Abstract 1273: High Density Lipoprotein Modulates Glucose Metabolism by Multiple Mechanisms
Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome (MS). We hypothesize that low HDL may play a causative role in the MS and be able to modulate glucose metabolism via mechanisms including
stimulation of insulin secretion
stimulation of skeletal muscle AMP-activated protein kinase (AMPK) and
enhanced insulin sensitivity via suppression of lipid-induced macrophage inflammation.
In patients with type 2 diabetes (T2DM; n=13), reconstituted HDL infusion (rHDL [rH]; 80mg/kg over 4hrs) reduced plasma glucose (−0.7±0.7mmol/L) compared with placebo [P] (p<0.05). rHDL increased plasma insulin (rH=3.4±10.0; P= −19.2±7.4pmol/L, p=0.034) and also the HOMA β-cell function index (rH=18.9±5.9; P=8.6±4.4%, p=0.025). Insulin data were strengthened by in-vitro findings in MIN6 β-cells, demonstrating a direct action of HDL on first phase insulin secretion (HDL=1.62±0.2, P=0.24±0.01%, p<0.01). Activation of the AMPK pathway was demonstrated in skeletal muscle biopsies by increased phosphorylation of ACCβ (1.7±0.3 fold after rH vs. P) after rHDL infusion. Skeletal muscle cell culture also showed that HDL increases glucose uptake (177±12%; p<0.05) via activation of AMPK by binding ABCA1 and activating calcium/calmodulin-dependent protein kinase kinase. In addition, we show that rHDL infusion suppresses inflammation (CD11b expression) of circulating monocytes (p=0.021). This is consistent with in-vitro findings that HDL reduces fatty acid (FA)-induced cytokine release from macrophages (FA=159±51% vs. FA+HDL=104±39% vs. cont for IL-1β, p<0.05) by suppressing the JNK pathway (p/tJNK ratio, FA=1.8±0.1 vs. FA+HDL=1.1±0.05 vs. cont, p<0.01). Furthermore, insulin resistance induced by incubation of muscle cells with media from FA-treated macrophages is reduced when macrophages are co-treated with HDL. In conclusion, HDL acutely modulates glucose metabolism by a number of mechanisms including increased insulin secretion, activation of AMPK in skeletal muscle and improved insulin sensitivity via reduced lipid-induced macrophage inflammation. These findings suggest that therapeutics aimed at elevating plasma HDL may provide efficacy in treating T2DM.