Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 8/2010

01-08-2010 | Article

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Authors: M. Szabat, J. D. Johnson, J. M. Piret

Published in: Diabetologia | Issue 8/2010

Login to get access

Abstract

Aims/hypothesis

The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function.

Methods

MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein–Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.

Results

Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin.

Conclusions/interpretation

These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.
Appendix
Available only for authorised users
Literature
1.
Szabat M, Luciani DS, Piret JM, Johnson JD (2009) Maturation of adult beta-cells revealed using a Pdx1/insulin dual-reporter lentivirus. Endocrinology 150:1627–1635CrossRefPubMed
2.
Sachdeva MM, Stoffers DA (2009) Minireview: meeting the demand for insulin: molecular mechanisms of adaptive postnatal beta-cell mass expansion. Mol Endocrinol 23:747–758CrossRefPubMed
3.
Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455:627–632
4.
Russ HA, Ravassard P, Kerr-Conte J, Pattou F, Efrat S (2009) Epithelial–mesenchymal transition in cells expanded in vitro from lineage-traced adult human pancreatic beta cells. PLoS One 4:e6417CrossRefPubMed
5.
Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117:2553–2561CrossRefPubMed
6.
Audet J, Miller CL, Eaves CJ, Piret JM (2002) Common and distinct features of cytokine effects on hematopoietic stem and progenitor cells revealed by dose–response surface analysis. Biotechnol Bioeng 80:393–404CrossRefPubMed
7.
Rafiq I, da Silva XG, Hooper S, Rutter GA (2000) Glucose-stimulated preproinsulin gene expression and nuclear trans-location of pancreatic duodenum homeobox-1 require activation of phosphatidylinositol 3-kinase but not p38 MAPK/SAPK2. J Biol Chem 275:15977–15984CrossRefPubMed
8.
Otonkoski T, Beattie GM, Mally MI, Ricordi C, Hayek A (1993) Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest 92:1459–1466CrossRefPubMed
9.
Movassat J, Beattie GM, Lopez AD, Hayek A (2002) Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells. J Clin Endocrinol Metab 87:4775–4781CrossRefPubMed
10.
Beith JL, Alejandro EU, Johnson JD (2008) Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 149:2251–2260CrossRefPubMed
11.
Johnson JD, Bernal-Mizrachi E, Alejandro EU et al (2006) Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome. Proc Natl Acad Sci U S A 103:19575–19580CrossRefPubMed
12.
Huotari MA, Palgi J, Otonkoski T (1998) Growth factor-mediated proliferation and differentiation of insulin-producing INS-1 and RINm5F cells: identification of betacellulin as a novel beta-cell mitogen. Endocrinology 139:1494–1499CrossRefPubMed
13.
Jiang FX, Cram DS, DeAizpurua HJ, Harrison LC (1999) Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. Diabetes 48:722–730CrossRefPubMed
14.
Suarez-Pinzon WL, Yan Y, Power R, Brand SJ, Rabinovitch A (2005) Combination therapy with epidermal growth factor and gastrin increases beta-cell mass and reverses hyperglycemia in diabetic NOD mice. Diabetes 54:2596–2601CrossRefPubMed
15.
Micallef SJ, Janes ME, Knezevic K, Davis RP, Elefanty AG, Stanley EG (2005) Retinoic acid induces Pdx1-positive endoderm in differentiating mouse embryonic stem cells. Diabetes 54:301–305CrossRefPubMed
16.
Zhan XR, Li XY, Liu XM et al (2009) Generation of insulin-secreting cells from adult rat pancreatic ductal epithelial cells induced by hepatocyte growth factor and betacellulin-delta4. Biochem Biophys Res Commun 382:375–380CrossRefPubMed
17.
Demeterco C, Beattie GM, Dib SA, Lopez AD, Hayek A (2000) A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth. J Clin Endocrinol Metab 85:3892–3897CrossRefPubMed
18.
Tsuchida K, Nakatani M, Hitachi K et al (2009) Activin signaling as an emerging target for therapeutic interventions. Cell Commun Signal 7:15–25PubMed
19.
Kim SK, Hebrok M, Li E et al (2000) Activin receptor patterning of foregut organogenesis. Genes Dev 14:1866–1871PubMed
20.
Zhang YQ, Cleary MM, Si Y et al (2004) Inhibition of activin signaling induces pancreatic epithelial cell expansion and diminishes terminal differentiation of pancreatic beta-cells. Diabetes 53:2024–2033CrossRefPubMed
21.
Totsuka Y, Tabuchi M, Kojima I, Shibai H, Ogata E (1988) A novel action of activin A: stimulation of insulin secretion in rat pancreatic islets. Biochem Biophys Res Commun 156:335–339CrossRefPubMed
22.
Florio P, Luisi S, Marchetti P et al (2000) Activin A stimulates insulin secretion in cultured human pancreatic islets. J Endocrinol Invest 23:231–234PubMed
23.
