Academic Journal
View in EDS

α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion.

Bibliographic Details
Title: α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion.
Authors: Cui C; Duke Molecular Physiology Institute, Durham, NC, USA., Leander DC; Duke Molecular Physiology Institute, Durham, NC, USA., Gray SM; Duke Molecular Physiology Institute, Durham, NC, USA., El K; Duke Molecular Physiology Institute, Durham, NC, USA., Chen A; Duke Molecular Physiology Institute, Durham, NC, USA., Grimsrud PA; Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Department of Medicine, Duke University, Durham, NC, USA., Becker JO; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Taylor A; Departments of Surgery and Pathology and Laboratory Medicine, Faculty of Medicine, BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada., Zhang GF; Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Department of Medicine, Duke University, Durham, NC, USA., Sloop KW; Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Verchere CB; Departments of Surgery and Pathology and Laboratory Medicine, Faculty of Medicine, BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada., Hoofnagle AN; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., D'Alessio DA; Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Department of Medicine, Duke University, Durham, NC, USA., Campbell JE; Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Department of Medicine, Duke University, Durham, NC, USA.; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
Source: Science advances [Sci Adv] 2025 Sep 19; Vol. 11 (38), pp. eady8048. Date of Electronic Publication: 2025 Sep 19.
Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
Language: English
Journal Info: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
Imprint Name(s): Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
MeSH Terms: Proglucagon*/metabolism , Glucagon-Secreting Cells*/metabolism , Proprotein Convertase 1*/metabolism , Proprotein Convertase 1*/genetics , Insulin*/metabolism , Proprotein Convertase 2*/metabolism , Proprotein Convertase 2*/genetics , Insulin Secretion*, Glucagon-Like Peptide 1/metabolism ; Insulin-Secreting Cells/metabolism ; Animals ; Humans ; Mice ; Mice, Transgenic
Abstract: α cells secrete proglucagon peptides to regulate nutrient metabolism. Recent findings support an α cell-to-β cell axis that is mediated by paracrine signaling through the glucagon receptor and glucagon-like peptide 1 (GLP-1) receptor in β cells. To address which proglucagon peptides stimulate insulin secretion, we developed an assay to quantify levels of GLP-1(7-36)NH2. We also generated three transgenic mouse lines that allow α cell-specific, inducible deletion of the genes for the two prohormone convertase enzymes that process proglucagon . Our studies reveal that both mouse and human islets contain GLP-1(7-36)NH2, but glucagon mediates α cell-to-β cell communication in mice. However, in the absence of normal production of glucagon, α cells up-regulate prohormone convertase 1 (PC1/3) to generate GLP-1 and enhance glucose tolerance. Human islets have substantially higher levels of GLP-1 than mice, which positively correlate with rates of insulin secretion. These studies show plasticity in proglucagon processing to support α cell-to-β cell communication.
References: J Diabetes Investig. 2016 Apr;7 Suppl 1:50-5. (PMID: 27186356)
J Histochem Cytochem. 2024 Aug-Sep;72(8-9):545-550. (PMID: 39248433)
JCI Insight. 2019 Mar 7;4(5):. (PMID: 30720465)
Diabetes. 2011 Nov;60(11):2872-82. (PMID: 21926270)
Sci Adv. 2021 Mar 12;7(11):. (PMID: 33712466)
JCI Insight. 2021 Feb 8;6(3):. (PMID: 33554958)
Endocrinology. 2004 Mar;145(3):1349-55. (PMID: 14630721)
J Mass Spectrom Adv Clin Lab. 2025 Apr 11;36:37-45. (PMID: 40385697)
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6646-51. (PMID: 9192619)
Diabetologia. 2012 Dec;55(12):3262-72. (PMID: 22965295)
