Circulating matrix metalloproteinases in children with diabetic ketoacidosis

Background and objective: Matrix metalloproteinases (MMPs) mediate blood-brain barrier dysfunction in inflammatory disease states. Our objective was to compare circulating MMPs in children with diabetic ketoacidosis (DKA) to children with type 1 diabetes mellitus without DKA. Research design and methods: This was a prospective study performed at five tertiary-care pediatric hospitals. We measured plasma MMP-2, MMP-3, and MMP-9 early during DKA (time 1; within 2h of beginning intravenous fluids) and during therapy (time 2; median 8 h; range: 4-16h). The primary outcome was MMP levels in 34 children with DKA vs. 23 children with type 1 diabetes without DKA. Secondary outcomes included correlations between MMPs and measures of DKA severity. Results: In children with DKA compared with diabetes controls, circulating MMP-2 levels were lower (mean 77 vs. 244ng/mL, p<0.001), MMP-3 levels were similar (mean 5 vs. 4ng/mL, p=0.57), and MMP-9 levels were higher (mean 67 vs. 25ng/mL, p=0.002) early in DKA treatment. MMP-2 levels were correlated with pH at time 1 (r=0.45, p=0.018) and time 2 (r=0.47, p=0.015) and with initial serum bicarbonate at time 2 (r=0.5, p=0.008). MMP-9 levels correlated with hemoglobin A1c in DKA and diabetes controls, but remained significantly elevated in DKA after controlling for hemoglobin A1c (β=-31.3, p=0.04). Conclusions: Circulating MMP-2 levels are lower and MMP-9 levels are higher in children during DKA compared with levels in children with diabetes without DKA. Alterations in MMP expression could mediate BBB dysfunction occurring during DKA.