Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, United States.
Department for Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
Elife. 2020 Nov 9;9:e62506. doi: 10.7554/eLife.62506.
Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics. We show that this behavior is correlated with two subpopulations of insulin granules whose relative abundance is differentially shifted depending on diabetic model condition. The two types of granules have different release characteristics, distinct lipid and protein compositions, and package different secretory contents alongside insulin. This complexity of β-cell secretory physiology establishes a direct link between granule subpopulation and type of diabetes and leads to a revised model of secretory changes in the diabetogenic process.
β 细胞的胰岛素分泌在 1 型和 2 型糖尿病发病时减少。虽然 β 细胞的炎症和代谢功能障碍引起与 1 型或 2 型糖尿病相关的分泌缺陷，但伴随的胰岛素颗粒变化尚未确定。为了解决这个问题，我们对从模拟 1 型和 2 型糖尿病条件的细胞中纯化的胰岛素颗粒进行了详细的功能分析，发现钙亲和力和融合特性发生了显著变化。我们表明，这种行为与胰岛素颗粒的两个亚群相关，其相对丰度根据糖尿病模型条件的不同而有差异。这两种类型的颗粒具有不同的释放特性、不同的脂质和蛋白质组成，并与胰岛素一起包装不同的分泌内容物。β 细胞分泌生理学的这种复杂性将颗粒亚群与糖尿病类型直接联系起来，并导致对糖尿病发病过程中分泌变化的修正模型。
