Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastric inhibitory polypeptide, originally isolated from porcine intestine, is a gastrointestinal hormone belonging to the vasoactive intestinal peptide (VIP)/glucagon/secretin family. GIP consists of 42 amino acid residues which is derived by proteolytic processing of a GIP precursor. In vivo and in vitro experiments have indicated that GIP auguments glucose-stimulated insulin secretion, suggesting that GIP plays an important role in the regulation of insulin secretion as an incretin. Thus, GIP now is generally referred to as glucose-dependent insulinotropic polypeptide. It is also suggested that GIP may be involved in the pathogenesis of non insulin-dependent diabetes mellitus (NIDDM). GIP exerts its biological actions by binding to its specific receptors, which appear to be coupled to G proteins. We have isolated a cDNA encoding a GIP receptor from a hamster insulinoma(HIT-T15) cDNA library. The hamster GIP receptor is a 462 amino acid protein having seven transmembrane segments. Expression of recombinant of hamster GIP receptors in Chinese hamster ovary (CHO) cells shows that it binds specifically to GIP with high affinity (IC50 = 9.6 nM) and is positively coupled to adenylate cyclase. RNA blot analysis reveals that a 3.8-kb GIP receptor mRNA is expressed at high levels in rat pancreatic islets as well as in HIT-T15 cells.
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PMID:[Gastric inhibitory polypeptide (GIP) and GIP receptor (GIPR)]. 892 Jun 77

Rats were rendered diabetic by streptozotocin, after which serum glucose-dependent insulinotropic polypeptide (GIP) levels, duodenal mucosal GIP content, and GIP mRNA levels were nine times, 50% and 80%, respectively, greater than in control rats. To determine whether an increase in GIP gene expression might induce chronic desensitization of its receptor, normal rats were subjected to continuous intravenous GIP infusion. Serum GIP levels increased gradually in GIP-infused rats, and by 4 h a threefold increase was detected. In response to GIP infusion, the serum insulin concentration increased at 30 min, followed by a gradual decrease, and at 4 h, no increase in insulin levels was detected despite a sustained elevated serum GIP level. The response to glucagon-like peptide-1 (GLP-1) was preserved, a reporter cell line (LGIPR2) stably transfected with rat GIP receptor cDNA was studied. GIP stimulated adenosine 3', 5'-cyclic monophosphate (cAMP) production in LGIPR2 cells, which was first detected after 1 h of stimulation, reached maximum level at 4 h, and returned to basal concentrations by 16 h. Additional stimulation with GIP at 16 h did not affect cAMP generation, indicating desensitization of the GIP receptor by the ligand. In contrast, a response to prostaglandin E1 or forskolin in GIP-desensitization was a receptor-specific process. The results of these studies indicate that GIP gene expression is enhanced in diabetic animals and that elevated serum GIP level induces chronic desensitization of the GIP receptor in vivo and in a stably transfected cell line.
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PMID:Chronic desensitization of the glucose-dependent insulinotropic polypeptide receptor in diabetic rats. 892 74

Evidence has accumulated that the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1(7-36) amide) are degraded and rendered biologically inactive in plasma by the enzyme dipeptidyl peptidase IV (DPIV). A strain of Fischer rats lacking the DPIV enzyme were used in the current investigation as a model for examining the enteroinsular axis under conditions in which normal inactivation of GIP and GLP-1(7-36) does not occur. This was assessed by comparing GIP and GLP-1(7-36) responses following oral glucose in normal versus DPIV-deficient Fischer rats, and by comparing the insulinotropic potency of both peptides in the perfused pancreas of both groups. The insulin response to an oral glucose challenge was decreased slightly in DPIV-negative rats compared with control animals. Of the two incretins, the GIP response to oral glucose was reduced by 50% compared with controls, whereas GLP-1(7-36) release in response to glucose was unchanged. A decrease of 30% in the sensitivity of the perfused pancreas of DPIV-negative rats to GIP was observed, whereas the insulin response to GLP(7-36) was identical in both groups. Incubation of both peptides in plasma from DPIV-positive and -negative rats was performed to determine the effect of the presence or absence of DPIV on the insulinotropic activity of GLP-1(7-36) and GIP in the isolated perfused rat pancreas. Incubation in plasma from DPIV-positive rats resulted in a 65% decrease in insulinotropic activity of both incretins compared with incubation in plasma from DPIV-deficient rats. It was hypothesized that the reduced GIP response and decreased sensitivity of the pancreas to GIP are compensatory mechanisms that maintain insulin and glucose levels within a normal range despite abnormal degradation of GIP. An explanation of the lack of effect of the absence of DPIV on the GLP-1(7-36) response to oral glucose and insulinotropic action of this peptide must await further study.
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PMID:The enteroinsular axis in dipeptidyl peptidase IV-negative rats. 893 36

