Hyperglycemia, Both Chronic and in Short-Term Peaks, Results in Rapid Increase of Expression of Monocyte Inducible Cyclooxygenase (COX-2) in Subjects with T2DM

: T2DM is associated with a two-to-four fold increase of vascular complications as result of both chronic hyperglycemia (elevated A1C) and isolated spikes of post-prandial hyperglycemia. Monocyte inducible COX-2 has been advocated as a player in the pathogenesis of ischemic events. Aim of our study was to establish if both chronic and acute, short-term hyperglycemia affect COX-2 expression in monocytes of subjects with T2DM. Peripheral blood monocyte COX-2 was measured (Western Blotting) in 120 subjects with T2DM (A1C 7.9±1.0%; fasting BG (FBG) 180±9 mg/dl; age 67±9 years) and 50 age and sex-matched healthy controls (A1C 5.9±0.3%; FBG 94±9 mg/dl; age 62±14). COX-2 was expressed in monocytes of 84% of T2DM subjects and 4% of normal volunteers (p<0.01). Average monocyte COX-2 was 0.31±0.05ng/μg total proteins in T2DM and correlated with FBG (r=0.52; p=0.05) and A1C (r=0.52; p=0.03). In 5 T2DM subjects with poor control at baseline in whom BG was optimally improved for 3 months (A1C decreased from 8.1±0.4% to 7±0.6%; p<0.01), monocytes COX-2 decreased from 0.18±0.06 to 0.12±0.05 ng/μg total proteins, p<0.05. Following this observations, monocytes were isolated from healthy volunteers and cultured in 22mM glucose-containing medium for 4 hours, showing increase of COX-2 (0 to 0.6±0.15 ng/μg total protein, p<0.001). After 4-h additional incubation at 5.5 mM glucose-containing medium, COX-2 reduced to 0.3±0.11 ng/μg total protein, p<0.01, and incubation for additional 20-h abolished it (p<0.01). Five T2DM subjects with good baseline glycemic control (A1C 6.4±0.3%, FBG 110±6 mg/d), underwent two subsequent differential steps (4h-each) of hyperglycemia (clamp, BG 13.9mM) and euglycaemia (clamp, BG 5.5 mM). After acute hyperglycemia monocyte COX-2 expression increased by 56%. However a prompt normalization of BG reached after 30 min and maintained thereafter (i.v. insulin bolus of 100 mU/kg, folllowed by a constant infusion of 0.5 mU/Kg/min) decreased COX-2 expression by 71% after 4-h. Conclusions: hyperglycemia is associates with COX-2 induction both in chronic as well as acute states. Short-term hyperglycemia mimicking post-prandial spikes, induces a rapid upregulation of monocyte COX-2. This phenomenon is rapidly reversible after BG normalization. These observations may have practical implications for clinical management of T2DM