Glucagon-like peptide-1 binding to rat hepatic membranes

Villanueva-Peñacarrillo, María Luisa; Delgado, Elena; Trapote, M. A.; Alcántara, Ana; Clemente, Felipe; Luque, Miguel Angel Limón; Perea, A.; Valverde, Isabel

doi:10.1677/joe.0.1460183

Cited by 73 publications

(46 citation statements)

References 28 publications

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“…The liver has repeatedly been reported to be a target for GLP-1, although initial careful studies indicated that hepatocytes did not express GLP-1 receptor (17). Thus GLP-1 has been reported to bind to rat hepatic membranes but without influencing adenylate cyclase activity, as expected from the classical GLP-1 receptor (308). Rather, inositol phosphoglycans were thought to act as mediators (291).…”

Section: Whole Body Effects Peripheral Effects and Effects On Inmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,703

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 Inmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,703

2,385

View full text Add to dashboard Cite

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“…However, it is known that GLP-1 specifically binds to the plasma membranes of major extrapancreatic tissues participating in glucose homeostasis and lipid metabolism, indicating the presence of receptors which, in liver and muscle at least, seem to be structurally or functionally different (8)(9)(10)(11) from that in the pancreas (12).…”

Section: Introductionmentioning

confidence: 99%

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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“…[Diabetologia (2002[Diabetologia ( ) 45:1410[Diabetologia ( -1415 Keywords GLP-1, exendin-4, insulin action, glucose production, cortisol secretion. [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16].…”

Section: Introductionmentioning

confidence: 99%

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

et al. 2003

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Aims/hypothesis. The aim of this study was to determine whether rapid conversion to inactive and potentially antagonistic peptides could alter the response to GLP-1. Methods. We evaluated the ability of exendin-4, a GLP-1 analogue resistant to degradation by dipeptidyl peptidase IV, to modulate insulin-induced stimulation of glucose uptake and suppression of glucose production in eight healthy subjects during infusion of GLP-1 (1.2 pmol·kg -1 ·min -1 ), exendin-4 (0.12 pmol·kg -1 · min -1 ), or saline. Glucose was clamped at 5.3 mmol/l and insulin was infused to progressively increase insulin concentrations to about 65, 190 and 700 pmol/l, respectively. Endogenous insulin secretion was inhibited with somatostatin to ensure comparable portal insulin concentrations while glucagon and growth hormone were maintained at basal concentrations. Results. Glucose, insulin, C-peptide, glucagon and growth hormone concentrations did not differ on the three occasions. In contrast, cortisol concentrations were greater during both exendin-4 (25.1±4.4 mmol/l per 7 h; p<0.01) and GLP-1, (17.0±2.0 mmol/l 7 h; p<0.05) than saline (13.5±1.5 mmol/l per 7 h). While insulin-induced stimulation of glucose disappearance at the highest insulin concentrations tended to be greater and insulin-induced suppression of glucose production lower in the presence of exendin-4 or GLP-1 than saline, the differences were not significant. Conclusion/interpretation. Exendin-4 and GLP-1 increase cortisol secretion in human subjects. However, neither alters insulin action in non-diabetic human subjects. These data also suggest that the lack of an effect of GLP-1 on insulin action is not likely to be explained by rapid degradation to inactive or antagonistic peptides. [Diabetologia (2002[Diabetologia ( ) 45:1410[Diabetologia ( -1415 Keywords GLP-1, exendin-4, insulin action, glucose production, cortisol secretion. [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16]. In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus. GLP-1 (7-36) increases insulin secretion, decreases glucagon secretion and delays gastric emptying [1,2,3,4,5,6,7]. In vitro data suggest it might also enhance insulin action. Although controversial, GLP-1 receptors, to which Exendin-4

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Glucagon-like peptide-1 binding to rat hepatic membranes

Cited by 73 publications

References 28 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

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

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