To examine whether incretin hormones, truncated glucagon-like peptide-1 (tGLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are recognized by the hepatic vagal nerve, changes of the impulse discharge rate in the afferent vagus upon their intraportal administrations were measured in situ in rats anesthetized with urethan and chloralose. One-min injection of tGLP-1 at a periphysiological dose of 0.2 pmol or a pharmacological dose of 4.0 pmol, but not of the vehicle, significantly facilitated the hepatic vagal afferents. However, the injection of GIP at either a physiological dose of 0.2 pmol, a periphysiological dose of 4.0 pmol, or an even much larger dose of 40.0 pmol did not change the afferents at all. The present results indicate that the hepatic vagus specifically recognizes an intraportal appearance of tGLP-1 in the hepatoportal area, suggesting that the vagal monitoring system for intraportal levels of the incretin hormone operates on ingestion of a mixed meal.
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PMID:The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein. 894 34

This study was designed to investigate postprandial responses to a mixed meal in simulated shift work conditions. Nine normal healthy subjects (six males and three females) were studied on two occasions at the same clock time (1330 h) after consuming test meals, first in their normal environment and secondly after a 9 h phase advance (body clock time 2230 h). Plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), triacylglycerol (TAG) and non-esterified fatty acids (NEFAs) were determined at intervals for 6 h after each test meal. Postprandial plasma glucose, insulin, GIP and GLP-1 profiles were evaluated by calculating areas under the curve (AUC) for the first 2 h and the last 4 h of the sampling together with total AUC. Significantly higher postprandial glucose responses (total AUC) were observed after the phase shift than before (AUC 0-360 min, 2.01 (1.51-2.19) vs 1.79 (1.56-2.04) mmol/l.min; P < 0.02; mean (range)). No significant difference was observed when the first 2 h of each response was compared, but significantly higher glucose levels were observed in the last 4 h of the study after the phase shift than before (AUC 120-360 min, 1.32 (1.08-1.42) vs 1.16 (1.00-1.28) mmol/l.min; P < 0.05). Similar results were obtained for insulin (AUC 0-360 min, 81.72 (30.75-124.97) vs 58.98 (28.03-92.57) pmol/l.min; P < 0.01; AUC 120-360 min, 40.73 (16.20-65.25) vs 25.71 (14.25-37.33) pmol/l.min; P < 0.02). No differences were observed in postprandial plasma GIP and GLP-1 responses before and after the phase shift. Postprandial circulating lipid levels were affected by phase shifting. Peak plasma TAG levels occurred 5 h postprandially before the phase shift. Postprandial rises in plasma TAG were significantly delayed after the phase shift and TAG levels continued to rise throughout the study. Plasma postprandial NEFA levels fell during the first 3 h both before and after the phase shift. Their rate of return to basal levels was significantly delayed after the phase shift compared with before. This study demonstrates that a simulated phase shift can significantly alter pancreatic B-cell responses and postprandial glucose and lipid metabolism.
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PMID:Postprandial hormone and metabolic responses in simulated shift work. 895 86

To elucidate the question of whether production of the insulinotropic gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is altered by a diabetic metabolic state, their intestinal expression pattern was evaluated. Two rodent models for diabetes mellitus were used, non-obese diabetic (NOD) mice as a model for insulin-dependent diabetes and Zucker diabetic fatty (ZDF) rats for non-insulin-dependent diabetes mellitus (NIDDM). Expression of both incretin hormones followed typical patterns, which were similar in both animals and unaltered by the diabetic state. The GIP gene was greatly expressed in the duodenum, jejunum, and ileum, with a continuous decrease from the upper to lower intestines. This pattern was observed in both NOD mice and ZDF rats regardless of the diabetic state. This expression data was corroborated by radioimmunoassay (RIA) analysis of the gene product GIP. Expression of the proglucagon gene encoding GLP-1 had an opposite appearance. The highest expression was seen in the large bowel and the ileum. RIA analysis of the gene product GLP-1 mirrored these data. Although the distribution pattern was similar in both animal models, in contrast to diabetic NOD mice, a regulated expression was found in diabetic ZDF rats. Compared with lean nondiabetic controls, fatty hyperglycemic animals showed an increased expression of the proglucagon gene in the colon and a concomitant reduction in the small intestine. This was mirrored by the GLP-1 content of the colon and ileum. Overall, basal GLP-1 plasma levels were increased in ZDF rats (17.0 +/- 2.8 pmol) compared with lean Zucker rats (12.4 +/- 1.8 pmol). In conclusion, incretin hormone expression (GIP and GLP-1) follows specific patterns throughout the gut and is unaltered by the diabetic state. In ZDF rats, regulation of proglucagon expression occurs mainly in the large intestine.
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PMID:Incretin hormone expression in the gut of diabetic mice and rats. 905 67

