Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes.
Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes.
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DOI：
10.1007/s00125-014-3269-x
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发表时间：
2014-08
期刊：
影响因子：
8.2
通讯作者：
Ashford, Michael L. J.
中科院分区：
文献类型：
--
作者：
Hamilton, D. Lee;Findlay, John A.;Montagut, Gemma;Meakin, Paul J.;Bestow, Dawn;Jalicy, Susan M.;Ashford, Michael L. J.
骨骼肌葡萄糖摄取受损是2型糖尿病葡萄糖耐受不良的重要原因。天冬氨酸蛋白酶β位点APP裂解酶1（BACE 1）是淀粉样前体蛋白（APP）加工的关键调节因子，可调节小鼠体内葡萄糖处理和胰岛素敏感性。刺激葡萄糖摄取和GLUT 4易位的胰岛素非依赖性途径可能为糖尿病的治疗提供替代治疗途径。因此，我们讨论了BACE 1活性是否通过APP加工在骨骼肌中独立于胰岛素改变葡萄糖摄取和氧化。以骨骼肌细胞为研究对象，研究BACE 1和α-分泌酶抑制以及BACE 1和APP过表达对骨骼肌细胞葡萄糖摄取、GLUT 4细胞表面转位、葡萄糖氧化和细胞呼吸的影响。在没有胰岛素的情况下，BACE 1活性的降低增加了葡萄糖的摄取和氧化，GLUT 4 myc细胞表面易位和基础耗氧率。相反，在C2 C12肌管中过表达BACE 1降低葡萄糖摄取、葡萄糖氧化和氧消耗速率。APP过表达增加C2 C12肌管的葡萄糖摄取，α-分泌酶抑制降低C2 C12肌管葡萄糖摄取。BACE 1抑制引起的葡萄糖摄取增加依赖于磷酸肌醇3-激酶（PI 3 K），并由可溶性APPα（sAPPα）模拟。抑制肌肉BACE 1活性可增加胰岛素非依赖性、PI 3 K依赖性葡萄糖摄取和GLUT 4的细胞表面易位。由于APP过度表达增加了基础葡萄糖摄取，并且直接应用sAPPα增加了肌管中的PI 3 K-蛋白激酶B信号传导和葡萄糖摄取，因此我们认为sAPPα的α-分泌酶依赖性脱落调节了骨骼肌中胰岛素非依赖性葡萄糖摄取。
Impaired glucose uptake in skeletal muscle is an important contributor to glucose intolerance in type 2 diabetes. The aspartate protease, beta-site APP-cleaving enzyme 1 (BACE1), a critical regulator of amyloid precursor protein (APP) processing, modulates in vivo glucose disposal and insulin sensitivity in mice. Insulin-independent pathways to stimulate glucose uptake and GLUT4 translocation may offer alternative therapeutic avenues for the treatment of diabetes. We therefore addressed whether BACE1 activity, via APP processing, in skeletal muscle modifies glucose uptake and oxidation independently of insulin. Skeletal muscle cell lines were used to investigate the effects of BACE1 and α-secretase inhibition and BACE1 and APP overexpression on glucose uptake, GLUT4 cell surface translocation, glucose oxidation and cellular respiration. In the absence of insulin, reduction of BACE1 activity increased glucose uptake and oxidation, GLUT4myc cell surface translocation, and basal rate of oxygen consumption. In contrast, overexpressing BACE1 in C2C12 myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C2C12 myotubes. The increase in glucose uptake elicited by BACE1 inhibition is dependent on phosphoinositide 3-kinase (PI3K) and mimicked by soluble APPα (sAPPα). Inhibition of muscle BACE1 activity increases insulin-independent, PI3K-dependent glucose uptake and cell surface translocation of GLUT4. As APP overexpression raises basal glucose uptake, and direct application of sAPPα increases PI3K–protein kinase B signalling and glucose uptake in myotubes, we suggest that α-secretase-dependent shedding of sAPPα regulates insulin-independent glucose uptake in skeletal muscle.
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DOI：
10.1042/bj20110512
发表时间：
2012-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Meakin PJ;Harper AJ;Hamilton DL;Gallagher J;McNeilly AD;Burgess LA;Vaanholt LM;Bannon KA;Latcham J;Hussain I;Speakman JR;Howlett DR;Ashford ML
通讯作者：
Ashford ML
影响因子：
--
作者：
Abdul-Ghani MA;DeFronzo RA
通讯作者：
DeFronzo RA
影响因子：
158.5
作者：
Cline, GW;Petersen, KF;Shulman, GI
通讯作者：
Shulman, GI
影响因子：
7.7
作者：
Kelley, DE;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
7.7
作者：
PEDERSEN, O;BAK, JF;KAHN, BB
通讯作者：
KAHN, BB