Effect of GLP-1 on glucose transport and its cell signalling in human myocytes

González, Nieves; Acitores, Alicia; Sancho, Verónica; Valverde, Isabel; Villanueva-Peñacarrillo, María Luisa

doi:10.1016/j.regpep.2004.10.002

Cited by 78 publications

(67 citation statements)

References 50 publications

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“…Similar observations were made in studies of L6 myotubes, and there was evidence that the effects were transmitted via receptors distinct from the classical GLP-1 receptor (336). Most recently, GLP-1 was again reported to enhance glucose uptake in human myocytes, and evidence for the involved signaling pathways was provided (80). It should be mentioned that other studies failed to identify actions of GLP-1 on glucose metabolism in muscle tissue (72).…”

Section: Whole Body Effects Peripheral Effects and Effects On Insupporting

confidence: 65%

“…Thus exendin 4, but not GLP-1, was reported to enhance insulin sensitivity in 3T3 adipocytes (137). The two peptides were also reported to activate different signaling pathways in human myotubes (80). Again, it should be noted that these in vitro studies are in sharp contrast to the in vivo studies, particularly in humans, as discussed above.…”

Section: Whole Body Effects Peripheral Effects and Effects On Inmentioning

confidence: 96%

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The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,709

2,385

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Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

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Section: Whole Body Effects Peripheral Effects and Effects On Insupporting

confidence: 65%

Section: Whole Body Effects Peripheral Effects and Effects On Inmentioning

confidence: 96%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,709

2,385

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“…Ex-9, an antagonist of GLP-1 receptors in certain cell systems and also of some of the effects of GLP-1 and Ex-4 (7), although also augmenting the activity of the same kinases as those augmented by Ex-4, except that of PKB, failed to modify the glucose transport basal value in normal rat skeletal muscle. This last is at variance with its characteristics in human muscle, tissue and cells, in which, perhaps due to species differences, Ex-9 shows GLP-1-like actions upon parameters involved in glucose metabolism (6,8,15,16).…”

Section: Discussionmentioning

confidence: 96%

“…Ex-4, like GLP-1, is insulinotropic (4), and has GLP-1-and insulin-like effects on parameters related to glucose or lipid metabolism in extrapancreatic tissues. Ex-4 increases glucose transport in rat adipocytes (5) and human myocytes (6), and glycogen synthase a activity in rat liver and rat and human muscle (7,8), and stimulates lipogenesis and lipolysis in rat fat tissue (5). The reported extrapancreatic effects of Ex-4 seem to be dependent on certain kinases, some of which also participate in GLP-1 action (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…The Ex-4 truncated form, exendin(9-39)amide (Ex-9), is an antagonist of GLP-1 receptor in several cell systems (3,13) and of its insulinotropic effects in rat pancreas (14), and of GLP-1 action upon glucose metabolism in rat liver cells and muscle tissue (7); however, in adipocyte (15) and myocyte (16) cell lines, and in normal human muscle (6,8), Ex-9 acts as an agonist of GLP-1 action.…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of GLP-1 and exendins action upon glucose transport and metabolism in type 2 diabetic rat skeletal muscle

Arnés

González²,

Tornero-Esteban³

et al. 2008

Int J Mol Med

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Abstract. Exendin-4, a peptide 53% structurally homologous with glucagon-like peptide 1 (GLP-1), is insulinotropic and has an antidiabetic effect even more prolonged than that of GLP-1. Exendin-9 is an antagonist of GLP-1 receptor and action in several cell systems, but shows GLP-1-and exendin-4-agonistic characteristics in human muscle cells and tissue. The action of GLP-1 upon glucose transport and metabolism in muscle is mediated by specific receptors. In this study we investigated the effect of both exendin-4 and -9, relative to that of GLP-1, upon glucose transport and metabolism in the skeletal muscle from a streptozotocin-induced type 2 diabetic rat model, compared to normal. In normal rats, exendin-4, like GLP-1 and insulin, enhanced glucose uptake. This effect, which is mediated to a certain extent by some kinases (PI3K/ PKB, p70s6k and MAPKs), may be caused by the peptide acting, at least in part, through the muscle GLP-1 receptors. Exendin-9 also stimulated the same kinases, except for PKB, but failed to modify basal glucose uptake. Type 2 diabetic rats showed lower than normal basal muscle glucose transport and oxidation value, and higher glycogen synthase a activity and pyruvate release; however, no modification of glucose uptake by GLP-1 or exendin-4 was detected, at variance with insulin, and basal activity of PI3K/PKB was lower than normal, while that of p70s6k and MAPKs was higher. GLP-1 failed to affect the activity of any of the kinases, while exendin-4 increased the activity of PI3K, p70s6k and MAPKs, but not PKB, suggesting that this enzyme plays a major role in exendin-4 effect upon glucose transport in muscle.

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Gut Peptide Agonism in the Treatment of Obesity and Diabetes

Grandl

Novikoff

DiMarchi

et al. 2019

Comprehensive Physiology

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Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism.

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Effect of GLP-1 on glucose transport and its cell signalling in human myocytes

Cited by 78 publications

References 50 publications

The Physiology of Glucagon-like Peptide 1

The Physiology of Glucagon-like Peptide 1

Characteristics of GLP-1 and exendins action upon glucose transport and metabolism in type 2 diabetic rat skeletal muscle

Gut Peptide Agonism in the Treatment of Obesity and Diabetes

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