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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have designed a four lumen tube which has enabled us to aspirate duodenal juice while infusing endogenous stimuli into the lower part of duodenum. Exocrine pancreatic secretion and plasma immunoreactive secretin (IRS) levels have been simultaneously observed in response to intraduodenal infusion of 1-phenyl-1-hydroxy-n-pentane (PHP) and 0.1 N HCl in normal subjects, patients with diabetes mellitus and patients with chronic pancreatitis by use of this tube. (1) Pancreatic flow rate and bicarbonate concentration were found to increase to twice those of basal levels and plasma IRS levels rose significantly after infusion of PHP or HCl in normal subjects. The same tendency was observed in patients with diabetes mellitus. (2) Exocrine pancreatic secretion did not change after infusion of PHP or HCl in patients with chronic pancreatitis. Pancreatic flow rate, bicarbonate concentration and amylase output were significantly low in patients with diabetes mellitus. (3) Pancreatic flow rate and bicarbonate concentration incresed to about twice those of basal levels after both PHP and HCl infusion. On the other hand, although pancreatic amylase output increased significantly after infusion of HCl as compared with basal secretion, it did not change after infusion of PHP. It appeared reasonable to conclude that PHP is a morespecific substance for releasing secretin than HCl.
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PMID:Plasma secretin level and exocrine pancreatic secretion in response to intraduodenal infusion of 1-phenyl-1-hydroxy-n-pentane and HCl by using a new four lumen tube. 746 2

Glucose-dependent insulinotropic polypeptide (GIP) is a hormone secreted by the endocrine K-cells from the duodenum that stimulates glucose-induced insulin secretion. Here, we present the molecular characterization of the human pancreatic islet GIP receptor. cDNA clones for the GIP receptor were isolated from a human pancreatic islet cDNA library. They encoded two different forms of the receptor, which differed by a 27-amino acid insertion in the COOH-terminal cytoplasmic tail. The receptor protein sequence was 81% identical to that of the rat GIP receptor. When expressed in Chinese hamster lung fibroblasts, both forms of the receptor displayed high-affinity binding for GIP (180 and 600 pmol/l). GIP binding was displaced by < 20% by 1 mumol/l glucagon, glucagon-like peptide (GLP-I)(7-36) amide, vasoactive intestinal peptide, and secretin. However exendin-4 and exendin-(9-39) at 1 mumol/l displaced binding by approximately 70 and approximately 100% at 10 mumol/l. GIP binding to both forms of the receptor induced a dose-dependent increase in intracellular cAMP levels (EC50 values of 0.6-0.8 nmol/l) but no elevation of cytoplasmic calcium concentrations. Interestingly, both exendin-4 and exendin-(9-39) were antagonists of the receptor, inhibiting GIP-induced cAMP formation by up to 60% when present at a concentration of 10 mumol/l. Finally, the physical and genetic chromosomal localization of the receptor gene was determined to be on 19q13.3, close to the ApoC2 gene. These data will help study the physiology and pathophysiology of the human GIP receptor.
Diabetes 1995 Oct
PMID:Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. 755 58

