Type 1 Diabetes Is Associated With Increased Cyclooxygenase- and Cytokine-Mediated Inflammation

Abstract

OBJECTIVE -The extent of involvement of cyclooxygenase (COX)-mediated inflammation in type 1 diabetes is unknown, and the association between the COX-and cytokine-mediated inflammatory responses in type 1 diabetes is not fully understood.RESEARCH DESIGN AND METHODS -Plasma high-sensitivity C-reactive protein (CRP), 24-h urinary and plasma 15-keto-dihydro-prostaglandin F 2␣ (a metabolite of prostaglandin F 2␣ [PGF 2␣ ] and an indicator of COX-mediated inflammation), serum amyloid protein A (SAA), and interleukin (IL)-6 (indicators of inflammation) were measured in 38 subjects with type 1 diabetes and 41 healthy age-and sex-matched control subjects.RESULTS -The inflammatory indicators (urinary 15-keto-dihydro-PGF 2␣ , P Ͻ 0.01; IL-6, P Ͻ 0.04) were increased in men with diabetes. CRP and SAA did not show any significant difference between the diabetic and the control subjects. Urinary levels of 15-keto-dihydro-PGF 2␣ correlated with the degree of glycemic control, HbA 1c (r ϭ 0.42, P Ͻ 0.0005). No correlation was found between the duration of diabetes and the inflammatory biomarkers or metabolic measurements.CONCLUSIONS -These results suggest that an early low-grade inflammatory process reflected by elevated levels of PGF 2␣ and IL-6 is involved in type 1 diabetes. Thus, both COX-and cytokine-mediated inflammatory pathways are significantly related to type 1 diabetes. Diabetes Care 28:1371-1375, 2005C ompared with a control population, type 1 diabetes is associated with an increased risk of microvascular complications and premature atherosclerosis (1). Atherosclerosis is considered to be in part a consequence of a chronic lowgrade inflammation (2,3), and it has been suggested that atherosclerosis and diabetes might share the mutual inflammatory phenomenon hypothesis (4,5). In recent years inflammation has been suggested to be involved in type 1 diabetes (6). Blood levels of interleukin (IL)-6 have been shown to be normal (7) or higher (8,9) in type 1 diabetic patients compared with levels in control subjects. Cytokinemediated acute-phase proteins have also been studied (9,10), but their role in diabetes without atherosclerosis is inconclusive.An ongoing inflammatory process can lead to gradual cell destruction followed by arachidonic acid release and its bioconversion by cyclooxygenase (COX) to various bioactive prostaglandins. Prostaglandin F 2␣ (PGF 2␣ ) is a potent vasoconstrictive compound (11). Moreover, prostaglandins are important mediators of the inflammatory process (12,13), and 15-keto-dihydro-PGF 2␣ , a major metabolite of PGF 2␣ , has been shown to be a reliable indicator of in vivo COX-mediated inflammation (14,15). In a recent study, 15-keto-dihydro-PGF 2␣ , high-sensitivity C-reactive protein (CRP), and serum amyloid protein A (SAA), which are all inflammatory indicators, were increased in men with type 2 diabetes in a population-based cross-sectional study (16). Cytokine-mediated CRP and SAA were more closely related to obesity and insulin than to the diagnosis of diabetes, suggesting that COX-med...

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