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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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Introduction Glucose-dependent insulinotropic polypeptide (GIP) is secreted as a 42-amino acid peptide from the K cells of the upper small intestine in response to meal ingestion ( Ugleholdt et al. 2006 ). Initially identified as gastric
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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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Introduction Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid polypeptide hormone secreted from intestinal K-cells of the duodenum and proximal jejunum ( Buchan et al. 1978 ). GIP was discovered in 1969, through
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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
