Circulating matrix metalloproteinases in children with diabetic ketoacidosis

Abstract

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 2 h of beginning intravenous fluids) and during therapy (time 2; median 8 h; range: 4–16 h). 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. 244 ng/mL, p < 0.001), MMP-3 levels were similar (mean 5 vs. 4 ng/mL, p = 0.57), and MMP-9 levels were higher (mean 67 vs. 25 ng/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.

Risk factors for cerebral oedema in children and adolescents with diabetic ketoacidosis

“…We support the suggestion that severe acidosis is one of the major risk factors for CO in DKA À it diminishes cerebral blood flow and inhibits the activity of pH-dependent glycolytic enzymes [17,28À30]. Moreover, it has recently been shown that the severity of acidosis correlates unidirectionally with alterations in the expression of matrix metalloproteinases, which in turn mediate bloodÀbrain barrier (BBB) dysfunction during DKA [31].…”

Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis

“…16,34–36 Elevated levels of matrix metalloproteinase may promote blood–brain barrier dysfunction. 37 …”

Frequency and Risk Factors of Acute Kidney Injury During Diabetic Ketoacidosis in Children and Association With Neurocognitive Outcomes

“…Although cerebral injury was previously assumed to be caused by osmotic shifts resulting from extreme hyperglycemia and rapid rehydration, recent data suggest that other mechanisms are more likely, including hypoperfusion and reperfusion injury, and damage resulting from inflammatory mechanisms. [5][6][7][8][9] Decreased kidney perfusion likely contributes to AKI in DKA; however, evidence of cerebral inflammatory injury, 7 and the association of AKI with cognitive dysfunction, raises the possibility of more diffuse inflammatory organ injuries, a physiological process that has not been studied in DKA, to our knowledge. Interestingly, in animal models, diabetes worsens kidney injury from ischemic events, and inflammatory mechanisms have been proposed to explain this association.…”