Glutamine-Elicited Secretion of Glucagon-Like Peptide 1 Is Governed by an Activated Glutamate Dehydrogenase
Glutamine-Elicited Secretion of Glucagon-Like Peptide 1 Is Governed by an Activated Glutamate Dehydrogenase
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DOI：
10.2337/db16-1441
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发表时间：
2018-03-01
期刊：
影响因子：
7.7
通讯作者：
Spegel, Peter
中科院分区：
文献类型：
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作者：
Andersson, Lotta E.;Shcherbina, Liliya;Spegel, Peter
胰高血糖素样肽1（GLP-1），由肠L细胞分泌，葡萄糖依赖性地刺激β细胞的胰岛素分泌。这种葡萄糖依赖性可预防低血糖，使GLP-1类似物成为2型糖尿病中有用且安全的治疗方式。虽然氨基酸谷氨酰胺是GLP-1分泌的有效激发子，但其负责机制仍不清楚。我们以胰岛素分泌细胞系INS-1 832/13为参照，研究了GLP-1分泌在L细胞（GLUTag）和小鼠体内的代谢偶联。膜渗透性谷氨酸类似物（二甲基谷氨酸[DMG]），作用于产电转运蛋白的下游，在两种细胞系中引起与谷氨酰胺类似的代谢改变。DMG和谷氨酰胺单独在GLUTag细胞和体内均引起GLP-1分泌，而谷氨酸脱氢酶（GDH）的激活需要刺激INS-1 832/13细胞的胰岛素分泌。GDH的体内药理学抑制阻断了响应DMG的GLP-1的分泌。总之，我们的研究结果表明，非产电营养吸收和代谢在L细胞刺激分泌耦合中起着重要作用。L细胞中GDH对谷氨酰胺和相关类似物的代谢可能解释了为什么GLP-1分泌而不是胰岛素分泌在体内被这些促分泌素激活。
Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from beta-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.