Inositolphosphoglycans and diacylglycerol are possible mediators in the glycogenic effect of GLP‐1(7‐36)amide in BC3H‐1 myocytes

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

doi:10.1002/cbf.639

Cited by 27 publications

(8 citation statements)

References 40 publications

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“…In these tissues, GLP-1 does not stimulate cAMP but induces the rapid hydrolysis of GPIs (Márquez et al, 1998;Luque et al, 2002) related to a short-lived generation of IPGs , a well characterized signaling pathway in the action of different hormones (Jarett and Seals, 1979;Larner et al, 1979;Suzuki et al, 1984a,b;Larner, 1988). In the present study, GLP-1 has shown to promote the immediate hydrolysis of GPIs in osteoblastic MC3T3-E1 cellsmaximal between 1 and 2 min-and its subsequent re-synthesis thereafter, following the same pattern than that previously shown in other extrapancreatic tissues and cells (Galera et al, 1996;Márquez et al, 1998;Luque et al, 2002). These data suggest that IPGs could be acting as second messengers of the GLP-1 receptor in osteoblastic cells.…”

Section: Discussionsupporting

confidence: 87%

Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

Nuche-Berenguer

Portal‐Núñez

Moreno

et al. 2010

Journal Cellular Physiology

127

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Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [(125)I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25 degrees C; in these conditions, [(125)I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10(-6) M GLP-1. GLP-1, Ex-9, insulin or glucagon failed to modify cellular cAMP content, while GLP-2 and Ex-4 increased it. However, GLP-1 induced an immediate hydrolysis of glycosylphosphatidylinositols (GPIs) generating short-lived inositolphosphoglycans (IPGs), and an increase in phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) activities; Ex-4 also affected GPIs, but its action was delayed with respect to that of GLP-1. This incretin was found to decrease Runx2 but increased osteocalcin gene expression, without affecting that of osteoprotegerin or the canonical Wnt pathway activity in MC3T3-E1 cells which do not express the pancreatic GLP-1 receptor. Our data demonstrate for the first time that GLP-1 can directly and functionally interact with osteoblastic cells, possibly through a GPI/IPG-coupled receptor.

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Section: Discussionsupporting

confidence: 87%

Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

Nuche-Berenguer

Portal‐Núñez

Moreno

et al. 2010

Journal Cellular Physiology

127

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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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“…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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Inositolphosphoglycans and diacylglycerol are possible mediators in the glycogenic effect of GLP‐1(7‐36)amide in BC3H‐1 myocytes

Cited by 27 publications

References 40 publications

Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

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

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