mehta, A.; Makdissi, A.; Batra, M.; Sandhu, S.; Hejna, J.; Green, K.; Bellini, N.; et al. Addition of Liraglutide to Insulin in Patients with Type 1 Diabetes: A Randomized Placebo-Controlled Clinical Trial of 12 Weeks. Diabetes Care 2016, 39, 1027–1035. [CrossRef]eng
dcterms.referencesGalderisi, A.; Sherr, J.; VanName, M.; Carria, L.; Zgorski, M.; Tichy, E.; Weyman, K.; Cengiz, E.; Weinzimer, S.; Tamborlane, W. Pramlintide but Not Liraglutide Suppresses Meal-Stimulated Glucagon Responses in Type 1 Diabetes. J. Clin. Endocrinol. Metab. 2018, 103, 1088–1094. [CrossRef]eng
dcterms.referencesPieber, T.R.; Deller, S.; Korsatko, S.; Jensen, L.; Christiansen, E.; Madsen, J.; Heller, S.R. Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: A randomized, placebo-controlled, double-blind, crossover trial. Diabetes Obes. Metab. 2015, 17, 742–750. [CrossRef]eng
dcterms.referencesMuscelli, E.; Casolaro, A.; Gastaldelli, A.; Mari, A.; Seghieri, G.; Astiarraga, B.; Chen, Y.; Alba, M.; Holst, J.; Ferrannini, E. Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2012, 97, 2818–2826. [CrossRef]eng
dcterms.referencesVan Raalte, D.H.; van Genugten, R.E.; Eliasson, B.; Möller-Goede, D.L.; Mari, A.; Tura, A.; Wilson, C.; Fleck, P.; Taskinen, M.R.; Smith, U.; et al. The effect of alogliptin and pioglitazone combination therapy on various aspects of β-cell function in patients with recent-onset type 2 diabetes. Eur. J. Endocrinol. 2014, 170, 565–574. [CrossRef]eng
dcterms.referencesHansen, L.; Iqbal, N.; Ekholm, E.; Cook, W.; Hirshberg, B. Postprandial Dynamics of Plasma Glucose, Insulin, and Glucagon in Patients with Type 2 Diabetes Treated with Saxagliptin Plus Dapagliflozin Add-On to Metformin Therapy. Endocr. Pract. 2014, 20, 1187–1197. [CrossRef]eng
dcterms.referencesSolis-Herrera, C.; Triplitt, C.; de Jesús Garduno-Garcia, J.; Adams, J.; DeFronzo, R.A.; Cersosimo, E. Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or with Metformin in Type 2 Diabetes: A double-tracer study. Diabetes Care 2013, 36, 2756–2762. [CrossRef]eng
dcterms.referencesAhren, B.; Foley, J.E.; Ferrannini, E.; Matthews, D.R.; Zinman, B.; Dejager, S.; Fonseca, V.A. Changes in Prandial Glucagon Levels After a 2-Year Treatment with Vildagliptin or Glimepiride in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy. Diabetes Care 2010, 33, 730–732. [CrossRef] [PubMed]eng
dcterms.referencesAwata, T.; Shimada, A.; Maruyama, T.; Oikawa, Y.; Yasukawa, N.; Kurihara, S.; Miyashita, Y.; Hatano, M.; Ikegami, Y.; Matsuda, M.; et al. Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S). Diabetes Ther. 2017, 8, 1123–1134. [CrossRef] [PubMed]eng
dcterms.referencesUnderland, L.J.; Ilkowitz, J.T.; Katikaneni, R.; Dowd, A.; Heptulla, R.A. Use of Sitagliptin with Closed-Loop Technology to Decrease Postprandial Blood Glucose in Type 1 Diabetes. J. Diabetes Sci. Technol. 2017, 11, 602–610. [CrossRef] [PubMed]eng
dcterms.referencesGarg, S.K.; Moser, E.G.; Bode, B.W.; Klaff, L.J.; Hiatt, W.R.; Beatson, C.; Snell-Bergeon, J.K. Effect of Sitagliptin on Post-Prandial Glucagon and GLP-1 Levels in Patients with Type 1 Diabetes: Investigator-Initiated, Double-Blind, Randomized, PlaceboControlled Trial. Endocr. Pract. 2013, 19, 19–28. [CrossRef] [PubMed]eng
dcterms.referencesAmbery, P.D.; Klammt, S.; Posch, M.G.; Petrone, M.; Pu, W.; Rondinone, C.; Jermutus, L.; Hirshberg, B. MEDI0382, a GLP1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, Phase 1 study: Single-dose MEDI0382 in healthy subjects. Br. J. Clin. Pharmacol. 2018, 84, 2325–2335. [CrossRef] [PubMed]eng
dcterms.referencesSeghieri, M.; Christensen, A.S.; Andersen, A.; Solini, A.; Knop, F.K.; Vilsbøll, T. Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD. Front. Endocrinol. 2018, 9, 649. [CrossRef]eng
dcterms.referencesPatel, V.; Joharapurkar, A.; Kshirsagar, S.; Sutariya, B.; Patel, M.; Patel, H.; Pandey, D.; Patel, D.; Ranvir, R.; Kadam, S.; et al. Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease. Cardiovasc. Hematol. Agents Med. Chem. 2018, 16, 35–43. [CrossRef]eng
dcterms.referencesSánchez-Garrido, M.A.; Brandt, S.J.; Clemmensen, C.; Müller, T.D.; DiMarchi, R.D.; Tschöp, M.H. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia 2017, 60, 1851–1861. [CrossRef]eng


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