Incretins are endogenous peptides released from the gastrointestinal tract into the circulation during a meal that potentiate glucose-stimulated insulin secretion. At present, there are two established incretins: glucose-dependent insulinotropic polypeptide (GIP) and the truncated glucagon-like peptides (tGLPs), which are now being investigated for use in the treatment of diabetes mellitus. In the present study we cloned a rat islet GIP receptor complementary DNA (GIP-R1) to answer several important questions regarding the ligand-binding and intracellular signaling properties of the GP receptor. GIP-R1, when expressed transiently in monkey kidney (COS-7) or stably in Chinese hamster ovary (CHO-K1) cells, demonstrated comparable high affinity binding for either synthetic porcine (sp) GIP or synthetic human (sh) GIP. The IC50 values for displacement of [125I]spGIP in CHO-K1 cells were 2.6 +/- 0.8 and 3.1 +/- 0.9 nM for two different preparations of shGIP, and 3.7 +/- 1.5 and 3.6 +/- 0.4 nM for two preparations of spGIP. Saturation isotherms obtained with both intact cells and membranes gave monophasic binding curves with apparent Kd values of 204 +/- 17 and 334 +/- 94 pM, respectively. Cells expressed 12-15 x 10(3) receptors/cell. In COS-7 cells, spGIP and shGIP also exhibited similar IC50 values (7.6 +/- 1.2 and 8.9 +/- 1.8 nM, respectively). The receptor in CHO-K1 cells bound GIP-(1-30) with lower affinity (IC50 = 39 +/- 17 nM), whereas the fragments GIP-(19-30), GIP-(18-28), and GIP-(21-26) showed no apparent binding. The specificity of the receptor was further examined using several structurally related peptides. Surprisingly, exendin-(9-39) [Ex-(9-39)], a GLP-1 receptor antagonist, and Ex-4-(1-39), a GLP-1 receptor agonist, demonstrated some affinity for the GIP receptor, with 39% and 21% displacement of [125I]spGIP, respectively, at 1 microM. Other members of the secretin/vasoactive intestinal peptide family of peptides tested showed no interaction. GIP-R1 receptor binding correlated with activation of the adenylyl cyclase system, whereby spGIP and shGIP evoked concentration-dependent increases in cAMP accumulation with EC50 values of 8.7 +/- 1.5 x 10(-10)M and 8.1 +/- 1.6 x 10(-10)M for spGIP and shGIP, respectively. Increases in cAMP in the presence of 10 nM spGIP were not dependent on the ambient glucose concentration, with 22- and 18-fold increases in cAMP accumulation at 0.1 and 5.5 mM glucose, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties. 766 83

Pancreatic polypeptide (PP) can be used as a marker for endocrine active tumors originating from the pancreas. After intravenous administration of secretin, individually divergent increases in plasma PP concentration can be observed hampering interpretation of the stimulation test. Under certain circumstances elevated basal PP concentrations can be observed. Besides age, renal insufficiency and diabetes, hypoglycemia can cause high PP levels. We therefore inquired whether in patients with atypically high increase of PP after secretin this increase could be caused by hypoglycemia during the secretin stimulation test. In order to test this hypothesis we prospectively determined the plasma glucose and insulin concentrations in addition to the routinely measured gastro-intestinal hormones in 19 patients referred for secretin provocation test. In the 16 patients in whom the increase of PP was not due to an endocrine active tumor or renal insufficiency, PP rose to 170 +/- 57 pmol/l (+/- SEM) 2 minutes after secretin administration. In parallel, plasma insulin concentration increased to 365 +/- 51 pmol/l 2 minutes after secretin. The maximal insulin concentrations correlated significantly with the PP concentrations observed at the same time (R = 0.73, p < 0.01). The mean glucose concentration, however, remained constantly between 4.8 +/- 0.3 and 5.2 +/- 0.3 mmol/l and there was no correlation between the peak plasma PP concentrations after secretin and the plasma glucose concentrations (R = 0.07). The minimal glucose concentrations observed were 3.3 mmol/l in three patients (30 minutes after secretin in 2 patients and 45 minutes after secretin in one). The mean plasma glucagon concentration rose to 22.5 +/- 4.1 pmol/l 10 minutes after secretin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Abnormal increase in pancreatic polypeptide in the secretin-provocation test: hypoglycemia-induced?]. 774 Feb 87

