Department of Medical and Surgical Sciences (E.M., G.C.M., A.F., C.A., R.S., F.A.), University Magna Graecia of Catanzaro, Italy.
Department of Science of Health (A.L., R.C., E.R., G.D.S.), University Magna Graecia of Catanzaro, Italy.
Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2941-2952. doi: 10.1161/ATVBAHA.120.314640. Epub 2020 Oct 22.
Subjects with low levels of HDL (high-density lipoprotein) and ApoA-1 (apolipoprotein A-1) have increased risk to develop type 2 diabetes. HDL levels are an independent predictor of β-cell function and positively modulate it. Type 2 diabetes is characterized by defects in both β and α-cell function, but the effect of HDL and ApoA1 on α-cell function is unknown. Approach and Results: We observed a significant negative correlation (=-0.422, <0.0001) between HDL levels and fasting glucagon in a cohort of 132 Italian subjects. In a multivariable regression analysis including potential confounders such as age, sex, BMI, triglycerides, total cholesterol, fasting and 2-hour postload glucose, and fasting insulin, the association between HDL and fasting glucagon remained statistically significant (β=-0.318, =0.006). CD1 mice treated with HDL or ApoA-1 for 3 consecutive days showed a 32% (<0.001) and 23% (<0.05) reduction, respectively, in glucagon levels following insulin-induced hypoglycemia, compared with controls. Treatment of pancreatic αTC1 clone 6 cells with HDL or ApoA-1 for 24 hours resulted in a significant reduction of glucagon expression (<0.04) and secretion (<0.01) after an hypoglycemic stimulus and increased Akt (RAC-alpha serine/threonine-protein kinase) and FoxO1 (forkhead/winged helix box gene, group O-1) phosphorylation. Pretreatment with Akt inhibitor VIII, PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002, and HDL receptor SCARB-1 (scavenger receptor class B type 1) inhibitor BLT-1 (block lipid transport-1) restored αTC1 cell response to low glucose levels.
These results support the notion that HDL and ApoA-1 modulate glucagon expression and secretion by binding their cognate receptor SCARB-1, and activating the PI3K/Akt/FoxO1 signaling cascade in an in vitro α-cell model. Overall, these results raise the hypothesis that HDL and ApoA-1 may have a role in modulating glucagon secretion.
载脂蛋白 A-1（ApoA-1）和高密度脂蛋白（HDL）水平较低的受试者发生 2 型糖尿病的风险增加。HDL 水平是β细胞功能的独立预测因子，并对其具有正向调节作用。2 型糖尿病的特征是β和α细胞功能均存在缺陷，但 HDL 和 ApoA1 对α细胞功能的影响尚不清楚。方法和结果：我们观察到 132 名意大利受试者的队列中，HDL 水平与空腹胰高血糖素之间存在显著的负相关（=-0.422，<0.0001）。在包含年龄、性别、BMI、甘油三酯、总胆固醇、空腹和 2 小时餐后血糖以及空腹胰岛素等潜在混杂因素的多变量回归分析中，HDL 与空腹胰高血糖素之间的关联仍然具有统计学意义（β=-0.318，=0.006）。用 HDL 或 ApoA-1 连续治疗 CD1 小鼠 3 天，与对照组相比，胰岛素诱导低血糖后，胰高血糖素水平分别降低 32%（<0.001）和 23%（<0.05）。用 HDL 或 ApoA-1 处理胰腺αTC1 克隆 6 细胞 24 小时后，低血糖刺激下，胰高血糖素的表达（<0.04）和分泌（<0.01）显著降低，Akt（RAC-α丝氨酸/苏氨酸蛋白激酶）和 FoxO1（叉头/翼状螺旋转录因子基因，O 组-1）磷酸化增加。用 Akt 抑制剂 VIII、PI3K（磷脂酰肌醇 3-激酶）抑制剂 LY294002 和 HDL 受体 SCARB-1（清道夫受体 B 类 1 型）抑制剂 BLT-1（阻断脂质转运-1）预处理可恢复αTC1 细胞对低血糖水平的反应。结论：这些结果支持以下观点，即 HDL 和 ApoA-1 通过与其同源受体 SCARB-1 结合，并在体外α细胞模型中激活 PI3K/Akt/FoxO1 信号级联，调节胰高血糖素的表达和分泌。总的来说，这些结果提出了一个假设，即 HDL 和 ApoA-1 可能在调节胰高血糖素分泌中发挥作用。