JCI Insight. 2019 Jul 23;5:. (PMID: 31335319)
Sci Adv. 2022 Jul 22;8(29):eabn3773. (PMID: 35867787)
Nat Med. 1996 Nov;2(11):1254-8. (PMID: 8898756)
Endocrinology. 2021 Jul 1;162(7):. (PMID: 33782700)
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2500-2510. (PMID: 35775723)
Nat Med. 2016 Jan;22(1):84-90. (PMID: 26642437)
J Clin Invest. 2007 Jan;117(1):143-52. (PMID: 17187081)
Diabetes. 1998 Jan;47(1):66-72. (PMID: 9421376)
Diabetes. 2020 Apr;69(4):542-549. (PMID: 31653720)
Cell Metab. 2018 Mar 6;27(3):549-558.e4. (PMID: 29514065)
Diabetologia. 2017 Mar;60(3):453-463. (PMID: 27999871)
Endocrinology. 2020 Nov 1;161(11):. (PMID: 32964214)
Cell Metab. 2022 Nov 1;34(11):1654-1674. (PMID: 36323234)
JCI Insight. 2019 Apr 23;5:. (PMID: 31012868)
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10299-304. (PMID: 12136131)
Cell Metab. 2017 Apr 4;25(4):927-934.e3. (PMID: 28325479)
Diabetes. 2019 May;68(5):906-917. (PMID: 30626611)
Cell Metab. 2014 Jun 3;19(6):1050-7. (PMID: 24836562)
Diabetologia. 2024 Dec;67(12):2771-2785. (PMID: 39404844)
Mol Metab. 2020 Sep;39:101014. (PMID: 32413586)
Nat Metab. 2024 Sep;6(9):1791-1806. (PMID: 39169271)
Diabetes. 2015 Mar;64(3):819-27. (PMID: 25288673)
J Clin Invest. 2000 Apr;105(7):955-65. (PMID: 10749575)
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10293-8. (PMID: 12145326)
Nat Rev Endocrinol. 2025 Jul;21(7):397-412. (PMID: 40055529)
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13468-73. (PMID: 16938896)
Diabetes. 2023 Dec 1;72(12):1741-1747. (PMID: 37983524)
Cell Rep. 2017 Mar 28;18(13):3192-3203. (PMID: 28355570)
Diabetes. 2024 Mar 1;73(3):412-425. (PMID: 38015721)
J Clin Invest. 2011 May;121(5):1917-29. (PMID: 21540554)
Cell Metab. 2017 Jun 6;25(6):1348-1361.e8. (PMID: 28591637)
Diabetologia. 1986 Jan;29(1):46-52. (PMID: 3514343)
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1438-43. (PMID: 12552113)
Nat Rev Endocrinol. 2015 Jun;11(6):329-38. (PMID: 25850661)
Physiol Rev. 2022 Jan 1;102(1):155-208. (PMID: 34280055)
J Proteome Res. 2017 Feb 3;16(2):538-549. (PMID: 27966365)
J Biol Chem. 2020 Aug 14;295(33):11529-11541. (PMID: 32554468)
Diabetes Obes Metab. 2014 Nov;16(11):1155-64. (PMID: 25041349)
Cell Rep. 2018 Oct 30;25(5):1127-1134.e2. (PMID: 30380405)
Cell Metab. 2013 Jun 4;17(6):819-837. (PMID: 23684623)
Mass Spectrom Rev. 2020 May;39(3):229-244. (PMID: 28691345)
Diabetes Obes Metab. 2018 Sep;20 Suppl 2:64-76. (PMID: 30230179)
Mol Metab. 2017 Jan 12;6(3):236-244. (PMID: 28271030)
Nat Rev Mol Cell Biol. 2021 Feb;22(2):142-158. (PMID: 33398164)
Int J Clin Pract Suppl. 2001 Sep;(123):13-8. (PMID: 11594291)
Mol Genet Metab. 2021 Nov;134(3):257-266. (PMID: 34635437)
Mol Metab. 2020 Feb;32:44-55. (PMID: 32029229)
Cell Metab. 2017 Jun 6;25(6):1362-1373.e5. (PMID: 28591638)
J Biol Chem. 1995 Nov 3;270(44):26488-96. (PMID: 7592866)
Islets. 2021 Mar 4;13(1-2):32-50. (PMID: 33724156)
Diabetes. 2023 Sep 1;72(9):1180-1183. (PMID: 37603722)
Cell Rep. 2018 Apr 24;23(4):967-973. (PMID: 29694904)
Grant Information: U01 DK137097 United States DK NIDDK NIH HHS; T32 DK007012 United States DK NIDDK NIH HHS; R01 DK141090 United States DK NIDDK NIH HHS; R01 DK142423 United States DK NIDDK NIH HHS; K01 DK132461 United States DK NIDDK NIH HHS; P30 DK124723 United States DK NIDDK NIH HHS; R01 DK046492 United States DK NIDDK NIH HHS; R01 DK125353 United States DK NIDDK NIH HHS; R01 DK123075 United States DK NIDDK NIH HHS; F32 DK121420 United States DK NIDDK NIH HHS
Substance Nomenclature: 55963-74-1 (Proglucagon)
EC 3.4.21.93 (Proprotein Convertase 1)
89750-14-1 (Glucagon-Like Peptide 1)
0 (Insulin)
EC 3.4.21.94 (Proprotein Convertase 2)
Entry Date(s): Date Created: 20250919 Date Completed: 20250919 Latest Revision: 20260828
Update Code: 20260829
PubMed Central ID: PMC12448133
DOI: 10.1126/sciadv.ady8048
PMID: 40971442
Database: MEDLINE
Description
ISSN:2375-2548
DOI:10.1126/sciadv.ady8048