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Eun Young Lee, Shuji Kaneko, Promsuk Jutabha, Xilin Zhang, Susumu Seino, Takahito Jomori, Naohiko Anzai and Takashi Miki

Introduction Oral ingestion of nutrients triggers the secretion of gut hormones from various enteroendocrine cells ( Ezcurra et al . 2013 , Cho et al . 2014 ). Among these, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic

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Berit Svendsen, Ramona Pais, Maja S Engelstoft, Nikolay B Milev, Paul Richards, Charlotte B Christiansen, Kristoffer L Egerod, Signe M Jensen, Abdella M Habib, Fiona M Gribble, Thue W Schwartz, Frank Reimann and Jens J Holst

Introduction The incretin hormones, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) strongly potentiate postprandial insulin secretion and are therefore important regulators of glucose homeostasis. They are

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Paul Millar, Nupur Pathak, Vadivel Parthsarathy, Anthony J Bjourson, Maurice O’Kane, Varun Pathak, R Charlotte Moffett, Peter R Flatt and Victor A Gault

surge in the number of new drug classes such as glucagon-like peptide-1 (GLP-1) agonists, dipeptidylpeptidase-4 (DPP4) inhibitors and sodium glucose cotransporter-2 (SGLT2) inhibitors ( Bailey et al . 2016 ). Although these agents may be used as

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Yingxin Xian, Zonglan Chen, Hongrong Deng, Mengyin Cai, Hua Liang, Wen Xu, Jianping Weng and Fen Xu

visceral omental fat in subjects with obesity exhibit severely impaired endothelium-dependent vasodilation ( Farb et al. 2012 ). Clinical studies demonstrated that exenatide, a glucagon-like peptide 1 (GLP-1) receptor agonist, improved glycemic control

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Rebecca McGirr, Leonardo Guizzetti and Savita Dhanvantari

al . 1994 , Furuta et al . 2001 ). By contrast, proglucagon is processed to glucagon-like peptide (GLP)-1 and GLP-2 in the intestine and brain by PC1/3 ( Dhanvantari et al . 1996 , Dhanvantari & Brubaker 1998 , Damholt et al . 1999 ). Glucagon

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J C Parker, K S Lavery, N Irwin, B D Green, B Greer, P Harriott, F P M O’Harte, V A Gault and P R Flatt

Introduction Glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important gastrointestinal-releasing hormones involved in the regulation of postprandial nutrient homeostasis ( Meier et al

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G Üçkaya, P Delagrange, A Chavanieu, G Grassy, M-F Berthault, A Ktorza, E Cerasi, G Leibowitz and N Kaiser

that aim to improve β-cell function and survival. Glucagon-like peptide 1 (GLP-1) is a potent incretin hormone secreted by the intestinal L cells in response to food intake ( Drucker 2001 ). GLP-1 exerts multiple effects on pancreatic β

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MA Luque, N Gonzalez, L Marquez, A Acitores, A Redondo, M Morales, I Valverde and ML Villanueva-Penacarrillo

Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not - at least in liver and muscle - cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10(-13) mol/l, a dose-related increase of the D-[U-(14)C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10(-11) mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.

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Weijuan Shao, Wenjuan Liu, Ping Liang, Zhuolun Song, Odisho Israel, Gerald J Prud'homme, Qinghua Wang and Tianru Jin

Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ) induced diabetes in rodent models with unclear underlying mechanisms. We found that GABA and Sitagliptin possess additive effect on pancreatic β-cells, prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic β-cells. Effect of GABA on expression of thioredoxin-interacting protein (TxNIP) was assessed in the INS-1 832/13 (INS-1) cell line, wild type (WT) and GLP-1R-/- mouse islets. GABA was also orally administrated in STZ-challenged WT or GLP-1R-/- mice, followed by immunohistochemistry assessment of pancreatic islets. Effect of GABA on Wnt pathway effector β-catenin (β-cat) was examined in INS-1 cells, WT and GLP-1R-/- islets. We found that GABA shares a common feature with GLP-1 on inhibiting TxNIP, while this function was attenuated in GLP-1R-/- islets. In WT mice with STZ challenge, GABA alleviated several ‘diabetic syndromes’, associated with increased β-cell mass. These features were virtually absent in GLP-1R-/- mice. Knockdown TxNIP in INS-1 cells increased GLP-1R, Pdx1, Nkx6.1 and Mafa levels, associated with increased responses to GABA or GLP-1 on stimulating insulin secretion. Cleaved caspase-3 level can be induced by high-glucose, dexamethasone, or STZ in INS-1 cell, while GABA treatment blocked the induction. Finally, GABA treatment increased cellular cAMP level and β-cat S675 phosphorylation in WT but not GLP-1R-/- islets. We hence identified TxNIP as a common target of GABA and GLP-1, and suggest that upon STZ or other stress challenge, the GLP-1R-cAMP-β-cat signaling cascade also mediates beneficial effects of GABA in pancreatic β-cell, involving TxNIP reduction.

Open access

Alyce M Martin, Emily W Sun and Damien J Keating

-like peptide 1 (GLP-1), peptide YY (PYY) and oxyntomodulin (OXM), and glucose-dependent insulinotropic peptide (GIP) secreting K cells. It is now clear that such a classification system is not accurate given the accumulation of evidence that cross-over in