Urocortin 3 contributes to paracrine inhibition of islet alpha cells in mice

in Journal of Endocrinology
Authors:
Glyn M Noguchi Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, California, USA

Search for other papers by Glyn M Noguchi in
Current site
Google Scholar
PubMed Close
,
Vincent C Castillo Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, California, USA

Search for other papers by Vincent C Castillo in
Current site
Google Scholar
PubMed Close
,
Cynthia J Donaldson Salk Institute for Biological Studies, La Jolla, California, USA

Search for other papers by Cynthia J Donaldson in
Current site
Google Scholar
PubMed Close
,
Marcus R Flisher Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, California, USA

Search for other papers by Marcus R Flisher in
Current site
Google Scholar
PubMed Close
,
Ariana T Momen Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, California, USA

Search for other papers by Ariana T Momen in
Current site
Google Scholar
PubMed Close
,
Alan Saghatelian Salk Institute for Biological Studies, La Jolla, California, USA

Search for other papers by Alan Saghatelian in
Current site
Google Scholar
PubMed Close
, and
Mark O Huising Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, California, USA
Department of Physiology & Membrane Biology, University of California Davis, Davis, California, USA

Search for other papers by Mark O Huising in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-6594-2205

Correspondence should be addressed to M O Huising: mhuising@ucdavis.edu
DOI:
https://doi.org/10.1530/JOE-24-0018
Volume/Issue:
Volume 261: Issue 3
Article Type:
Research Article
Article ID:
e240018
Online Publication Date:
02 May 2024
Copyright:
© the author(s) 2024
Restricted access
Rent on DeepDyve

Sign up for journal news

Pancreatic alpha cell activity and glucagon secretion lower as glucose levels increase. While part of the decrease is regulated by glucose itself, paracrine signaling by their neighboring beta and delta cells also plays an important role. Somatostatin from delta cells is an important local inhibitor of alpha cells at high glucose. Additionally, urocortin 3 (UCN3) is a hormone that is co-released from beta cells with insulin and acts locally to potentiate somatostatin secretion from delta cells. UCN3 thus inhibits insulin secretion via a negative feedback loop with delta cells, but its role with respect to alpha cells and glucagon secretion is not understood. We hypothesize that the somatostatin-driven glucagon inhibition at high glucose is regulated in part by UCN3 from beta cells. Here, we use a combination of live functional Ca2+ and cAMP imaging as well as direct glucagon secretion measurement, all from alpha cells in intact mouse islets, to determine the contributions of UCN3 to alpha cell behavior. Exogenous UCN3 treatment decreased alpha cell Ca2+ and cAMP levels and inhibited glucagon release. Blocking endogenous UCN3 signaling increased alpha cell Ca2+ by 26.8 ± 7.6%, but this did not result in increased glucagon release at high glucose. Furthermore, constitutive deletion of Ucn3 did not increase Ca2+ activity or glucagon secretion relative to controls. UCN3 is thus capable of inhibiting mouse alpha cells, but, given the subtle effects of endogenous UCN3 signaling on alpha cells, we propose that UCN3-driven somatostatin may serve to regulate local paracrine glucagon levels in the islet instead of inhibiting gross systemic glucagon release.

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 201 201 19
PDF Downloads 256 256 23

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2024
Article ID:
e240018
Article Type:
Research Article
Received Date:
18 Jan 2024
Accepted Date:
08 Apr 2024
Print Publication Date:
01 Jun 2024
Online Publication Date:
02 May 2024
Keywords:
alpha cell; delta cell; glucagon; paracrine; somatostatin; urocortin 3

