title: The effects of insulin and liraglutide on osteoprotegerin and vascular calcification in vitro and in patients with type 2 diabetes.
abstract: OBJECTIVE
  Vascular calcification (VC) is inhibited by the glycoprotein osteoprotegerin (OPG). It is unclear whether treatments for type 2 diabetes are capable of promoting or inhibiting VC. The present study examined the effects of insulin and liraglutide on i) the production of OPG and ii) the emergence of VC, both in vitro in human aortic smooth muscle cells (HASMCs) and in vivo in type 2 diabetes.
  
  
  METHODS
  HASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels of Runx2, ALP and bone sialoprotein (BSP) mRNA were measured. A prospective, nonrandomised human subject study was also conducted, in which OPG levels and coronary artery calcification (CAC) were measured in a type 2 diabetes population before and 16 months after the commencement of either insulin or liraglutide treatment and in a control group that took oral hypoglycemics only.
  
  
  RESULTS
  Exposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913±1409 pg/10(4) cells vs 282±13 pg/10(4) cells, control vs 10 nmol/l insulin, P<0.0001), increased ALP activity (0.82±0.06 IU/10(4) cells vs 2.40±0.16 IU/10(4) cells, control vs 10 nmol/l insulin, P<0.0001) and increased osteogenic gene expression by HASMCs. In the clinical study (n=101), insulin treatment was associated with a significant reduction in OPG levels and, despite not achieving full statistical significance, a trend towards increased CAC in patients.
  
  
  CONCLUSIONS
  Exogenous insulin down-regulated OPG in vitro and in vivo and promoted VC in vitro. Although neither insulin nor liraglutide significantly affected CAC in the present pilot study, these data support the establishment of randomised trials to investigate medications and VC in diabetes.
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland drcdavenport@gmail.com.
authors.forename: Colin
authors.initials: C
authors.lastname: Davenport
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Wan A
authors.initials: WA
authors.lastname: Mahmood
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Hannah
authors.initials: H
authors.lastname: Forde
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: David T
authors.initials: DT
authors.lastname: Ashley
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Amar
authors.initials: A
authors.lastname: Agha
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: McDermott
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Seamus
authors.initials: S
authors.lastname: Sreenan
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Thompson
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Frank
authors.initials: F
authors.lastname: McGrath
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: McAdam
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Cummins
authors.affiliation: Department of Academic EndocrinologyDiabetes Day Centre, Beaumont Hospital, County Dublin, Dublin 9, IrelandDepartment of Diabetes and EndocrinologyConnolly Hospital, Blanchardstown, County Dublin, Dublin 9, IrelandDepartments of RadiologyCardiologyBeaumont Hospital, County Dublin, Dublin 9, IrelandSchool of BiotechnologyCentre for Preventive Medicine, Dublin City University, County Dublin, Dublin 9, Ireland.
authors.forename: Diarmuid
authors.initials: D
authors.lastname: Smith
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy*; D023381:Endpoint Determination; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D066298:In Vitro Techniques; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D000069450:Liraglutide; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D053244:Osteoprotegerin / Q000097:blood*; D010865:Pilot Projects; D011446:Prospective Studies; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D061205:Vascular Calcification / Q000139:chemically induced*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D053244:Osteoprotegerin; C493709:RUNX2 protein, human; D012795:Sialoglycoproteins; D000069036:Insulin Glargine; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D000469:Alkaline Phosphatase