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

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2016

Open Access 01-12-2016 | Original investigation

Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study

Authors: Fahad W. Ahmed, Rachel Rider, Michael Glanville, Kilimangalam Narayanan, Salman Razvi, Jolanta U. Weaver

Published in: Cardiovascular Diabetology | Issue 1/2016

Login to get access

Background

Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.

Methods

This study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45dimCD34+VEGFR-2+ and CD45dimCD133−CD34+CD144+ respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill’s colonies).

Results

At baseline TG had lower cEPCs, PACs, CFU-Hills’ colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill’s colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill’s colonies with cECs.

Conclusions

Metformin has potential cardio-protective effect through improving cEPCs, CFU-Hill’s colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long term cardiovascular outcome studies in type 1 diabetes.
Trial registration ISRCTN26092132
Appendix
Available only for authorised users
Literature
1.
Soedamah-Muthu SS, Fuller JH, Mulnier HE, Raleigh VS, Lawrenson RA, Colhoun HM. High risk of cardiovascular disease in patients with type 1 diabetes in the U.K.: a cohort study using the general practice research database. Diabetes Care. 2006;29:798–804.CrossRefPubMed
2.
Livingstone SJ, Looker HC, Hothersall EJ, Wild SH, Lindsay RS, Chalmers J, Cleland S, Leese GP, McKnight J, Morris AD, et al. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med. 2012;9:e1001321.CrossRefPubMedPubMedCentral
3.
Livingstone SJ, Levin D, Looker HC, Lindsay RS, Wild SH, Joss N, Leese G, Leslie P, McCrimmon RJ, Metcalfe W, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA. 2015;313:37–44.CrossRefPubMedPubMedCentral
4.
Snell-Bergeon JK, Maahs DM. Diabetes: Elevated risk of mortality in type 1 diabetes mellitus. Nat Rev Endocrinol. 2015;11:136–8.CrossRefPubMed
5.
Lind M, Svensson A-M, Kosiborod M, Gudbjörnsdottir S, Pivodic A, Wedel H, Dahlqvist S, Clements M, Rosengren A. Glycemic control and excess mortality in type 1 diabetes. New Engl J Med. 2014;371:1972–82.CrossRefPubMed
6.
Sibal L, Aldibbiat A, Agarwal SC, Mitchell G, Oates C, Razvi S, Weaver JU, Shaw JA, Home PD. Circulating endothelial progenitor cells, endothelial function, carotid intima-media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria. Diabetologia. 2009;52:1464–73.CrossRefPubMed
7.
Goon PK, Lip GY, Boos CJ, Stonelake PS, Blann AD. Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer. Neoplasia. 2006;8:79–88.CrossRefPubMedPubMedCentral
8.
Burger D, Touyz RM. Cellular biomarkers of endothelial health: microparticles, endothelial progenitor cells, and circulating endothelial cells. J Am Soc Hypertens. 2012;6:85–99.CrossRefPubMed
9.
Asicioglu E. Gogas Yavuz D, Koc M, Ozben B, Yazici D, Deyneli O, Akalin S: Circulating endothelial cells are elevated in patients with type 1 diabetes mellitus. Eur J Endocrinol. 2010;162:711–7.CrossRefPubMed
10.
McClung JA, Naseer N, Saleem M, Rossi GP, Weiss MB, Abraham NG, Kappas A. Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA(1)c. Diabetologia. 2005;48:345–50.CrossRefPubMed
11.
Koc M, Richards HB, Bihorac A, Ross EA, Schold JD, Segal MS. Circulating endothelial cells are associated with future vascular events in hemodialysis patients. Kidney Int. 2005;67:1078–83.CrossRefPubMed
12.
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.CrossRefPubMed
13.
Urbich C, Dimmeler S. Endothelial progenitor cells functional characterization. Trends Cardiovasc Med. 2004;14:318–22.CrossRefPubMed
14.
Timmermans F, Plum J, Yöder MC, Ingram DA, Vandekerckhove B, Case J. Endothelial progenitor cells: identity defined? J Cell Mol Med. 2009;13:87–102.CrossRefPubMed
15.
Yoder MC. Human endothelial progenitor cells. In: Cold Spring Harb Perspect Med, vol. 2; 2012.
16.
Hristov M, Erl W, Weber PC. Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol. 2003;23:1185–9.CrossRefPubMed
17.
