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 4/2012

Open Access 01-04-2012 | Article

The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways

Authors: E. Favaro, R. Granata, I. Miceli, A. Baragli, F. Settanni, P. Cavallo Perin, E. Ghigo, G. Camussi, M. M. Zanone

Published in: Diabetologia | Issue 4/2012

Login to get access

Abstract

Aims/hypothesis

Pancreatic islet microendothelium exhibits unique features in interdependent relationship with beta cells. Gastrointestinal products of the ghrelin gene, acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (Ob), and the incretin, glucagon-like peptide-1 (GLP-1), prevent apoptosis of pancreatic beta cells. We investigated whether the ghrelin gene products and the GLP-1 receptor agonist exendin-4 (Ex-4) display survival effects in human pancreatic islet microendothelial cells (MECs) exposed to chronic hyperglycaemia.

Methods

Islet MECs were cultured in high glucose concentration and treated with AG, UAG, Ob or Ex-4. Apoptosis was assessed by DNA fragmentation, Hoechst staining of the nuclei and caspase-3 activity. Western blot analyses and pharmacological inhibition of protein kinase B (Akt) and extracellular signal-related kinase (ERK)1/2 pathways, detection of intracellular cAMP levels and blockade of adenylyl cyclase (AC)/cAMP/protein kinase A (PKA) signalling were performed. Levels of NO, IL-1β and vascular endothelial growth factor (VEGF)-A in cell culture supernatant fractions were measured.

Results

Islet MECs express the ghrelin receptor GHS-R1A as well as GLP-1R. Treatment with AG, UAG, Ob and Ex-4 promoted cell survival and significantly inhibited glucose-induced apoptosis, through activation of PI3K/Akt, ERK1/2 phosphorylation and intracellular cAMP increase. Moreover, peptides upregulated B cell lymphoma 2 (BCL-2) and downregulated BCL-2-associated X protein (BAX) and CD40 ligand (CD40L) production, and significantly reduced the secretion of NO, IL-1β and VEGF-A.

