Inositolphosphoglycans are possible mediators of the glucagon-like peptide 1 (7–36)amide action in the liver

Trapote, M. A.; Clemente, Felipe; Galera, C.; Morales, Mónica; Alcántara, Ana; López‐Delgado, M. I.; Villanueva-Peñacarrillo, María Luisa; Valverde, Isabel

doi:10.1007/bf03349846

Cited by 28 publications

(10 citation statements)

References 29 publications

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“…However, several studies have shown that in the liver and skeletal muscle, GLP-1 seems to act through specific receptors, different in structure and signaling pathways from those in the pancreas, which are cAMP associated. Second messengers such as inositol phosphoglycan or phosphatidylinositol 3-phosphate have been proposed (18,23,28,40). In a more recent study (1), activation of phosphatidylinositol 3Ј-kinase, protein kinase B, and mitogen-activated protein kinases has been shown to be involved in the action of GLP-1 upon glycogen synthase a activity in rat skeletal muscle.…”

Section: Discussionmentioning

confidence: 97%

Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors

Dardevet¹,

Moore²,

DiCostanzo³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally, the PePo group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group (n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 ( approximately 50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 +/- 1.3 and 10.6 +/- 1.0 vs. 5.7 +/- 1.0 and 5.4 +/- 0.8 micromol.kg(-1).min(-1), respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.

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Section: Discussionmentioning

confidence: 97%

Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors

Dardevet¹,

Moore²,

DiCostanzo³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Further, two groups have reported that GLP-1 has insulin-like activity and stimulates glycogen formation (59) and inhibits glycogenolysis (27) in isolated hepatocytes. These investigators suggest that GLP-1 action in the liver is mediated by receptors that are different in structure and signaling pathways (20,26,27,32,38,56,59). It is also possible that Ex-4 is mediating its actions in the IUGR neonate through GLP-1 receptors in the portal vein, as a number of investigators have shown that Ex-4 can reduce glucose, independent of islet hormones or gastric emptying (3,4,9,28,38,39,41,57).…”

Section: Discussionmentioning

confidence: 99%

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Raab

Vuguin

Stoffers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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(IUGR) has been linked to the development of Type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagonlike-peptide-1 agonist, Exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of Exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given Exendin-4 on days 1-6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to Exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance. intrauterine growth retardation; diabetes; liver; insulin resistance UTEROPLACENTAL INSUFFICIENCY limits availability of substrates to the fetus and retards growth during gestation (40, 47). We have previously shown in a rat model of uteroplacental insufficiency and intrauterine growth retardation (IUGR) that this abnormal metabolic intrauterine milieu affects the development of the fetus by inducing mitochondrial dysfunction and oxidative stress which, in turn, modifies gene expression and function of susceptible cells in the pancreas, muscle, and liver (43,46,48). The end result is the later development of diabetes in adulthood with the salient features of most forms of Type 2 diabetes (T2DM) in the human: defects in insulin action and insulin secretion (49). IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin (62). Basal HGP is also mildly elevated in IUGR rats (62). These defects in hepatic glucose metabolism are secondary to oxidative stress, which impairs insulin signaling (43,62).We have also demonstrated that short-term administration of the long-acting incretin hormone glucagon-like peptide-1 (GLP-1) receptor agonist, Exendin-4 (Ex-4), during the neonatal period, improves glucose tolerance, prevents the progressive reduction in ␤-cell mass tha...

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“…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). The same group also described activation of phosphatidylinositol 3-kinase/protein kinase B, protein kinase C, and protein phosphatase-1 pathways to transmit the actions on glycogen synthase in rat hepatocytes (250).…”

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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Inositolphosphoglycans are possible mediators of the glucagon-like peptide 1 (7–36)amide action in the liver

Cited by 28 publications

References 29 publications

Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors

Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

The Physiology of Glucagon-like Peptide 1

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