Collet G, Lamerant-Fayel N, Tertil M, El Hafny-Rahbi B, Stepniewski J, Guichard A, Foucault-Collet A, Klimkiewicz K, Petoud S, Matejuk A, et al. Hypoxia-regulated overexpression of soluble VEGFR2 controls angiogenesis and inhibits tumor growth. Mol Cancer Ther. 2014;13:165–78.CrossRefPubMed
18.
Rigato M, Bittante C, Albiero M, Avogaro A, Fadini GP. Circulating progenitor cell count predicts microvascular outcomes in type 2 diabetic patients. J Clin Endocrinol Metab. 2015;100:2666–72.CrossRefPubMed
19.
Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999–1007.CrossRefPubMed
20.
Hörtenhuber T, Rami-Mehar B, Satler M, Nagl K, Höbaus C, Höllerl F, Koppensteiner R, Schernthaner G, Schober E, Schernthaner G-H. Endothelial progenitor cells are related to glycemic control in children with type 1 diabetes over time. Diabetes Care. 2013;36:1647–53.CrossRefPubMedPubMedCentral
21.
Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600.CrossRefPubMed
22.
Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106:2781–6.CrossRefPubMed
23.
Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004;53:195–9.CrossRefPubMed
24.
Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol. 2005;45:1449–57.CrossRefPubMed
25.
Dessapt C, Karalliedde J, Hernandez-Fuentes M, Prieto PM, Maltese G, Dattani N, Atkar R, Viberti G, Gnudi L. Circulating vascular progenitor cells in patients with type 1 diabetes and microalbuminuria. Diabetes Care. 2010;33:875–7.CrossRefPubMedPubMedCentral
26.
Nauta ST, Deckers JW, Akkerhuis KM, van Domburg RT. Short- and long-term mortality after myocardial infarction in patients with and without diabetes: changes from 1985 to 2008. Diabetes Care. 2012;35:2043–7.CrossRefPubMedPubMedCentral
27.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352:854–865.
28.
Fung CS, Wan EY, Wong CK, Jiao F, Chan AK. Effect of metformin monotherapy on cardiovascular diseases and mortality: a retrospective cohort study on Chinese type 2 diabetes mellitus patients. Cardiovasc Diabetol. 2015;14:137.CrossRefPubMedPubMedCentral
29.
Lexis CH, Wieringa W, Hiemstra B, van Deursen V, Lipsic E, van der Harst P, van Veldhuisen D, van der Horst IC. Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with st-segment elevation myocardial infarction. Cardiovasc Drugs Ther. 2014;28:163–71.CrossRefPubMed
30.
Pitocco D, Zaccardi F, Tarzia P, Milo M, Scavone G, Rizzo P, Pagliaccia F, Nerla R, Di Franco A, Manto A, et al. Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study. Diabetes Obes Metab. 2013;15:427–31.CrossRefPubMed
31.
Eriksson L, Nyström T. Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovasc Diabetol. 2014;13:152.CrossRefPubMedPubMedCentral
32.
Lexis CH, van der Horst IC, Lipsic E, et al. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the gips-iii randomized clinical trial. JAMA. 2014;311:1526–35.CrossRefPubMed
33.
Elmessaoudi S, Nederlof R, Zuurbier CJ, van Swieten HA, Pickkers P, Noyez L, Dieker HJ, Coenen MJ, Donders ART, Vos A, et al. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2014;3:615–23.CrossRef
34.
Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther. 2011;13:921–8.CrossRefPubMedPubMedCentral
35.
Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95:343–53.CrossRefPubMed
36.
Schoenaker DAJM, Simon D, Chaturvedi N, Fuller JH, Soedamah-Muthu SS. Glycemic control and all-cause mortality risk in type 1 diabetes patients: the EURODIAB prospective complications study. J Clin Endocrinol Metab. 2014;99:800–7.PubMed
37.
Chen LL, Liao YF, Zeng TS, Yu F, Li HQ, Feng Y. Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. Endocrine. 2010;38:266–75.CrossRefPubMed
38.
Gundewar S, Calvert JW, Jha S, Toedt-Pingel I, Ji SY, Nunez D, Ramachandran A, Anaya-Cisneros M, Tian R, Lefer DJ. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res. 2009;104:403–11.CrossRefPubMed
39.
Takahashi N, Shibata R, Ouchi N, Sugimoto M, Murohara T, Komori K. Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model. J Vasc Surg. 2015;61:489–96.CrossRefPubMed
40.
