The effects of insulin and liraglutide on osteoprotegerin and vascular calcification in vitro and in patients with type 2 diabetes

Abstract

ObjectiveVascular 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, bothin vitroin human aortic smooth muscle cells (HASMCs) andin vivoin type 2 diabetes.Design/methodsHASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels ofRunx2,ALPand 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.ResultsExposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913±1409 pg/104cells vs 282±13 pg/104cells, control vs 10 nmol/l insulin,P<0.0001), increasedALPactivity (0.82±0.06 IU/104cells vs 2.40±0.16 IU/104cells, 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.ConclusionExogenous insulin down-regulated OPGin vitroandin vivoand promoted VCin 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.