Glucagon-like peptide-1 (GLP-1) is promptly released from endocrine cells of the distal part of the gut after oral ingestion of a meal. To test the possibility that hormones produced by the proximal small intestine or transmitters of the enteric nervous system may be involved in the early phase of meal-induced GLP-1 secretion, various intestinal regulatory peptides and neurotransmitters of the gut were administered intraarterially in the isolated vascularly perfused rat colon preparation. The release of GLP-1 in the portal effluent was measured by a specific RIA. Intraarterial infusion of glucose-dependent insulinotropic peptide (GIP) over the concentration range 0.25-1 nM evoked a dose-dependent release of GLP-1, with a maximal response of 350% of the basal value. Tetrodotoxin did not modify the GIP-induced release of GLP-1. Secretin or cholecystokinin did not stimulate the secretion of GLP-1. Bombesin (10(-9)-10(-7) M) provoked a dose-dependent release of GLP-1, consisting of an early peak, followed by a sustained response. Calcitonin gene-related peptide (5 x 10(-8) M) induced a dramatic rise of GLP-1 immunoreactivity in the portal effluent (peak at 800% of the basal value 10 min after the start of infusion). Similarly, the beta-adrenergic agonist isoproterenol at concentrations of 10(-7) and 10(-6) M provoked a pronounced release of GLP-1 (peak at 500% of the basal value with 10(-6) M isoproterenol). Finally, the muscarinic cholinergic agonist bethanechol at a concentration of 10(-4) M evoked a gradual increase in GLP-1 immunoreactivity, which reached a maximal value (900% over basal) at the end of the 30-min infusion period. The lowest concentration of bethanechol used in the present study (10(-5) M) did not increase portal GLP-1 immunoreactivity over the basal value. Tetrodotoxin did not modify the bethanechol-, isoproterenol-, calcitonin gene-related peptide-, or bombesin-induced GLP-1 release. In conclusion, the present study conducted with the isolated vascularly perfused rat colon shows that there are interactions between the two most potent incretins, GIP and GLP-1, probably through an enteroendocrine pathway. Additionally, several transmitters of the gut are potent stimulants of GLP-1 release and, therefore, represent potential tools in the treatment of the noninsulin-dependent diabetes mellitus.
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PMID:Regulation of glucagon-like peptide-1-(7-36) amide secretion by intestinal neurotransmitters and hormones in the isolated vascularly perfused rat colon. 798 23

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and is considered as a new therapeutic tool in the treatment of diabetes mellitus. This study was designed to precisely characterize the binding behavior and activation of the recombinant GLP-I receptor against naturally occurring ligands of the glucagon/VIP/secretin peptide hormone family. CHO-cells were stably transfected with a plasmid containing a cDNA encoding for the rat GLP-I receptor. Northern blot analysis with this cDNA showed a single band of 2.7 kb in CHO cells, while in RINm5F cells, three bands of 2.7, 3.4, and 3.6 kb were specifically labelled. In receptor-binding studies 125I-GLP-I was displaced by GLP-I and weakly by PHI and oxyntomodulin but not by helodermin, helospectin I, helospectin II, secretin, VIP, and PACAP-38. Intracellular cAMP generation was stimulated by GLP-I, PHI, and oxyntomodulin. Helodermin, helospectin I, helospectin II, secretin, VIP, and PACAP-38 were not able to displace 125I-GLP-I from its receptor or to stimulate intracellular cAMP production. This data shows that the GLP-I receptor is characterized by a high ligand specificity.
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PMID:Ligand-specificity of the rat GLP-I receptor recombinantly expressed in Chinese hamster ovary (CHO-) cells. 801 94

A surgical and experimental procedure was developed to enable the collection of pure and inactivated pancreatic juice during the growth of the pig. Studies have shown that, during the suckling period, both the basal and the secretory responses to suckling are low, if present at all. After weaning, basal levels of the total exocrine secretion, total protein, amylase, and trypsin, respectively, increase slightly, while the postprandial levels of total protein, amylase, trypsin, lipase, colipase, and carboxylester lipase, respectively, increase markedly. The pancreatic juice enzyme composition changes qualitatively and the antibacterial activity of the pancreatic juice also significantly increases. Piglet age appeared to be of minor importance, since weaning at either 4 or 6 wk of age gave the same results. Secretin and CCK administered together in supraphysiological doses only significantly affect exocrine function from 3-4 wk of age. However, CCK may also affect the exocrine pancreas indirectly via reflexes initiated intraduodenally. Milk consumption in the suckling pig leads to a postprandial increase in glucose levels but not insulin. Milk appears to be able to regulate the exocrine pancreas to produce only the amount and type of enzymes required for digestion. Thus, milk components or digestive products may affect pancreas function regulation. Studies show that enterostatin, the procolipase activation peptide, may inhibit pancreatic secretion mediated indirectly through the GI tract. Pancreastatin, an endocrine peptide, inhibits both insulin secretion and protein and trypsin secretion to pancreatic juice. In hypoinsulinemic (alloxan+streptozotocin diabetes) pigs (15-20 kg), no postprandial pancreatic juice response is seen, although CCK 33 + secretin can stimulate pancreatic secretion. Hypoinsulinemic pigs have a reduced capacity for glucose tissue utilization, suggesting that tissue metabolism and exocrine pancreas secretion are related.
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PMID:Development and regulation of porcine pancreatic function. 853 Aug 34