Wada M, Shintani Y, Kosaka M, Sano T, Hizawa K, Saito S (1996) Immunohistochemical localization of activin A and follistatin in human tissues. Endocr J 43:375–385CrossRefPubMed
24.
Ogawa K, Abe K, Kurosawa N et al (1993) Expression of alpha, beta A and beta B subunits of inhibin or activin and follistatin in rat pancreatic islets. FEBS Lett 319:217–220CrossRefPubMed
25.
Johnson JD, Ford EL, Bernal-Mizrachi E et al (2006) Suppressed insulin signaling and increased apoptosis in CD38-null islets. Diabetes 55:2737–2746CrossRefPubMed
26.
27.
Olbrot M, Rud J, Moss LG, Sharma A (2002) Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A 99:6737–6742CrossRefPubMed
28.
Artner I, Blanchi B, Raum JC et al (2007) MafB is required for islet beta cell maturation. Proc Natl Acad Sci U S A 104:3853–3858CrossRefPubMed
29.
Tsuchida K, Nakatani M, Yamakawa N, Hashimoto O, Hasegawa Y, Sugino H (2004) Activin isoforms signal through type I receptor serine/threonine kinase ALK7. Mol Cell Endocrinol 220:59–65CrossRefPubMed
30.
Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H (1990) Activin-binding protein from rat ovary is follistatin. Science 247:836–838CrossRefPubMed
31.
Montgomery DC (2001) Design and analysis of experiments. Wiley, New York
32.
Titmarsh D, Cooper-White J (2009) Microbioreactor array for full-factorial analysis of provision of multiple soluble factors in cellular microenvironments. Biotechnol Bioeng 104:1240–1244CrossRefPubMed
33.
Johnson JD, Ao Z, Ao P et al (2009) Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant 18:833–845CrossRefPubMed
34.
Drucker DJ (2005) Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nat Clin Pract Endocrinol Metab 1:22–31CrossRefPubMed
35.
Inada A, Nienaber C, Katsuta H et al (2008) Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci U S A 105:19915–19919CrossRefPubMed
36.
Bernardo AS, Hay CW, Docherty K (2008) Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol 294:1–9CrossRefPubMed
37.
Wandzioch E, Zaret KS (2009) Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 324:1707–1710CrossRefPubMed
38.
Lin HM, Lee JH, Yadav H et al (2009) Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem 284:12246–12257CrossRefPubMed
39.
Chung WS, Andersson O, Row R, Kimelman D, Stainier DY (2010) Suppression of Alk8-mediated Bmp signaling cell-autonomously induces pancreatic β-cells in zebrafish. Proc Natl Acad Sci U S A 107:1142–1147CrossRefPubMed
40.
Nishimura W, Kondo T, Salameh T et al (2006) A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol 293:526–539CrossRefPubMed
41.
Artner I, Le Lay J, Hang Y et al (2006) MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes 55:297–304CrossRefPubMed
42.
Dror V, Nguyen V, Walia P, Kalynyak TB, Hill JA, Johnson JD (2007) Notch signalling suppresses apoptosis in adult human and mouse pancreatic islet cells. Diabetologia 50:2504–2515CrossRefPubMed
43.
Wang S, Jensen JN, Seymour PA et al (2009) Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proc Natl Acad Sci U S A 106:9715–9720CrossRefPubMed
44.
Guillam MT, Hummler E, Schaerer E et al (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17:327–330CrossRefPubMed
45.
Reimer MK, Ahren B (2002) Altered beta-cell distribution of pdx-1 and GLUT-2 after a short-term challenge with a high-fat diet in C57BL/6J mice. Diabetes 51(Suppl 1):S138–S143CrossRefPubMed
46.
Brissova M, Shiota M, Nicholson WE et al (2002) Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem 277:11225–11232CrossRefPubMed
47.
Brun T, Franklin I, St-Onge L et al (2004) The diabetes-linked transcription factor PAX4 promotes β-cell proliferation and survival in rat and human islets. J Cell Biol 167:1123–1135CrossRefPubMed
48.
49.
Beattie GM, Lopez AD, Bucay N et al (2005) Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem Cells 23:489–495CrossRefPubMed
50.
D’Amour KA, Bang AG, Eliazer S et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401CrossRefPubMed
Metadata
Title
Reciprocal modulation of adult beta cell maturity by activin A and follistatin
Authors
M. Szabat
J. D. Johnson
J. M. Piret
Publication date
01-08-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 8/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1758-0

Other articles of this Issue 8/2010

Diabetologia 8/2010 Go to the issue

Erratum

Erratum to: Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis

Article

Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein

Short Communication

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

Article

Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure

Commentary

Vitamin D and diabetes: the devil is in the D-tails

Short Communication

Optimal antiproteinuric dose of aliskiren in type 2 diabetes mellitus: a randomised crossover trial
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits