Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Diabetes. 2015 Aug;64(8):2928-38. doi: 10.2337/db14-1752. Epub 2015 Apr 27.
Loss of pancreatic islet β-cell mass and β-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulin-containing β-cells can convert into glucagon-containing α-cells ex vivo. This loss of β-cell identity was characterized by the presence of β-cell transcription factors (Nkx6.1, Pdx1) in glucagon(+) cells. Here, we investigated whether the loss of β-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin(+) cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1(+) but insulin(-) coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1(+)glucagon(+)insulin(-) cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1(+)glucagon(+)insulin(-) cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of β-cell identity occurs in T2DM and could contribute to the decrease of functional β-cell mass. Maintenance of β-cell identity is a potential novel strategy to preserve β-cell function in diabetes.
胰岛β细胞质量的损失和β细胞功能障碍是 2 型糖尿病（T2DM）发展的核心。我们最近表明，成熟的人含胰岛素β细胞可以在体外转化为含胰高血糖素的α细胞。β细胞特征的丧失表现为β细胞转录因子（Nkx6.1、Pdx1）在胰高血糖素（+）细胞中的存在。在这里，我们研究了β细胞特征的丧失是否也发生在体内，以及它是否与人类和非人类灵长类动物（NHP）糖尿病前期的存在有关。我们观察到，糖尿病供体中胰岛素（+）细胞共表达胰高血糖素的频率增加了 8 倍。多达 5%的 Nkx6.1（+）但胰岛素（-）的细胞共表达胰高血糖素，与对照组相比增加了五倍。在糖尿病猕猴的胰岛中也发现了这种双激素和 Nkx6.1（+）胰高血糖素（+）胰岛素（-）细胞的增加。糖尿病猕猴和人类中双激素细胞和 Nkx6.1（+）胰高血糖素（+）胰岛素（-）细胞的比例较高与胰岛淀粉样变性的存在和程度相关。这些数据表明，β细胞特征的丧失发生在 T2DM 中，并可能导致功能性β细胞质量的下降。维持β细胞特征是保护糖尿病β细胞功能的一种潜在的新策略。
