Abstract
BackgroundHyperglycemia is a frequent and important metabolic derangement that accompanies severe sepsis and septic shock. Matrix-Metalloproteinase 9 (MMP-9) has been shown to be elevated in acute stress hyperglycemia, chronic hyperglycemia, and in patient with sepsis. The objective of this study was to examine the clinical and pathogenic link between MMP-9 and blood glucose (BG) levels in patients with early severe sepsis and septic shock.MethodsWe prospectively examined 230 patients with severe sepsis and septic shock immediately upon hospital presentation and before any treatment including insulin administration. Clinical and laboratory data were obtained along with blood samples for the purpose of this study. Univariate tests for mean and median distribution using Spearman correlation and analysis of variance (ANOVA) were performed. A p value ≤ 0.05 was considered statistically significant.ResultsPatients were grouped based on their presenting BG level (mg/dL): BG <80 (n = 32), 80–120 (n = 53), 121–150 (n = 38), 151–200 (n = 23), and > 201 (n = 84). Rising MMP-9 levels were significantly associated with rising BG levels (p = 0.043). A corresponding increase in the prevalence of diabetes for each glucose grouping from 6.3 to 54.1 % (p = 0.0001) was also found. As MMP-9 levels increased a significantly (p < 0.001) decreases in IL-8 (pg/mL) and ICAM-1 (ng/mL) were noted.ConclusionThis is the first study in humans demonstrating a significant and early association between MMP-9 and BG levels in in patients with severe sepsis and septic shock. Neutrophil affecting biomarkers such as IL-8 and ICAM-1 are noted to decrease as MMP-9 levels increase. Clinical risk stratification using MMP-9 levels could potentially help determine which patients would benefit from intensive versus conventional insulin therapy. In addition, antagonizing the up-regulation of MMP-9 could serve as a potential treatment option in severe sepsis or septic shock patients.
Highlights
Hyperglycemia is a frequent and important metabolic derangement that accompanies severe sepsis and septic shock
We demonstrate that as blood glucose (BG) increased an inverse relationship between Matrix-Metalloproteinase 9 (MMP-9) and IL-8 levels, and MMP-9 and ICAM-1 levels was observed. It is well-known that in severe sepsis and septic shock patients, hyperglycemia develops due to a combination of several factors: 1) Insulin clearance is increased leading to a reduction in insulin-mediated glucose uptake; 2) Stress induced elevation in plasma levels of counter-regulatory hormones, such as catecholamines, glucagon, cortisol, and growth hormone
These hormones lead to hyperglycemia due to muscle glycolysis and lipolysis, and subsequent gluconeogenesis and glycolysis in the liver; 3) Hyperlactatemia due to glycolysis in muscle caused by the counterregulatory hormones and cytokines, sometimes referred to as the “lactate shuttle” 4) Insulin resistance which could be due to a defective GLUT4 transporter and to the deleterious effects of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α [16,17,18]
Summary
Hyperglycemia is a frequent and important metabolic derangement that accompanies severe sepsis and septic shock. Matrix-Metalloproteinase 9 (MMP-9) has been shown to be elevated in acute stress hyperglycemia, chronic hyperglycemia, and in patient with sepsis. The objective of this study was to examine the clinical and pathogenic link between MMP-9 and blood glucose (BG) levels in patients with early severe sepsis and septic shock. Hyperglycemia is a frequent and important metabolic derangement that can occur in severe sepsis or septic shock. Elevated blood glucose (BG) has been associated with an increase in oxidative stress, as reflected by increase in oxygen free radical Insulin administration is important in modulating glycemic control, but it aids in antagonizing the pro-inflammatory effects of elevated blood glucose levels in critically illness.
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