Horvath Peter, Oliver Stacy R, Zaldivar Frank P, Radom-Aizik Shlomit, Galassetti Pietro R
Institute for Clinical Translational Science, University of California, Irvine, California.
Department of Pharmacology, School of Medicine, University of California, Irvine, California.
Physiol Rep. 2015 Feb 12;3(2). doi: 10.14814/phy2.12249. Print 2015 Feb 1.
Atherosclerosis/cardiovascular disease are major causes of morbidity/mortality in obesity and type 2 diabetes (T2D), and have been associated with activation of innate immune cells, their diapedesis to the arterial intima and formation of the atherosclerotic plaque. While in obesity/T2D immune cell activation likely depends on dysregulated metabolism, the interaction between individual metabolic factors typical of these conditions (hyperglycemia, hyperlipidemia), innate immune cell activation, and the progression of atherosclerosis remains unclear. We, therefore, measured by flow cytometry cell surface expression of CD11b, CD14, CD16, CD62L, and CD66b, known markers of granulocyte (Gc) and monocyte (Mc) activation, in five healthy, five obese, and five T2D subjects, during 4-h i.v. infusions of 20% dextrose (raising blood sugar levels to ~220 mg/dL), 20% Intralipid (raising trygliceride levels to ~6 mmol/L), or a combination of the two. We hypothesized that both glucose and lipids would increase Gc/Mc surface marker expression, and simultaneous infusion would have an additive or synergistic effect. Surprisingly, though, infusion of glucose alone had little effect, while lipids, alone or combined with glucose, significantly increased expression of several markers (such as CD11b in Gc and Mc, and CD66 b in GC) within 60-90 min. Less pronounced increases in systemic inflammatory cytokines also occurred in obese and T2D subject, with no acute changes in gene expression of the the proinflammatory genes NFκB and CCR2. Our results suggest that lipids may be stronger acute contributors to innate cell activation than acute hyperglycemia per se, possibly helping shape more effective preventive dietary guidelines in T2D.
动脉粥样硬化/心血管疾病是肥胖和2型糖尿病（T2D）发病和死亡的主要原因，并且与固有免疫细胞的激活、其向动脉内膜的渗出以及动脉粥样硬化斑块的形成有关。虽然在肥胖/T2D中免疫细胞激活可能取决于代谢失调，但这些病症典型的个体代谢因素（高血糖、高血脂）、固有免疫细胞激活与动脉粥样硬化进展之间的相互作用仍不清楚。因此，我们通过流式细胞术测量了5名健康受试者、5名肥胖受试者和5名T2D受试者在静脉输注20%葡萄糖（将血糖水平提高至约220mg/dL）、20%英脱利匹特（将甘油三酯水平提高至约6mmol/L）或两者组合4小时期间粒细胞（Gc）和单核细胞（Mc）激活的已知标志物CD11b、CD14、CD16、CD62L和CD66b的细胞表面表达。我们假设葡萄糖和脂质都会增加Gc/Mc表面标志物的表达，同时输注会产生相加或协同作用。然而，令人惊讶的是，单独输注葡萄糖几乎没有效果，而脂质单独或与葡萄糖联合输注在60 - 90分钟内显著增加了几种标志物的表达（如Gc和Mc中的CD11b以及Gc中的CD66b）。肥胖和T2D受试者中全身炎症细胞因子也有不太明显的增加，促炎基因NFκB和CCR2的基因表达没有急性变化。我们的结果表明，脂质可能比急性高血糖本身更能强烈地急性促进固有细胞激活，这可能有助于制定更有效的T糖尿病预防性饮食指南。
