Inflammatory profile of diabetic ketoacidosis in children with type 1 diabetes
Zachary Chaffin1, Simona Ghetti2, Daniel Tancredi3
1Department of Pediatrics, University of California Davis School of Medicine, Sacramento, California, USA zrchaffin@ucdavis.edu.
Insights
Diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1D) triggers a distinct inflammatory response, primarily involving matrix metalloproteinases (MMPs) and their inhibitors. This unique inflammatory profile differs from acute hyperglycemia or T1D autoimmunity.
Area of Science:
- Pediatric Endocrinology
- Immunology
- Metabolic Disorders
Background:
- Diabetic ketoacidosis (DKA) is a frequent complication in children with type 1 diabetes (T1D).
- The inflammatory response during DKA is not fully understood and may influence disease outcomes.
- Characterizing the inflammatory profile is crucial for understanding DKA pathophysiology.
Purpose of the Study:
- To delineate the inflammatory mediator profile in children during and after DKA.
- To compare the inflammatory patterns of DKA with new-onset T1D without DKA and chronic T1D.
- To identify key inflammatory markers associated with DKA.
Main Methods:
- Multiplex immunoassays were used to quantify cytokines, chemokines, growth factors, and matrix metalloproteinases (MMPs).
- Inflammatory mediators were analyzed in four groups of children: acute DKA, post-DKA, new-onset T1D without DKA (<24 hours and 2-5 days post-insulin), and a chronic T1D reference group.
- Statistical analysis, including false discovery rate adjustment, was applied to identify significant differences.
Main Results:
- Children with acute DKA exhibited significant alterations in numerous inflammatory mediators, including interleukins (IL-1RA, IL-6, IL-8, IL-10, IL-18), chemokines (CXCL5, CXCL10, CCL27), and MMPs (MMP-2, MMP-3, MMP-7, MMP-9, MMP-10) compared to controls.
- Elevated levels of MMP-3, MMP-10, TIMP-1, and IL-1RA persisted 2-5 days after DKA resolution.
- New-onset T1D without DKA showed altered MMP-2 and MMP-9 levels acutely, but no significant inflammatory changes were observed later.
Conclusions:
- DKA induces a unique inflammatory signature in children with type 1 diabetes, distinct from other hyperglycemic states or autoimmune processes.
- Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are key players in the inflammatory profile associated with DKA.
- The findings highlight the significant role of MMPs in the pathophysiology and potential complications of DKA in pediatric T1D.
Introduction:
Diabetic ketoacidosis (DKA) occurs frequently in children with type 1 diabetes (T1D). The inflammatory response to DKA may play a role in complications, but the inflammatory pattern is not well characterized. We aimed to describe the inflammatory profile during and after DKA.
Research Design And Methods:
We evaluated inflammatory mediators (cytokines, chemokines, growth factors, and matrix metalloproteinases) using multiplex immunoassays in children (1) hospitalized with acute DKA (6-8 hours after beginning treatment, (n=15), (2) seen in the outpatient diabetes clinic 2-5 days after DKA (n=14), (3) hospitalized with new-onset T1D without DKA <24 hours after beginning insulin (n=9), and (4) referred to the outpatient diabetes clinic for new-onset T1D without DKA 2-5 days after beginning insulin (n=14). Children with chronic T1D and glycated hemoglobin <8.0% (n=59) undergoing routine phlebotomy served as a reference group.
Results:
Compared with the reference group, children with acute DKA had significant alterations in interleukin 1 (IL-1) receptor antagonist (IL-1RA), IL-6, IL-8, IL-10, IL-18, chemokine C-X-C motif ligand (CXCL) 5, CXCL10, chemokine C-C motif ligand (CCL) 27, tumor necrosis factor-related apoptosis-inducing ligand, granulocyte colony-stimulating factor, tissue inhibitor of metalloproteinase 2 (TIMP-2), TIMP-4, matrix metalloproteinase 2 (MMP-2), MMP-3, MMP-7, MMP-9, and MMP-10. MMP-3, MMP-10, TIMP-1, and IL-1RA were also elevated 2-5 days after DKA (false discovery rate-adjusted p<0.10 for all). MMP-2 and MMP-9 levels were altered in children with new-onset T1D without DKA <24 hours after starting insulin, but no significant inflammatory changes were found in new-onset T1D 2-5 days after starting insulin.
Conclusions:
DKA causes a unique inflammatory pattern distinct from inflammatory changes in acute hyperglycemia or T1D-related autoimmunity. Alterations in MMPs and their tissue inhibitors play a dominant role in this inflammatory profile.
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