胰岛δ-α/β细胞功能组模式调控异常致胰岛功能障碍的研究

胰岛功能障碍表现为β和α细胞分泌数量和节律异常，及δ细胞旁分泌对α/β细胞负调控失常。最近发现α和β细胞分泌脉冲与胞内Ca2+流动一致性相悖，提示胰岛各细胞间反馈调节异常难从二元角度阐明。我们提出胰岛功能障碍是以δ细胞(接收前馈信号)为调控角色、以β和α细胞(接收反馈信号)为功能行使的糖稳态调节细胞功能组(cell functionome)的模式调控(pattern regulation)异常，我们假设其分子机制是静态与负荷时δ细胞GPR120棕榈酰化感受外周脂代谢水平及接收脑-胃肠ghrelin信号量化调控局部生长抑素分泌异常，而引起α/β细胞功能平衡点偏移。故拟应用胰岛δ细胞特异性GPR120棕榈酰化位点突变鼠、BCHE条件性敲除鼠、胰岛微生理分析平台等，探讨δ-α/β细胞功能组模式调控异常的分子机制、模式干预对α/β细胞功能平衡点失衡的影响，以期为胰岛功能障碍评估和干预提供有效手段。

Islet dysfunction is characterized by β-cell loss of response to metabolic demands, inappropriate secretion of α-cell, and impaired inhibitory regulation of δ-cell to α/β-cells via somatostatin (SST), together ultimately leading to hyperglycemia. As demonstrated by electrophysiological and mathematical model, pulsatile oscillations of glucagon from α-cell and insulin from β-cell failed to synchronize with intracellular calcium fluctuation and δ-cell might be the key to illustrate this phenomenon. These findings indicated that the dysregulation of islet feedback loops from one-to-one binary perspective is difficult to illustrate the mechanism of islet dysfunction. We hypothesize islet dysfunction is a result of aberrant pattern regulation of the “islet cell functionome”, incorporating δ-cell as a regulator (feedforward regulation), β-cells and α-cells as functional players (feedback regulation). The underlying mechanism assumed is that δ-cell quantitatively regulates the secretion of SST by GPR120 palmitoylation in response to lipid metabolism in static state, and via receiving the brain-gut crosstalk of ghrelin under load condition, further regulating the functional equilibrium of α/β-cells as a downstream impact upon stress. We take the advantage of the transgenic mice with δ-cell-specific mutant GPR120 lacking of palmitoylated sites, δ-cell-specific BCHE-knockout mice, and the islet Microphysiological Analysis Platform (iMAP), in order to investigate the mechanism of pattern regulation in δ-α/β cell functionome and evaluate the efficacy of individually customized intervention in treating α/β-cells functional imbalance. It may provide effective methods for evaluating and determining islet dysfunction and for the clinical therapeutic interventions in the future.