Abstract 423: A Combination of Metformin, Quercetin, and Curcumin Restores HDL Function and Improves Atherosclerosis Burden in LDLr-/-/ob.ob leptin-/- and LDLr-/- Mice by attenuating Insulin Resistance, Hyperglycemia, and Low-grade Inflammation

Abstract

Cardiovascular disease risk in diabetics is 2-4 fold greater compared to non-diabetics. While dyslipidemia poorly explains excess risk in diabetics, glucose intolerance leads to increased macrophage infiltration, arterial stiffness, and modifies vascular tone. Enhanced lipid peroxidation in diabetes mellitus contributes to increased formation of free radicals, leading to accelerated glycation and oxidative stress, which causes HDL modification. The objective of the present study was to: a) investigate HDL function and atherosclerosis burden in animal model of diabetes, hyperlipidemia, and low-grade inflammation; and b) evaluate regression of preformed lesions following treatment with a proprietary formulation (COMB) of metformin (MET) with anti-oxidant and anti-inflammatory agents, quercetin and curcumin. We used LDLr-/-/leptin-/-ob/ob (DKO) and LDLr-/- (SKO) mice fed Western Diet for 10 weeks to develop lesion formation followed by treatment with MET (150 mpk) or COMB for 6 weeks (bid). Lipid profile, lesion formation, and OGTT were measured. We also measured HDL functionality by ABCA1-dependent cholesterol efflux in the serum, and in a separate cohort, cholesterol efflux using 3H-cholesterol-loaded J774 cells. Atherosclerotic lesion formation in DKO was greater (27%) compared to SKO. Impaired glucose tolerance, insulin resistance, and proinflammatory index was found to be associated with HDL functionality and atherosclerosis burden. Treatment with COMB attenuated hyperglycemia, insulin resistance and inflammation, and restored HDL function and promoted lesion regression (-24% in DKO, and -15% in SKO). COMB showed greater efficacy compared to MET, demonstrating the benefit of controlling glycemia and inflammation to restore HDL function and enhance lesion regression. Preliminary results in diabetics (n=10) and age and sex matched non-diabetic individuals (n=10) showed impairment in ABCA1-mediated cholesterol efflux in the serum of diabetics (-18% vs control). In summary, these data suggest that HDL dysfunction in diabetes mellitus is one of the risk factors of atherosclerotic lesion formation, and attenuation of hyperglycemia, oxidative stress, and inflammation may improve HDL function and promote lesion regression.