The mechanisms by which glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion were investigated by measurements of whole-cell Ca2+ currents, the cytoplasmic Ca2+ concentration, and cell capacitance as an indicator of exocytosis in individual mouse pancreatic beta-cells maintained in short-term culture. GIP produced a 4.2-fold potentiation of depolarization-induced exocytosis. This stimulation of exocytosis was not associated with a change in the whole-cell Ca2+-current, and there was only a small increase (30%) in the cytoplasmic Ca2+ concentration [intercellular free Ca2+([Ca2+]i)]. The stimulatory effect of GIP on exocytosis was blocked by pretreatment with the specific protein kinase A (PKA) inhibitor Rp-8-Br-cAMPS. Glucagon-like peptide-I(7-36) amide (GLP-I) stimulated exocytosis (90%) in the presence of a maximal GIP concentration (100 nmol/l). Replacement of GLP-I with forskolin produced a similar stimulatory action on exocytosis. These effects of GLP-I and forskolin in the presence of GIP did not involve a change in the whole-cell Ca2+-current or [Ca2+]i. GIP was ineffective in the presence of both forskolin and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Under the same experimental conditions, the protein kinase C (PKC)-activating phorbol ester 4-phorbol 12-myristate 13-acetate (PMA) stimulated exocytosis (60%). Collectively, our data indicate that the insulinotropic hormone GIP stimulates insulin secretion from pancreatic beta-cells, through the cAMP/PKA signaling pathway, by interacting with the secretory machinery at a level distal to an elevation in [Ca2+]i.
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PMID:Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. 907 1

High-resolution capacitance measurements were used to explore the effects of the gut hormones GLP-I(7-36) amide [glucagon-like peptide I(7-36) amide] and GIP (glucose-dependent insulinotropic polypeptide) on Ca2+-dependent exocytosis in glucagon-secreting rat pancreatic alpha-cells. Both peptides produced a greater than threefold potentiation of secretion evoked by voltage-clamp depolarizations, an effect that was associated with an approximately 35% increase of the Ca2+ current. The stimulatory actions of GLP-I(7-36) amide and GIP were mimicked by forskolin and antagonized by the protein kinase A (PKA)-inhibitor Rp-8-Br-cAMPS. The islet hormone somatostatin inhibited the stimulatory action of GLP-I(7-36) amide and GIP via a cyclic AMP-independent mechanism, whereas insulin had no effect on exocytosis. These data suggest that the alpha-cells are equipped with receptors for GLP-I and GIP and that these peptides, in addition to their well-established insulinotropic capacity, also stimulate glucagon secretion. We propose that the reported inhibitory action of GLP-I on glucagon secretion is accounted for by a paracrine mechanism (e.g., mediated by stimulated release of somatostatin that in turn suppresses exocytosis in the alpha-cell).
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PMID:Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. 913 46

This study concerns whether the pancreatic beta cell expresses cell-surface ectopeptidases that are capable of proteolysis of peptide hormones and neuropeptides that modify glucose-dependent insulin release. These biochemical investigations of the RINm5F cell line found that these cells express ectopeptidases. We have characterized the limited endoproteolysis of GLP-1 (7-36) amide that occurs in the presence of RINm5F plasma membranes. The products and the sensitivity to specific peptidase inhibitors of the proteolysis is characteristic of neutral endopeptidase (NEP) 24.11. Vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and exendin-4 also undergo proteolysis in the presence of RIN cell membranes. NEP 24.11-activity in RIN cell membranes was confirmed using a specific fluorogenic assay, by histochemistry, and by comparison with the recombinant enzyme with respect to the kinetics of proteolysis of GLP-1 (7-36) amide and of a fluorogenic substrate. Specific fluorogenic assays revealed the presence of aminopeptidase N and the absence of aminopeptidase A and of dipeptidylpeptidase IV.
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PMID:Endoproteolysis of glucagon-like peptide (GLP)-1 (7-36) amide by ectopeptidases in RINm5F cells. 921 54

We have studied the impact of liquid diets formulated for complete or supplemental enteral nutrition of type II, non insulin-dependent (NIDDM) diabetics on carbohydrate homeostasis. To achieve this, liquid formula tolerance tests were performed in NIDDM patients under an oral treatment regimen with a combination of diet plus glibenclamide (7 men, 3 women, age: 56 +/- 11 years; mean body mass index of 26.2 +/- 3.6 kg/m2). After an overnight fast, each patient received the usual morning medication and, thereafter, ingested formula diet in randomized order with 10 day intervals between tests. 500 ml were administered of either a standard liquid diet (Biosorb Sonde), a fibre containing diet (Biosorb Plus Sonde), or a carbohydrate modified, fructose containing "diabetes" diet (Fresubin Diabetes) (carbohydrate contents of approximately equal to 60 g, respectively). Blood samples were collected over 180 min. Considering minor variations in the nutritional values of the diets, IR-insulin, IR-C-peptide, IR-glucose-dependent insulinotropic polypeptide (GIP), and IR-glucagon-like peptide. 1 (GLP-1) in plasma did not significantly differ between the study groups. After ingestion of Biosorb Sonde area under the curve glucose was greater than that seen after uptake of fibre containing or carbohydrate modified, i.e. fructose containing "liquid diabetes diets". All diets challenged the entero-insular axis in non-insulin dependent diabetics to a comparable extent. This data does not support the contention to employ special "diabetes" formulas for enteral nutrition of patients with NIDDM.
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PMID:No apparent benefit of liquid formula diet in NIDDM. 922 8


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