Conclusions/interpretation

The ghrelin gene-derived peptides and Ex-4 exert cytoprotective effects in islet MECs. The anti-apoptotic effects involve phosphoinositide 3-kinase (PI3K)/Akt, ERK1/2 and cAMP/PKA pathways. These peptides could therefore represent a potential tool to improve islet vascularisation and, indirectly, islet cell function.
Appendix
Available only for authorised users
Literature
1.
Meier JJ (2008) Beta cell mass in diabetes: a realistic therapeutic target? Diabetologia 51:703–713PubMedCrossRef
2.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660PubMedCrossRef
3.
Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L (2004) Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 101:2924–2929PubMedCrossRef
4.
Broglio F, Gottero C, Prodam F et al (2004) Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab 89:3062–3065PubMedCrossRef
5.
Granata R, Baragli A, Settanni F, Scarlatti F, Ghigo E (2010) Unraveling the role of the ghrelin gene peptides in the endocrine pancreas. J Mol Endocrinol 45:107–118PubMedCrossRef
6.
Zhang JV, Ren PG, Avsian-Kretchmer O et al (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 310:996–999PubMedCrossRef
7.
Granata R, Settanni F, Gallo D et al (2008) Obestatin promotes survival of pancreatic beta-cells and human islets and induces expression of genes involved in the regulation of beta-cell mass and function. Diabetes 57:967–979PubMedCrossRef
8.
Farilla L, Bulotta A, Hirshberg B et al (2003) Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144:5149–5158PubMedCrossRef
9.
Arakawa M, Mita T, Azuma K et al (2010) Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59:1030–1037PubMedCrossRef
10.
Liu FQ, Zhang XL, Gong L et al (2011) Glucagon-like peptide 1 protects microvascular endothelial cells by inactivating the PARP-1/iNOS/NO pathway. Mol Cell Endocrinol 339:25–33PubMedCrossRef
11.
Baldanzi G, Filigheddu N, Cutrupi S et al (2002) Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/Akt. J Cell Biol 159:1029–1037PubMedCrossRef
12.
Togliatto G, Trombetta A, Dentelli P et al (2010) Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes 59:1016–10125PubMedCrossRef
13.
Li WG, Gavrila D, Liu X et al (2004) Ghrelin inhibits proinflammatory responses and nuclear factor-kB activation in human endothelial cells. Circulation 109:2221–2226PubMedCrossRef
14.
Zanone MM, Favaro E, Camussi G (2008) From endothelial to beta cells: insights into pancreatic islet microendothelium. Curr Diabetes Rev 4:1–9PubMedCrossRef
15.
Swerlick RA, Lee KH, Li LJ, Sepp NT, Caughman SW, Lawley TJ (1992) Regulation of vascular cell adhesion molecule 1 on human dermal microvascular endothelial cells. J Immunol 149:698–705PubMed
16.
Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–557PubMedCrossRef
17.
Lammert E, Gu G, McLaughlin M et al (2003) Role of VEGF-A in vascularization of pancreatic islets. Curr Biol 13:1070–1074PubMedCrossRef
18.
Brissova M, Shostak A, Shiota M et al (2006) Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vascularization, revascularization, and function. Diabetes 55:2974–2985PubMedCrossRef
19.
Johansson A, Lau J, Sandberg M, Borg LA, Magnusson PU, Carlsson PO (2009) Endothelial signalling supports pancreatic beta cell function in the rat. Diabetologia 52:2384–2394CrossRef
20.
Nikolova G, Jabs N, Konstantinova I et al (2006) The vascular basement membrane: a niche for insulin gene expression and beta cell proliferation. Dev Cell 10:397–405PubMedCrossRef
21.
Johansson M, Mattsson G, Andersson A, Jansson L, Carlsson PO (2006) Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats. Endocrinology 147:2315–2324PubMedCrossRef
22.
Mizuno A, Noma Y, Kuwajima M, Murakami T, Zhu M, Shima K (1999) Changes in islet capillary angioarchitecture coincide with impaired B cell function but not with insulin resistance in male Otsuka–Long–Evans–Tokushima fatty rats: dimorphism of the diabetic phenotype at an advance age. Metabolism 48:477–483PubMedCrossRef
23.
Carlsson PO, Flodstrom M, Sandler S (2000) Islet blood flow in multiple low dose streptozotocin-treated wild-type and inducible nitric oxide synthase-deficient mice. Endocrinology 141:2752–2757PubMedCrossRef
24.
Li X, Zhang L, Meshinchi S et al (2006) Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes. Diabetes 55:2965–2973PubMedCrossRef
25.
Favaro E, Miceli I, Bussolati B et al (2008) Hyperglycaemia induces apoptosis of human pancreatic islet endothelial cells: effects of pravastatin on the Akt survival pathway. Am J Pathol 173:442–450PubMedCrossRef
26.
Suschek C, Fehsel K, Kroncke KD, Sommer A, Kolb-Bachofen V (1994) Primary cultures of rat islet capillary endothelial cells. Constitutive and cytokine-inducible macrophagelike nitric oxide synthases are expressed and activities regulated by glucose concentration. Am J Pathol 145:685–695PubMed
27.
