Human duct yells contribute to β cell compensation in insulin resistance
Human duct yells contribute to β cell compensation in insulin resistance
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DOI：
10.1172/jci.insight.99576
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发表时间：
2019-04-18
期刊：
影响因子：
8
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
--
作者：
Dirice, Ercument;De Jesus, Dario F.;Kulkarni, Rohit N.
鉴定新的β细胞来源是一项对糖尿病治疗具有重要意义的努力。胰岛素抵抗，在妊娠等生理状态或 2 型糖尿病 (T2D) 等病理状态下，其特点是 β 细胞质量代偿性增加。为了探索动态 β 细胞储备的存在，我们将妊娠叠加到已经表现出 β 细胞增生的肝脏特异性胰岛素受体 KO (LIRKO) 胰岛素抵抗模型上，并使用谱系追踪来追踪新 β 细胞的来源。尽管对照小鼠和 LIRKO 小鼠均表现出因妊娠相对胰岛素抵抗而增加的 β 细胞质量，但后者质量的进一步增加支持了可追溯到胰管的动态来源。两项观察结果支持这些发现的转化意义。首先，在肾囊下共同移植人类胰岛和人类导管后怀孕的 NOD/SC1D-gamma LIRKO 小鼠表现出 ft 细胞增殖增强，并且对 β 细胞发育期间表达的转录因子呈阳性的导管细胞增加。其次，我们在孕妇和 T2D 患者的胰腺切片中发现了未成熟 β 细胞标记物呈阳性的导管细胞。总而言之，在胰岛素需求增加期间，导管细胞通过分化/新生对补偿性β细胞库做出贡献。
The identification of new sources of beta cells is an important endeavor with therapeutic implications for diabetes. Insulin resistance, in physiological states such as pregnancy or in pathological states such as type 2 diabetes (T2D), is characterized by a compensatory increase in beta cell mass. To explore the existence of a dynamic beta cell reserve, we superimposed pregnancy on the liver-specific insulin receptor-KO (LIRKO) model of insulin resistance that already exhibits beta cell hyperplasia and used lineage tracing to track the source of new beta cells. Although both control and LIRKO mice displayed increased beta cell mass in response to the relative insulin resistance of pregnancy, the further increase in mass in the latter supported a dynamic source that could be traced to pancreatic ducts. Two observations support the translational significance of these findings. First, NOD/SC1D-gamma LIRKO mice that became pregnant following cotransplantation of human islets and human ducts under the kidney capsule showed enhanced ft cell proliferation and an increase in ductal cells positive for transcription factors expressed during beta cell development. Second, we identified duct cells positive for immature beta cell markers in pancreas sections from pregnant humans and in individuals with T2D. Taken together, during increased insulin demand, ductal cells contribute to the compensatory beta cell pool by differentiation/neogenesis.