Diabetes is a chronic inflammatory disease that accelerate cardiovascular disease (CVD). However, the contribution of hyperglycemia to inflammation and CVD risk is unclear. Animal studies have shown that monocytes carry cholesterol to the atherosclerotic plaque. Thus, it is key to determine if hyperglycemia can exert a pro-atherogenic effect in human monocytes in vivo. We performed octreotide euglycemic-hyperglycemic clamps in 21 healthy subjects, 20-45 yo. Monocytes isolated during euglycemia (90 mg/dl) and after 2h of hyperglycemia (300 mg/dl) were evaluated for cholesterol metabolism and monocyte function (adhesion to fibronectin, transwell migration assays). Also, we assessed the effects of hyperglycemia on monocyte cholesterol metabolism and function from 10 healthy controls cultured in euglycemia or high glucose media with or without 2-deoxyglucose (2DG) at 2 and 6 hours. Acute hyperglycemia in vivo increased 37% total monocyte cholesterol content (TC) (p<0.02), 40% cholesterol ester (CE)(p<0.02) and upregulated oxidized low-density lipoprotein (oxLDL) cholesterol uptake by by 24%(p<0.01). Moreover, acute hyperglycemia increased monocyte adhesion and transwell migration (p<0.01) suggesting cholesterol full monocytes carry cholesterol into the vessel wall. In vitro studies confirmed that hyperglycemia increased monocyte adhesion and migration by 20% and monocyte TC by 20% and CE by 40% at 2 and 6 hours (p<0.03) by increasing oxLDL or LDL cholesterol uptake. Hyperglycemia didn’t affect monocyte cholesterol biosynthesis or cholesterol efflux induced by HDL or APOA1. Addition of 2DG cultured monocytes in both glucose conditions prevented hyperglycemia induced monocyte adhesion migration and monocyte CE and TC content at 2 and 6 hours. Thus, acute hyperglycemia in vivo without hyperinsulinemia induce monocyte glycolysis increasing monocyte cholesterol uptake, total cholesterol content it activates monocytes adhesion and migration, all key components to accelerate atherosclerosis.


R.M. Zhang: None. J. Oh: None. X. Lin: None. P. Stone: None. K.J. Wharton: None. A. Arbelaez: None. C. Bernal-Mizrachi: None.


National Heart, Lung, and Blood Institute (R01HL094818-06); National Institute of Neurological Disorders and Stroke (P01NS080675)

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