  • Ackermann AM, Zhang J, Heller A, Briker A & & Kaestner KH 2017 High-fidelity glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting. Molecular Metabolism 6 236–244. (https://doi.org/10.1016/j.molmet.2017.01.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Asplin CM, Paquette TL & & Palmer JP 1981 In vivo inhibition of glucagon secretion by paracrine beta cell activity in man. Journal of Clinical Investigation 68 314–318. (https://doi.org/10.1172/JCI110251)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Baker EN, Blundell TL, Cutfield JF, Dodson EJ, Dodson GG, Hodgkin DM, Hubbard RE, Isaacs NW, Reynolds CD & Sakabe K et al.1988 The structure of 2Zn pig insulin crystals at 1.5 Å resolution. Philosophical Transactions of the Royal Society of London Series B 319. (https://doi.org/10.1098/rstb.1988.0058)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Barg S, Galvanovskis J, Gopel SO, Rorsman P & & Eliasson L 2000 Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes 49 1500–1510. (https://doi.org/10.2337/diabetes.49.9.1500)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bjaaland T, Jones PM & & Howell SL 1988 Role of intracellular mediators in glucagon secretion: studies using intact and electrically permeabilized rat islets of Langerhans. Journal of Molecular Endocrinology 1 171–178. (https://doi.org/10.1677/jme.0.0010171)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Briant LJB, Reinbothe TM, Spilliotis I, Miranda C, Rodriquez B & & Rorsman P 2018 δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin. Journal of Physiology 596 197–215. (https://doi.org/10.1113/JP274581)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Butler PC & & Rizza RA 1991 Contribution to postprandial hyperglycemia and effect on initial splanchnic glucose clearance of hepatic glucose cycling in glucose-intolerant or NIDDM patients. Diabetes 40 73–81. (https://doi.org/10.2337/diab.40.1.73)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD, Lin H, Jaffe JL, Coch RW, Haldeman JM, MacDonald PE, et al.2019a β Cell tone is defined by proglucagon peptides through cAMP signaling. JCI Insight 4. (https://doi.org/10.1172/jci.insight.126742)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Capozzi ME, Wait JB, Koech J, Gordon AN, Coch RW, Svendsen B, Finan B, D’Alessio DA & & Campbell JE 2019b Glucagon lowers glycemia when β cells are active. JCI Insight 5. (https://doi.org/10.1172/jci.insight.129954)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cescato R, Erchegyi J, Waser B, Piccand V, Maecke HR, Rivier JE & & Reubi JC 2008 Design and in vitro characterization of highly sst 2 -Selective somatostatin antagonists suitable for radiotargeting. Journal of Medicinal Chemistry 51 4030–4037. (https://doi.org/10.1021/jm701618q)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • de Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R, Amisten S, et al.2010 GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metabolism 11 543–553. (https://doi.org/10.1016/j.cmet.2010.04.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Denwood G, Tarasov A, Salehi A, Vergari E, Ramracheya R, Takahashi H, Nikolaev VO, Seino S, Gribble F, Reimann F, et al.2019 Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release. Journal of General Physiology 151 1094–1115. (https://doi.org/10.1085/jgp.201912351)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dickerson MT, Dadi PK, Zaborska KE, Nakhe AY, Schaub CM, Dobson JR, Wright NM, Lynch JC, Scott CF, Robinson LD, et al.2022 Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation. Nature Communications 13 6461. (https://doi.org/10.1038/s41467-022-34166-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • DiGruccio MR, Mawla AM, Donaldson CJ, Noguchi GM, Vaughan J, Cowing-Zitron C, van der Meulen T & & Huising MO 2016 Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Molecular Metabolism 5 449–458. (https://doi.org/10.1016/j.molmet.2016.04.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • El K, Capozzi ME & & Campbell JE 2020 Repositioning the alpha cell in postprandial metabolism. Endocrinology 161. (https://doi.org/10.1210/endocr/bqaa169)