Maedler K, Sergeev P, Ris F et al (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860PubMed
28.
Huang GC, Zhao M, Jones P et al (2004) The development of new density gradient media for purifying human islets and islets-quality assessments. Transplantation 77:143–145PubMedCrossRef
29.
Favaro E, Bottelli A, Lozanoska-Ochser B et al (2005) Primary and immortalised human pancreatic islet endothelial cells: phenotypic and immunological characterisation. Diabetologia 48:2552–2562PubMedCrossRef
30.
Zanone MM, Favaro E, Doublier S et al (2005) Expression of nephrin by human pancreatic islet endothelial cells. Diabetologia 48:1789–1797PubMedCrossRef
31.
Granata R, Settanni F, Biancone L et al (2007) Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-kinase/Akt signalling. Endocrinology 148:512–529PubMedCrossRef
32.
Zanone MM, Favaro E, Conaldi PG et al (2003) Persistent infection of human microvascular endothelial cells by coxsackie B viruses induces increased expression of adhesion molecules. J Immunol 171:438–446PubMed
33.
Tremblay F, Perreault M, Klaman LD, Tobin JF, Smith E, Gimeno RE (2007) Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology 148:501–506PubMedCrossRef
34.
Volante M, Allia E, Gugliotta P et al (2002) Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab 87:1300–1308PubMedCrossRef
35.
Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927PubMedCrossRef
36.
Elghazi L, Balcazar N, Bernal-Mizrachi E (2006) Emerging role of protein kinase B/Akt signaling in pancreatic beta-cell mass and function. Int J Biochem Cell Biol 38:157–163PubMedCrossRef
37.
Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12:258–266PubMedCrossRef
38.
Choy JC, Granville DJ, Hunt DW, McManus BM (2001) Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol 33:1673–1690PubMedCrossRef
39.
Hattori Y, Jojima T, Tomizawa A et al (2010) A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia 53:2256–2263PubMedCrossRef
40.
Rickels MR, Mueller R, Markmann JF, Naji A (2009) Effect of glucagon-like peptide-1 on beta- and alpha-cell function in isolated islet and whole pancreas transplant recipients. J Clin Endocrinol Metab 94:181–189PubMedCrossRef
41.
Mach F, Schönbeck U, Sukhova GK et al (1997) Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A 94:1931–1936PubMedCrossRef
42.
Wagner AH, Güldenzoph B, Lienenlüke B, Hecker M (2004) CD154/CD40-mediated expression of CD154 in endothelial cells: consequences for endothelial cell-monocyte interaction. Arterioscler Thromb Vasc Biol 24:715–720PubMedCrossRef
43.
Homann D, Jahreis A, Wolfe T et al (2002) CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells. Immunity 16:403–415PubMedCrossRef
44.
Hänninen A, Taylor C, Streeter PR (1993) Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid cell binding to islet endothelium. J Clin Invest 92:2509–2515PubMedCrossRef
45.
Zheng L, Dengler TJ, Kluger MS et al (2000) Cytoprotection of human umbilical vein endothelial cells against apoptosis and CTL-mediated lysis provided by caspase-resistant Bcl-2 without alterations in growth or activation responses. J Immunol 164:4665–4671PubMed
46.
Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987):41–46PubMedCrossRef
47.
Corbett JA, Sweetland MA, Wang JL, Lancaster JR Jr, McDaniel ML (1993) Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci U S A 90:1731–1735PubMedCrossRef
48.
Ahluwalia A, Li A, Cheng G, Deng X, Tarnawski AS (2009) Reduced ghrelin in endothelial cells plays important mechanistic role in aging-related impairment of angiogenesis. J Physiol Pharmacol 60:29–34PubMed
49.
Erdogdu O, Nathanson D, Sjöholm A, Nyström T, Zhang Q (2010) Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol 325:26–35PubMedCrossRef
50.
Schrijver BF, Flyvbjerg A, Dr Vriese AS (2004) The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int 65:2003–2017CrossRef
Metadata
Title
The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways
Authors
E. Favaro
R. Granata
I. Miceli
A. Baragli
F. Settanni
P. Cavallo Perin
E. Ghigo
G. Camussi
M. M. Zanone
Publication date
01-04-2012
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 4/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2423-y

Other articles of this Issue 4/2012

Diabetologia 4/2012 Go to the issue

Article

Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways

Article

A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3

Commentary

Complement C3: an emerging risk factor in cardiometabolic disease

Commentary

Congenital anomalies in diabetic pregnancy: an important confirmation

Article

Visual sensitivity loss in the central 30° of visual field is associated with diabetic peripheral neuropathy

Then and Now

How the immunoassay transformed C-peptide from a duckling into a swan
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

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits