University of Michigan in Ann Arbor, Internal Medicine Department, MEND Division, Ann Arbor, MI, USA.
University of Miami Miller School of Medicine and Miami VA Health Care System, Division of Endocrinology, Diabetes and Metabolism, Miami, FL, USA.
Mol Metab. 2017 Mar 28;6(6):560-573. doi: 10.1016/j.molmet.2017.03.010. eCollection 2017 Jun.
Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis.
Pancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on β-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors.
We found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of β-cells.
Together, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of the components of this pathway during development could be a cause of pancreatic agenesis/hypoplasia and hyperglycemia.
胎儿营养不足会减少胚胎β细胞的生长和功能，从而增加后代患 2 型糖尿病的风险。然而，目前尚不完全清楚胎儿营养物质和生长因子如何在发育过程中影响β细胞，从而改变生命后期的葡萄糖稳态和代谢。本研究旨在探讨胎儿营养物质和生长因子对内分泌发育的影响，以及这些信号如何通过 mTOR 信号调节β细胞质量和葡萄糖稳态。
采用体外培养的胰腺原基研究葡萄糖、生长因子和氨基酸对β细胞发育的作用。在有无雷帕霉素的情况下，评估胰腺和内分泌前体细胞的数量和增殖情况。在 Pdx1 表达的胰腺祖细胞中缺乏 mTOR 或 Raptor 的模型中，评估 mTOR 信号对胰腺发育和葡萄糖稳态的影响。
我们发现，氨基酸浓度，特别是亮氨酸，可增加胰腺和内分泌前体细胞的数量，并对生长因子诱导的增殖至关重要。mTORC1 复合物抑制剂雷帕霉素可减少胰腺和内分泌前体细胞的数量和增殖。胰腺祖细胞中缺乏 mTOR 的小鼠在新生儿期出现高血糖，胰岛素减少，胰腺发育不全/发育不良，胰腺原基含有导管结构，缺乏分化的腺泡和内分泌细胞。此外，胰腺祖细胞中 Raptor 的缺失（即 mTORC1 的缺失）可减少β细胞数量，导致胰腺体积减小。
综上所述，这些结果表明，氨基酸浓度，特别是亮氨酸可调节胰腺和内分泌前体细胞的生长反应，而 mTOR 信号对这些反应至关重要。在胰腺祖细胞中失活 mTOR 和 Raptor 表明，发育过程中该途径的某些成分的改变可能是胰腺发育不全/发育不良和高血糖的原因。