  • Elliott AD, Ustione A & & Piston DW 2015 Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic-cell by lowering cAMP. American Journal of Physiology. Endocrinology and Metabolism 308 130–143. (https://doi.org/10.1152/ajpendo.00344.2014.-The)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gerich JE, Langlois M, Noacco C, Schneider V & & Forsham PH 1974 Adrenergic modulation of pancreatic glucagon secretion in man. Journal of Clinical Investigation 53 1441–1446. (https://doi.org/10.1172/JCI107692)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gilon P, Bertrand G, Loubatiéres-Mariani MM, Remacle C & & Henquin JC 1991 The influence of γ-aminobutyric acid on hormone release by the mouse and rat endocrine pancreas. Endocrinology 129 2521–2529. (https://doi.org/10.1210/endo-129-5-2521)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Grunddal KV, Trammell SAJ, Bæch-Laursen C, Andersen DB, Xu SFS, Andersen H, Gillum MP, Ghiasi SM, Novak I, Tyrberg B, et al.2022 Opposing roles of the enteropancreatic hormone urocortin-3 in glucose metabolism in rats. Diabetologia 65 1018–1031. (https://doi.org/10.1007/s00125-022-05675-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hamilton A, Zhang Q, Salehi A, Willems M, Knudsen JG, Ringgaard AK, Chapman CE, Gonzalez-Alvarez A, Surdo NC, Zaccolo M, et al.2018 Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells. Diabetes 67 1128–1139. (https://doi.org/10.2337/db17-1102)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hauge-Evans AC, King AJ, Carmignac D, Richardson CC, Robinson ICAF, Low MJ, Christie MR, Persaud SJ & & Jones PM 2009 Somatostatin secreted by islet δ-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58 403–411. (https://doi.org/10.2337/db08-0792)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hsu SY & & Hsueh AJW 2001 Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nature Medicine 7 605–611. (https://doi.org/10.1038/87936)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huang JL, Pourhosseinzadeh MS, Lee S, Krämer N, Guillen JV, Cinque NH, Aniceto P, Momen AT, Koiki S & & Huising MO 2024 Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice. Nature Metabolism 6 61–77 (https://doi.org/10.1038/s42255-023-00944-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huypens P, Ling Z, Pipeleers D & & Schuit F 2000 Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia 43 1012–1019. (https://doi.org/10.1007/s001250051484)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ishihara H, Maechler P, Gjinovci A, Herrera PL & & Wollheim CB 2003 Islet β-cell secretion determines glucagon release from neigbouring α-cells. Nature Cell Biology 5 330–335. (https://doi.org/10.1038/ncb951)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kellard JA, Rorsman NJG, Hill TG, Armour SL, van de Bunt M, Rorsman P, Knudsen JG & & Briant LJB 2020 Reduced somatostatin signaling leads to hypersecretion of glucagon in mice fed a high-fat diet. Molecular Metabolism 40 101021. (https://doi.org/10.1016/j.molmet.2020.101021)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lai BK, Chae H, Gómez-Ruiz A, Cheng P, Gallo P, Antoine N, Beauloye C, Jonas JC, Seghers V, Seino S, et al.2018 Somatostatin is only partly required for the glucagonostatic effect of glucose but is necessary for the glucagonostatic effect of KATP channel blockers. Diabetes 67 2239–2253. (https://doi.org/10.2337/db17-0880)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • le Marchand SJ & & Piston DW 2010 Glucose suppression of glucagon secretion: metabolic and calcium responses from α-cells in intact mouse pancreatic islets. Journal of Biological Chemistry 285 14389–14398. (https://doi.org/10.1074/jbc.M109.069195)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, et al.2001 Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proceedings of the National Academy of Sciences of the United States of America 98 7570–7575. (https://doi.org/10.1073/pnas.121165198)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li C, Chen P, Vaughan J, Lee KF & & Vale W 2007 Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America 104 4206–4211. (https://doi.org/10.1073/pnas.0611641104)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li J, Yu Q, Ahooghalandari P, Gribble FM, Reimann F, Tengholm A & & Gylfe E 2015 Submembrane ATP and Ca2+ kinetics in α-cells: unexpected signaling for glucagon secretion. FASEB Journal 29 3379–3388. (https://doi.org/10.1096/fj.14-265918)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • MacDonald PE, de Marinis YZ, Ramracheya R, Salehi A, Ma X, Johnson PRV, Cox R, Eliasson L & & Rorsman P 2007 A KATP channel-dependent pathway within α cells regulates glucagon release from both rodent and human islets of langerhans. PLoS Biology 5 1236–1247. (https://doi.org/10.1371/journal.pbio.0050143)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Madisen L, Garner AR, Shimaoka D, Chuong AS, Klapoetke NC, Li L, van der Bourg A, Niino Y, Egolf L, Monett Cet al. 2015 Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85 942–958. (https://doi.org/10.1016/j.neuron.2015.02.022)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Meier JJ, Kjems LL, Veldhuis JD, Lefebvre P & & Butler PC 2006 Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis. Diabetes 55 1051–1056. (https://doi.org/10.2337/diabetes.55.04.06.db05-1449)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Meier JJ, Ueberberg S, Korbas S & & Schneider S 2011 Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass. American Journal of Physiology-Endocrinology and Metabolism 300 E717–E723. (https://doi.org/10.1152/ajpendo.00315.2010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Menge BA, Grüber L, Jørgensen SM, Deacon CF, Schmidt WE, Veldhuis JD, Holst JJ & & Meier JJ 2011 Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes. Diabetes 60 2160–2168. (https://doi.org/10.2337/db11-0251)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Michalik M, Nelson J & & Erecinska M 1993 GABA production in rat islets of Langerhans. Diabetes 42 1506–1513. (https://doi.org/10.2337/diab.42.10.1506)

  • Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J & & Gerich J 1990 Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39 1381–1390. (https://doi.org/10.2337/diab.39.11.1381)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moens K, Flamez D, Schravendijk v. C, Ling Z, Pipeleers D & & Schuit F 1998 Dual glucagon recognition by pancreatic -Cells via glucagon and glucagon-like Peptide 1 receptors. Diabetes 47 66–72. (https://doi.org/10.2337/diab.47.1.66)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Müller WA, Faloona GR, Aguilar-Parada E & & Unger RH 1970 Abnormal alpha-cell function in diabetes. New England Journal of Medicine 283 109–115. (https://doi.org/10.1056/NEJM197007162830301)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Muntean BS, Zucca S, MacMullen CM, Dao MT, Johnston C, Iwamoto H, Blakely RD, Davis RL & & Martemyanov KA 2018 Interrogating the spatiotemporal landscape of neuromodulatory GPCR signaling by real-time imaging of cAMP in intact neurons and circuits. Cell Reports 22 255–258. (https://doi.org/10.1016/j.celrep.2017.12.022)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Noguchi GM & & Huising MO 2019 Integrating the inputs that shape pancreatic islet hormone release. Nature Metabolism 1 1189–1201. (https://doi.org/10.1038/s42255-019-0148-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB & & Gromada J 2005 Glucose stimulates glucagon release in single rat α-cells by mechanisms that mirror the stimulus-secretion coupling in β-cells. Endocrinology 146 4861–4870. (https://doi.org/10.1210/en.2005-0800)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Omar-Hmeadi M, Lund PE, Gandasi NR, Tengholm A & & Barg S 2020 Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes. Nature Communications 11 1896. (https://doi.org/10.1038/s41467-020-15717-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Quesada I, Todorova MG, Alonso-Magdalena P, Beltrá M, Carneiro EM, Martin F, Nadal A & & Soria B 2006a Glucose induces opposite intracellular Ca2+ concentration oscillatory patterns in identified {alpha}- and β-cells within intact human islets of Langerhans. Diabetes 55 2463–2469. (https://doi.org/10.2337/db06-0272)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Quesada I, Todorova MG & & Soria B 2006b Different metabolic responses in alpha-, beta-, and delta-cells of the islet of Langerhans monitored by redox confocal microscopy. Biophysical Journal 90 2641–2650. (https://doi.org/10.1529/biophysj.105.069906)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ramracheya R, Ward C, Shigeto M, Walker JN, Amisten S, Zhang Q, Johnson PR, Rorsman P & & Braun M 2010 Membrane potential-dependent inactivation of voltage-gated ion channels in alpha-cells inhibits glucagon secretion from human islets. Diabetes 59 2198–2208. (https://doi.org/10.2337/db09-1505)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ravier MA & & Rutter GA 2005 Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic -cells. Diabetes 54 1789–1797. (https://doi.org/10.2337/diabetes.54.6.1789)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rivier J, Gulyas J, Kirby D, Low W, Perrin MH, Kunitake K, DiGruccio M, Vaughan J, Reubi JC, Waser B, et al.2002 Potent and long-acting corticotropin releasing factor (CRF) Receptor 2 selective peptide competitive antagonists. Journal of Medicinal Chemistry 45 4737–4747. (https://doi.org/10.1021/jm0202122)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rorsman P, Berggren PO, Bokvist K, Ericson H, Möhler H, Östenson CG & & Smith PA 1989 Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 341 233–236. (https://doi.org/10.1038/341233a0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rorsman P, Ramracheya R, Rorsman NJG & & Zhang Q 2014 ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion. Diabetologia 57 1749–1761. (https://doi.org/10.1007/s00125-014-3279-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Samols E, Marri G & & Marks V 1965 Promotion of insulin secretion by glucagon. Lancet 286 415–416. (https://doi.org/10.1016/S0140-6736(6590761-0)