Humpert PM, Neuwirth R, Battista MJ, Voronko O, von Eynatten M, Konrade I, Rudofsky G, Wendt T, Hamann A, Morcos M, et al. SDF-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes. Diabetes Care. 2005;28:934–6.CrossRefPubMed
41.
Fadini GP, de Kreutzenberg SV, Mariano V, Boscaro E, Bertolini F, Mancuso P, Quarna J, Marescotti M, Agostini C, Tiengo A, Avogaro A. Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine. Diabetes Obes Metab. 2011;13:718–25.CrossRefPubMed
42.
Humpert PM, Djuric Z, Zeuge U, Oikonomou D, Seregin Y, Laine K, Eckstein V, Nawroth PP, Bierhaus A. Insulin Stimulates the Clonogenic Potential of Angiogenic Endothelial Progenitor Cells by IGF-1 Receptor-Dependent Signaling. Mol Med. 2008;14:301–8.CrossRefPubMedPubMedCentral
43.
Oikonomou D, Kopf S, von Bauer R, Djuric Z, Cebola R, Sander A, Englert S, Vittas S, Hidmark A, Morcos M, et al. Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study. Cardiovasc Diabetol. 2014;13:137.CrossRefPubMedPubMedCentral
44.
OvO Verhaar, Nieuwdorp M, Westerweel PE, Hoefer IE, Basser P, Stroes ESG. Reconstituted HDL increases circulating endothelial progenitor cells in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol. 2007;27:1864.CrossRef
45.
Nagai MS, Masataka S, Shin-ichiro M, Kerry-Anne R, Naoki T, Yuji K, Katsuhiko Y, Takao O, Keijiro S. Ryozo: Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol. 2007;27:813.CrossRefPubMed
46.
Rossi F, Bertone C, Montanile F, Miglietta F, Lubrano C, Gandini L, Santiemma V. HDL cholesterol is a strong determinant of endothelial progenitor cells in hypercholesterolemic subjects. Microvasc Res. 2010;80:274–9.CrossRefPubMed
47.
Avogaro GPF, Mattia A, Saulavigilide K, Elisa B, Roberta C, Mariacristina M, Nicol P, Carlo A. Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care. 2013;36:943.CrossRefPubMedPubMedCentral
48.
Arunachalam G, Samuel SM, Marei I, Ding H, Triggle CR. Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br J Pharmacol. 2014;171:523–35.CrossRefPubMed
49.
Xu ZZ, Haibing C, Jun L, Tao L, Bingqing Z, Ying Z, Huiyi J, Ying H, Qing G. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012;61:217.CrossRefPubMed
50.
Li WD, Du XL, Qian AM, Hu N, Kong LS, Wei S, Li CL, Li XQ. Metformin regulates differentiation of bone marrow-derived endothelial progenitor cells via multiple mechanisms. Biochem Biophys Res Commun. 2015;465:803–9.CrossRefPubMed
51.
Lu A, Wang L, Qian L. The role of eNOS in the migration and proliferation of bone-marrow derived endothelial progenitor cells and in vitro angiogenesis. Cell Biol Int. 2015;39:484–90.CrossRefPubMed
52.
Bakhashab S, Ahmed FW, Schulten H-J, Bashir A, Karim S, Al-Malki AL, Gari MA, Abuzenadah AM, Chaudhary AG, Alqahtani MH, et al. Metformin improves the angiogenic potential of human CD34+ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. Cardiovasc Diabetol. 2016;15:1–12.CrossRef
53.
Metadata
Title
Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study
Authors
Fahad W. Ahmed
Rachel Rider
Michael Glanville
Kilimangalam Narayanan
Salman Razvi
Jolanta U. Weaver
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2016
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-016-0413-6

Other articles of this Issue 1/2016

Cardiovascular Diabetology 1/2016 Go to the issue

Original investigation

Effect of the long-acting insulin analogues glargine and degludec on cardiomyocyte cell signalling and function

Methodology

Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design

Original investigation

Severely impaired microvascular reactivity in diabetic patients with an acute coronary syndrome

Original investigation

Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy. A multicenter prospective 8 years follow up study

Original investigation

Early cardiovascular events in women with a history of gestational diabetes mellitus

Original investigation

Impaired coronary microcirculation in type 2 diabetic patients is associated with elevated circulating regulatory T cells and reduced number of IL-21R+ T cells

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

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

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