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Departamento de Ciências Fisiológicas, Laboratório de Fisiologia Endócrina, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
Instituto de Ciências da Saúde, Universidade Federal de Mato Grosso, Sinop, Brazil
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Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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reestablishment (120 days old). The upper panel of each figure represents the area under the curve (AUC). * P < 0.05, ** P < 0.01, *** P < 0.001 by Student’s t test. Glucose and/or acetylcholine insulinotropic response Increasing
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glucocorticoids ( Lacroix et al . 2001 , 2004 ). GPCRs constitute a large and diverse family of proteins, whose primary function is to transduce extracellular stimuli into intracellular signals ( Kroeze et al . 2003 ). The glucose-dependent insulinotropic
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-dependent insulinotropic peptide and that alterations in endogenous nesfatin-1 in the pancreatic islets could contribute to diabetes and DIO. Materials and Methods Animals Age- and weight-matched male C57BL/6 mice were purchased from Charles River Canada (St
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Gastrointestinal peptides, including insulin, glucagon and glucose-dependent insulinotropic polypeptide (GIP) have previously been reported in salivary glands. Recent evidence has suggested they might influence postprandial macronutrient metabolism. This study therefore investigated and compared postprandial hormone concentrations in saliva and plasma to determine whether their secretion was influenced by oral food stimuli. In a within-subject randomised cross-over comparison of hormone concentrations in plasma and saliva following a mixed meal, 12 subjects were given two 1708 kJ mixed meals. On one occasion the meal was chewed and swallowed (swallowed meal), on the other it was chewed and expectorated (sham-fed meal). Salivary and plasma levels of immunoreactive insulin, GIP and glucagon-like peptide-1 (GLP-1), total protein, alpha-amylase, glucose and non-esterified fatty acid were measured before and for 90 min following the meals. Saliva total protein and alpha-amylase rose following both meals, indicating that the stimulus for salivary protein release is related to the presence of food in the mouth. GLP-1 was not detected in saliva. Fasting salivary insulin levels were lower in saliva than plasma (28+/-6 vs 40+/-25 pmol/l respectively). Both increased following the swallowed meal but the rise in saliva was slower and less marked than in plasma (peak levels 96+/-18 and 270+/-66 pmol/l for saliva and plasma respectively, P<0.01). Both were unchanged following the sham-fed meal. GIP was detected in saliva. Fasting GIP levels were significantly higher in saliva than plasma (183+/-23 compared with 20+/-7 pmol/l, P<0.01). They decreased in saliva following both swallowed and sham-fed meals to nadirs of 117+/-17 and 71+/-12 pmol/l respectively, but rose following the swallowed meal to peak levels of 268+/-66 pmol/l. These findings are consistent with insulin in saliva being an ultrafiltrate of that circulating in blood, but GIP in saliva being the product of local salivary gland synthesis, whose secretion is influenced, directly or indirectly, by oral stimuli. The function of salivary GIP is unknown, but we speculate that it may play a role in the regulation of gastric acid secretion in the fasting state.
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host defence peptides isolated from frog skin secretions were insulinotropic in vitro and could improve glucose tolerance in animal models in vivo ( Conlon et al. 2014 ). Esculentin-2CHa (GFSSIFRGVAKFASKGLGKDLAKLGVDLVACKISKQC), isolated from
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Glucose-dependent insulinotropic polypeptide (GIP) acts as a glucose-dependent growth factor for beta-cells. Here we show that GIP and glucose also act synergistically as anti-apoptotic factors for beta-cells, using the well-differentiated beta-cell line, INS-1. Mitogenic and anti-apoptotic signaling of GIP were dependent upon pleiotropic activation of protein kinase A (PKA)/cAMP regulatory element binder (CREB), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase)/PKB signaling modules. The signaling modules activated by GIP were dependent on glucose metabolism and calcium influx and were tightly linked by multiple activating and inhibiting cross-talk. These interactions included: (i) a central role of tyrosine phosphorylation for stimulation of PKA/CREB, MAPK and PI3-kinase/PKB, (ii) inhibition of PKA/CREB by the MAPK pathway at the level of MAPK kinase-1 or downstream, (iii) activation of MAPK signaling by PI3-kinase and PKA at the level of extracellular-signal regulated kinase 1/2 or upstream, and (iv) activation of PKB by MAPK and PKA signaling at the level of PKB or upstream. Furthermore, we demonstrated inhibition of CREB signaling by Ca(2+)/calmodulin kinase I/IV. These results indicated that GIP acts as a mitogenic and anti-apoptotic factor for beta-cells by pleiotropic activation of tightly linked signaling pathways in beta-cells.
Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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Instituto de Investigación Sanitaria Galicia Sur – IISGS, Vigo, Spain
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effects of Ex-4 suggest that its influence in regulating the HPA axis may be as relevant as its insulinotropic activity. Interestingly, the effects of Ex-4 on the activity of the HPA axis appear to be independent of the animal’s metabolic status, and
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Abstract
To examine the structure–activity relationships in the insulinotropic activity of glucagon-like peptide-1(7–36) amide (GLP-1(7–36)amide), we synthesized 16 analogues, including eight which were designed by amino acid substitutions at positions 10 (Ala10), 15 (Serl5), 16 (Tyr16), 17 (Arg17), 18 (Lys18), 21 (Gly21), 27 (Lys27) and 31 (Asp31) of GLP-1(7–36)amide with an amino acid of GH-releasing factor possessing only slight insulinotropic activity, and three tentative antagonists including [Glu15]-GLP-1(8–36)amide. Their insulinotropic activities were assessed by rat pancreas perfusion experiments, and binding affinity to GLP-1 receptors and stimulation of cyclic AMP (cAMP) production were evaluated using cultured RINm5F cells.
Insulinotropic activity was estimated as GLP-1(7–36)amide = Tyr16>Lys18, Lys27>Gly21>Asp31⪢Ser15,Arg17>Ala10⪢GRF>[Glu15]-GLP-1(8–36) amide. Displacement activity against 125I-labelled GLP-1 (7–36)amide binding and stimulatory activity for cAMP production in RINm5F cells correlated well with their insulinotropic activity in perfused rat pancreases.
These results demonstrate that (1) positions 10 (glycine), 15 (aspartic acid) and 17 (serine) in the amino acid sequence of GLP-1(7–36)amide, in addition to the N-terminal histidine, are essential for its insulinotropic activity through its binding to the receptor, (2) the amino acid sequences for the C-terminal half of GLP-1(7–36)amide also contribute to its binding to the receptor, although they are less important compared with those of the N-terminal half, and (3) [Glu15]-GLP-1(8–36)amide is not an antagonist of GLP-1(7–36)amide as opposed to des-His1 [Glu9]-glucagon amide which is a potent glucagon antagonist.
Journal of Endocrinology (1994) 140, 45–52
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The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is rapidly degraded in the circulation by dipeptidyl peptidase IV forming the N-terminally truncated peptide GIP(3-42). The present study examined the biological activity of this abundant circulating fragment peptide to establish its possible role in GIP action. Human GIP and GIP(3-42) were synthesised by Fmoc solid-phase peptide synthesis, purified by HPLC and characterised by electrospray ionisation-mass spectrometry. In GIP receptor-transfected Chinese hamster lung fibroblasts, GIP(3-42) dose dependently inhibited GIP-stimulated (10(-7) M) cAMP production (up to 75.4+/-5.4%; P<0.001). In BRIN-BD11 cells, GIP(3-42) was significantly less potent at stimulating insulin secretion (1.9- to 3.2-fold; P<0.001), compared with native GIP and significantly inhibited GIP-stimulated (10(-7) M) insulin secretion with maximal inhibition (48.8+/-6.2%; P<0.001) observed at 10(-7) M. In (ob/ob) mice, administration of GIP(3-42) significantly inhibited GIP-stimulated insulin release (2.1-fold decrease; P<0.001) and exaggerated the glycaemic excursion (1.4-fold; P<0.001) induced by a conjoint glucose load. These data indicate that the N-terminally truncated GIP(3-42) fragment acts as a GIP receptor antagonist, moderating the insulin secreting and metabolic actions of GIP in vivo.
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It is well documented that the release of insulin from isolated perifused islets attenuates over time, despite a continued glucose stimulation. In the current study we have shown that potentiation of insulin release by the intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) is also attenuated after its continuous application. In less than 20 h of maintained stimulus with either hyperglycaemia (11.0 mM glucose) or GIP (10 nM) under hyperglycaemic conditions, insulin release returned to basal values. This was not due to loss of islet viability or reduction in the releasable pool of insulin granules, as 1 mM isobutylmethylxanthine was able to stimulate equivalent insulin release under both conditions. Further examination of chronic GIP desensitization was examined in cultured mouse insulinoma (betaTC-3) cells. GIP-stimulated cAMP production was not greatly affected by the prevailing glucose conditions, suggesting that the glucose dependence of GIP-stimulated insulin release occurs distally to the increase in intracellular cAMP in betaTC-3 cells. The GIP-stimulated cAMP response curve after desensitization was of similar magnitude at all glucose concentrations, but GIP pretreatment did not affect forskolin-stimulated cAMP production. Desensitization of the cAMP response in betaTC-3 cells was shown not to involve induction of dipeptidyl peptidase IV or pertussis toxin-sensitive G-proteins, activation of protein kinase C or protein kinase A, or modulation of phosphodiesterase activity. Homologous desensitization of the insulin-potentiating activity of GIP was found to affect both GIP-stimulated and forskolin-stimulated insulin release, indicating desensitization of distal steps in the stimulus-exocytosis cascade.