Rat pancreatic alpha- and beta-cells are critically dependent on hormonal signals generating cyclic AMP (cAMP) as a synergistic messenger for nutrient-induced hormone release. Several peptides of the glucagon-secretin family have been proposed as physiological ligands for cAMP production in beta-cells, but their relative importance for islet function is still unknown. The present study shows expression at the RNA level in beta-cells of receptors for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide I(7-36) amide (GLP-I), while RNA from islet alpha-cells hybridized only with GIP receptor cDNA. Western blots confirmed that GLP-I receptors were expressed in beta-cells and not in alpha-cells. Receptor activity, measured as cellular cAMP production after exposing islet beta-cells for 15 min to a range of peptide concentrations, was already detected using 10 pmol/l GLP-I and 50 pmol/l GIP but required 1 nmol/l glucagon. EC50 values of GLP-I- and GIP-induced cAMP formation were comparable (0.2 nmol/l) and 45-fold lower than the EC50 of glucagon (9 nmol/l). Maximal stimulation of cAMP production was comparable for the three peptides. In purified alpha-cells, 1 nmol/l GLP-I failed to increase cAMP levels, while 10 pmol/l to 10 nmol/l GIP exerted similar stimulatory effects as in beta-cells. In conclusion, these data show that stimulation of glucagon, GLP-I, and GIP receptors in rat beta-cells causes cAMP production required for insulin release, while adenylate cyclase in alpha-cells is positively regulated by GIP.
Diabetes 1996 Feb
PMID:Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. 854 71

Three-dimensional magnetic resonance cholangiopancreatography is currently the most exciting new imaging technique for chronic pancreatitis. Endoscopy-assisted duodenal intubation during the secretin-cholecystokinin test reduces intubation time in difficult cases. The NBT-para-amino benzoic acid test has been refined to enhance its discriminant power. The cholesteryl-[C13]octanoate breath test and the faecal elastase test are newer highly sensitive and specific tubeless tests. Pain in chronic pancreatitis continues to be a vexing therapeutic issue. Enzyme treatment continues despite criticism. Neurotensin is the new suspected mediator of the feedback mechanism, which is downregulated by enzyme therapy. Steroid ganglion block is an exciting therapeutic tool for pain relief. Endoscopic pancreatic sphincterotomy, Dormia basketing and pancreatic stenting in conjunction with extracorporeal shock wave lithotripsy should be performed early in chronic pancreatitis to prevent parenchymal atrophy with ensuing exocrine and endocrine pancreatic dysfunction. The modified Puestow's procedure preserves endocrine and exocrine pancreatic functions besides relieving pain. Closed loop insulin infusion allows superior management of pancreatic diabetes following near total pancreatectomy. The standardised incidence rate of pancreatic cancer is 16.5 in patients with alcoholic chronic pancreatitis and 100 for tropical chronic pancreatitis. Aggressive treatment protocols combining neo-adjuvant chemoradiation and intra-operative radiation with surgery are being used to improve the prognosis in this dismal complication of chronic pancreatitis.
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PMID:Chronic pancreatitis: diagnosis and treatment. 875 8

Endocrine disorders associated with diabetes mellitus are described. When blood glucose control deteriorates, observed endocrine abnormalities are as follows. 1) Blood GH levels increase. This elevation is small but enough to disturb insulin secretion and glucose metabolism. Plama insulin-like growth factor-1 levels decrease in spite of their strong relation with diabetic retinopathy. 2) Blood thyroid hormones show the similarity with low T3 syndrome. 3) Hyporeninemic hypoaldosteronism occurs especially with patients who have hypertension or moderate diabetic complications. 4) Plasma pancreatic glucagon levels are elevated. Amino acids induce hypersecretion but hypoglycemia fails to response normally. Glucose administration shows impaired inhibition or paradoxical hypersecretion. 5) Other plasma levels of pancreatic hormones such as gastrin, secretin, motilin and somatostatin are usually elevated.
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PMID:[Endocrine disorders associated with impaired glucose tolerance]. 891 25


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