  • Samols E & & Weir GC 1979 Adrenergic modulation of pancreatic A, B, and D cells: alpha-Adrenergic suppression and beta-adrenergic stimulation of somatostatin secretion, alpha-adrenergic stimulation of glucagon secretion in the perfused dog pancreas. Journal of Clinical Investigation 63 230–238. (https://doi.org/10.1172/JCI109294)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schuit FC & & Pipeleers DG 1986 Differences in adrenergic recognition by pancreatic A and B cells. Science 232 875–877. (https://doi.org/10.1126/science.2871625)

  • Song Y, Koehler JA, Baggio LL, Powers AC, Sandoval DA & & Drucker DJ 2019 Gut-proglucagon-derived peptides are essential for regulating glucose homeostasis in mice. Cell Metabolism 30 976–986.e3. (https://doi.org/10.1016/j.cmet.2019.08.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Strowski MZ, Parmar RM, Blake AD & & Schaeffer JM 2000 Somatostatin inhibits insulin and glucagon secretion via two receptor subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 141 111–117 (https://doi.org/10.1210/endo.141.1.7263)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Svendsen B, Larsen O, Gabe MBN, Christiansen CB, Rosenkilde MM, Drucker DJ & & Holst JJ 2018 Insulin secretion depends on intra-islet glucagon signaling. Cell Reports 25 1127–1134.e2. (https://doi.org/10.1016/j.celrep.2018.10.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tian G, Sandler S, Gylfe E & & Tengholm A 2011 Glucose- and hormone-induced cAMP oscillations in α- and β-cells within intact pancreatic islets. Diabetes 60 1535–1543. (https://doi.org/10.2337/db10-1087)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van de Winkel MD & & Pipeleers D 1983 Autofluorescence-activated cell sorting of pancreatic islet cells: purification of insulin-containing B-cells according to glucose-induced changes in cellular redox state. Biochemical and Biophysical Research Communications 114 835–842 (https://doi.org/10.1016/0006-291x(8390857-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van der Meulen T, Donaldson CJ, Cáceres E, Hunter AE, Cowing-Zitron C, Pound LD, Adams MW, Zembrzycki A, Grove KL & & Huising MO 2015 Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nature Medicine 21 769–776. (https://doi.org/10.1038/nm.3872)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van der Meulen T, Mawla AM, DiGruccio MR, Adams MW, Nies V, Dólleman S, Liu S, Ackermann AM, Cáceres E, Hunter AE, et al.2017 Virgin beta cells persist throughout life at a neogenic niche within pancreatic islets. Cell Metabolism 25 911–926.e6. (https://doi.org/10.1016/j.cmet.2017.03.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vieira E, Salehi A & & Gylfe E 2007 Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50 370–379. (https://doi.org/10.1007/s00125-006-0511-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Walker JN, Ramracheya R, Zhang Q, Johnson PRV, Braun M & & Rorsman P 2011 Regulation of glucagon secretion by glucose: paracrine, intrinsic or both? Diabetes, Obesity and Metabolism 13(Supplement 1) 95–105. (https://doi.org/10.1111/j.1463-1326.2011.01450.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Weir GC, Knowlton SD & & Martin DB 1974 Somatostatin inhibition of epinephrine-induced glucagon secretion. Endocrinology 95 1744–1746. (https://doi.org/10.1210/endo-95-6-1744)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yoshimoto Y, Fukuyama Y, Horio Y, Inanobe A, Gotoh M & & Kurachi Y 1999 Somatostatin induces hyperpolarization in pancreatic islet alpha cells by activating a G protein-gated K+ channel. FEBS Letters 444 265–269. (https://doi.org/10.1016/s0014-5793(9900076-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yu Q, Shuai H, Ahooghalandari P, Gylfe E & & Tengholm A 2019 Glucose controls glucagon secretion by directly modulating cAMP in alpha cells. Diabetologia 62 1212–1224. (https://doi.org/10.1007/s00125-019-4857-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, Braun M, Brereton M, Collins S, Galvanovskis J, et al.2013 Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metabolism 18 871–882. (https://doi.org/10.1016/j.cmet.2013.10.014)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu L, Dattaroy D, Pham J, Wang L, Barella LF, Cui Y, Wilkins KJ, Roth BL, Hochgeschwender U, Matschinsky FM, et al.2019 Intra-islet glucagon signaling is critical for maintaining glucose homeostasis. JCI Insight 5 e127994. (https://doi.org/10.1172/jci.insight.127994)

    • PubMed
    • Search Google Scholar
    • Export Citation