title: Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study.
abstract: 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.
  
  
  
  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 CD45(dim)CD34(+)VEGFR-2(+) and CD45(dim)CD133(-)CD34(+)CD144(+) respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill's colonies).
  
  
  
  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.
  
  
  
  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.
authors: Department of Diabetes, Queen Elizabeth Hospital, Gateshead, UK.|Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle, NE2 4HH, UK.
authors: Fahad W
authors: FW
authors: Ahmed
authors: Department of Diabetes, Queen Elizabeth Hospital, Gateshead, UK.
authors: Rachel
authors: R
authors: Rider
authors: Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle, NE2 4HH, UK.
authors: Michael
authors: M
authors: Glanville
authors: Department of Diabetes, Queen Elizabeth Hospital, Gateshead, UK.
authors: Kilimangalam
authors: K
authors: Narayanan
authors: Department of Diabetes, Queen Elizabeth Hospital, Gateshead, UK.|Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Salman
authors: S
authors: Razvi
authors: Department of Diabetes, Queen Elizabeth Hospital, Gateshead, UK. Jolanta.Weaver@newcastle.ac.uk.|Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle, NE2 4HH, UK. Jolanta.Weaver@newcastle.ac.uk.
authors: Jolanta U
authors: JU
authors: Weaver
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004739:England; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010641:Phenotype; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D005353:Fibronectins; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin