Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass
Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass
复制标题
DOI：
10.1016/j.celrep.2015.06.034
复制
发表时间：
2015-07-21
期刊：
影响因子：
8.8
通讯作者：
Allan, Bernard B.
中科院分区：
文献类型：
--
作者：
Solloway, Mark J.;Madjidi, Azadeh;Allan, Bernard B.
了解胰岛细胞质量的调节对于发现糖尿病的再生疗法具有重要意义。肝脏在代谢和内分泌细胞数量的调节中起着核心作用，但调节α细胞和β细胞质量的肝源性因子仍未确定。我们提出了一个肝脏和胰腺之间的营养感应电路，其中胰高血糖素依赖性控制肝脏氨基酸代谢调节α细胞质量。我们发现，胰高血糖素受体抑制剂可降低肝脏氨基酸催化剂，增加血清氨基酸，并以mTOR依赖性方式诱导α细胞增殖。此外，mTOR抑制阻断了氨基酸依赖性α细胞的离体复制，并使α细胞在体内转化为β样细胞。新生小鼠血清氨基酸和α细胞增殖增加，但在整个出生后发育中以胰高血糖素依赖性方式下降。这些数据表明，氨基酸作为胰高血糖素信号传导的传感器，可以作为增加α细胞增殖的生长因子发挥作用。
Understanding the regulation of islet cell mass has important implications for the discovery of regenerative therapies for diabetes. The liver plays a central role in metabolism and the regulation of endocrine cell number, but liver-derived factors that regulate alpha-cell and beta-cell mass remain unidentified. We propose a nutrient-sensing circuit between liver and pancreas in which glucagon-dependent control of hepatic amino acid metabolism regulates alpha-cell mass. We found that glucagon receptor inhibition reduced hepatic amino acid catabolism, increased serum amino acids, and induced alpha-cell proliferation in an mTOR-dependent manner. In addition, mTOR inhibition blocked amino-acid-dependent alpha-cell replication ex vivo and enabled conversion of alpha-cells into beta-like cells in vivo. Serum amino acids and alpha-cell proliferation were increased in neonatal mice but fell throughout postnatal development in a glucagon-dependent manner. These data reveal that amino acids act as sensors of glucagon signaling and can function as growth factors that increase alpha-cell proliferation.