Navarro Guadalupe, Abdolazimi Yassan, Zhao Zhengshan, Xu Haixia, Lee Sooyeon, Armstrong Neali A, Annes Justin P
Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA.
Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
Diabetes. 2017 Jul;66(7):1928-1938. doi: 10.2337/db16-0816. Epub 2017 May 3.
Islet β-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-cell mass and/or protects against high-fat diet (HFD)-induced glucose dysregulation. Mice targeted at the locus were bred to Rip-Cre and Ins1-Cre/ERT mice to enable constitutive (βADKO) and conditional (iβADKO) disruption of ADK expression in β-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)-fed and HFD-fed mice. In addition, β-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult βADKO and iβADKO mice displayed glucose tolerance, insulin tolerance and β-cell mass comparable to control animals. By contrast, HFD-fed βADKO and iβADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased β-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive β-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive β-cell response.
胰岛β细胞通过增加胰岛素分泌和细胞增殖来适应胰岛素抵抗。当长期的胰岛素抵抗超过β细胞的适应能力时，通常会发生2型糖尿病。我们之前的筛选工作发现腺苷激酶（ADK）抑制剂可刺激β细胞复制。在此，我们评估了小鼠β细胞中ADK功能破坏是否会影响β细胞质量和/或预防高脂饮食（HFD）诱导的葡萄糖调节异常。将靶向该位点的小鼠与Rip-Cre和Ins1-Cre/ERT小鼠杂交，分别在β细胞中实现ADK表达的组成性（βADKO）和条件性（iβADKO）破坏。对正常饮食（NC）喂养和HFD喂养的小鼠纵向监测体重增加、葡萄糖耐量、胰岛素敏感性和葡萄糖刺激的胰岛素分泌（GSIS）。此外，通过基于免疫荧光的胰岛形态测量法测量β细胞质量和细胞增殖。NC喂养的成年βADKO和iβADKO小鼠的葡萄糖耐量、胰岛素耐量和β细胞质量与对照动物相当。相比之下，HFD喂养的βADKO和iβADKO动物的葡萄糖耐量得到改善，体内GSIS增加。改善的葡萄糖处理与β细胞增殖和质量增加有关。我们得出结论，ADK表达对β细胞对HFD挑战的适应性反应起负调节作用。因此，调节ADK活性是增强β细胞适应性反应的潜在策略。
