Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic β-cells: A potential beneficial effect in the pre-diabetic state?

被引：51

作者：

Pournourmohammadi, Shirin ^{[1
,2
]}

Grimaldi, Mariagrazia ^{[1
,2
]}

Stridh, Malin H. ^{[3
]}

Lavallard, Vanessa ^{[2
,4
]}

Waagepetersen, Helle S. ^{[3
]}

Wollheim, Claes B. ^{[1
,2
]}

Maechler, Pierre ^{[1
,2
]}

机构：

[1] Univ Geneva, Med Ctr, Dept Cell Physiol & Metab, 1 Rue Michel Servet, CH-1206 Geneva 4, Switzerland

[2] Univ Geneva, Med Ctr, Fac Diabet Ctr, 1 Rue Michel Servet, CH-1206 Geneva, Switzerland

[3] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacotherapy, 2 Univ Pk, DK-2100 Copenhagen, Denmark

[4] Geneva Univ Hosp, Cell Isolat & Transplantat Ctr, Dept Surg, Geneva, Switzerland

来源：

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY | 2017年 / 88卷

基金：

瑞士国家科学基金会;

关键词：

Glutamate dehydrogenase; Green tea; EGCG; Insulin secretion; AMPK; Beta-cell; Pancreatic islet; Muscle cells; DIET-INDUCED OBESITY; INSULIN-SECRETION; WEIGHT-LOSS; GREEN TEA; METABOLIC SYNDROME; POLYPHENOLS; RESISTANCE; FAILURE; PATHWAY; ISLETS;

D O I：

10.1016/j.biocel.2017.01.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Glucose homeostasis is determined by insulin secretion from the beta-cells in pancreatic islets and by glucose uptake in skeletal muscle and other insulin target tissues. While glutamate dehydrogenase (GDH) senses mitochondrial energy supply and regulates insulin secretion, its role in the muscle has not been elucidated. Here we investigated the possible interplay between GDH and the cytosolic energy sensing enzyme 5'-AMP kinase (AMPK), in both isolated islets and myotubes from mice and humans. The green tea polyphenol epigallocatechin-3-gallate (EGCG) was used to inhibit GDH. Insulin secretion was reduced by EGCG upon glucose stimulation and blocked in response to glutamine combined with the allosteric GDH activator BCH (2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid). Insulin secretion was similarly decreased in islets of mice with beta-cell-targeted deletion of GDH (beta Gludl(-/-)). EGCG did not further reduce insulin secretion in the mutant islets, validating its specificity. In human islets, EGCG attenuated both basal and nutrient-stimulated insulin secretion. Glutamine/BCH-induced lowering of AMPK phosphorylation did not operate in beta Glud1(-/-) islets and was similarly prevented by EGCG in control islets, while high glucose systematically inactivated AMPK. In mouse C2C12 myotubes, like in islets, the inhibition of AMPK following GDH activation with glutamine/BCH was reversed by EGCG. Stimulation of GDH in primary human myotubes caused lowering of insulin-induced 2-deoxy-glucose uptake, partially counteracted by EGCG. Thus, mitochondrial energy provision through anaplerotic input via GDH influences the activity of the cytosolic energy sensor AMPK. EGCG may be useful in obesity by resensitizing insulin-resistant muscle while blunting hypersecretion of insulin in hypermetabolic states. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：220 / 225

页数：6

共 36 条

[1] Green Tea Supplementation Affects Body Weight, Lipids, and Lipid Peroxidation in Obese Subjects with Metabolic Syndrome [J].