Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to clarify whether there is a negative feedback mechanism for CCK secretion, we investigated plasma CCK bioactivity in patients suffering from chronic pancreatitis (CP) according to the characteristics of their pancreatic disease. Basal, meal-stimulated, and integrated release of plasma cholecystokinin (CCK) bioactivity was measured in 24 patients with CP and in 12 healthy controls. The values obtained were compared between the healthy control group and the CP group, and between subgroups of CP patients established on the basis of the presence/absence of several parameters: abnormal gastric emptying, abdominal pain, steatorrhea, pancreatic calcification, insulin-requiring diabetes mellitus, and impairment of pancreatic exocrine functions as indicated by secretin test. A bioassay method using pancreatic acini was used to measure plasma CCK bioactivity. In the control group, plasma CCK bioactivity increased from a basal value of 1.6 +/- 0.7 pmol/L to a maximal increase of 6.6 +/- 4.1 pmol/L, and the integrated CCK release following a test meal was 37.7 +/- 19.3 pmol/L.150 min. In the CP group, plasma CCK bioactivity increased from 1.6 +/- 0.9 pmol/L to a maximal increase of 8.2 +/- 8.7 pmol/L, and the integrated release of CCK was 43.0 +/- 37.7 pmol/L.150 min. None of the differences between them were significant. No significant differences in basal value, maximal increase, or integrated plasma CCK release were noted according to any of the parameters of the CP patients and the control group. Nor was there any correlation between impairment of pancreatic exocrine function and plasma CCK bioactivity. These results provide no evidence of a negative feedback mechanism between pancreatic exocrine dysfunction and CCK secretion.
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PMID:Meal-related changes in plasma CCK bioactivity in patients with chronic pancreatitis. 992 89

This study investigates the effects of the islet hormones, insulin (Ins), glucagon (Glu) and somatostatin (Som) with cholecystokinin octapeptide (CCK-8) on amylase secretion and intracellular free calcium concentration [Ca2+]i and their pattern of distribution in the isolated pancreas of normal and diabetic rats. Ins and Glu evoked small increases in amylase output from pancreatic segments compared with a much enhanced effect of CCK-8. In contrast, Som induced a biphasic response comprising an initial decrease followed by a secondary increase and this biphasic response may be dependent upon the concentration. Combining the islet hormones with CCK-8 resulted in marked potentiation in amylase output compared with either CCK-8 alone or the individual hormone. Genistein and tyrphostin A25, the tyrosine kinase inhibitors, evoked a small decrease in amylase output from pancreatic segments. They had no effect on the CCK-8-evoked secretory response but markedly inhibited the potentiation of the islet hormones with CCK-8. In pancreatic acini and acinar cells Ins, Glu and Som individually evoked small increases in amylase output compared with a much larger response with CCK-8. When the islet hormones were combined with CCK-8 there was no potentiation of amylase output. Similarly, when rats were rendered diabetic by prior treatment with streptozotocin Ins, Glu and Som failed to potentiate the secretory response of CCK-8. In fura-2-loaded pancreatic acinar cells Ins or Glu evoked small increases in [Ca2+]i compared with a much larger elevation with CCK-8. Ins, Glu and Som each enhanced the CCK-8-evoked [Ca2+]i. Genistein elicited a decrease in [Ca2+]i both in the absence and presence of the islet hormones. It also decreased the elevation in [Ca2+]i resulting from the combined presence of CCK-8 with either Ins or Glu but it had no effect on CCK-8 in combination with Som. In pancreatic acinar cells from diabetic rat Ins, Glu and Som had no detectable effect on CCK-8-evoked elevation in [Ca2+]i compared with the response obtained with CCK-8 alone. CCK-8-immunopositive cells were distributed around the walls of blood vessels, numerous Ins-positive cells in the central and peripheral parts of the islets of Langerhans, Glu-immunoreactive cells in the periphery of islets and Som-positive cells in the outer part of the islets. During diabetes, the number of CCK-immunopositive cells remained unchanged whereas the number of Ins-positive cells decreased coupled with an increase in the number of Glu-positive cells. The results indicate that both tyrosine kinase and cellular Ca2+ seem to be the intracellular mediators involved with the enhanced secretory responses obtained with a combination of the islet hormones with CCK-8. Moreover, the presence of viable pancreatic islets of Langerhans seems to be associated with the potentiation of the islet hormones with CCK-8.
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PMID:Interaction of islet hormones with cholecystokinin octapeptide-evoked secretory responses in the isolated pancreas of normal and diabetic rats. 1022 72

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.
Diabetes 1999 Feb
PMID:A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q. 1033 20

This study examines whether there is a change in the pattern of distribution of cholecystokinin-octapeptide (CCK-8), calcitonin-gene-related peptide (CGRP), neuropeptide-Y (NPY), substance P (SP) and vasoactive intestinal polypeptide (VIP) in the pancreas of streptozotocin (STZ)-diabetic (host) rats after subcutaneous pancreatic transplantation. Varicose CCK-8-immunopositive nerve fibres were observed in the wall of blood vessels of both normal and diabetic host pancreata. The density of CCK-8-immunoreactive varicose nerve fibres appeared to have increased in host rat pancreas. CGRP was demonstrated in many nerve fibres located in the wall of blood vessels of both normal and host pancreas. CGRP, however, seemed to be better expressed in the nerves of host pancreas when compared to normal. The pancreata of both normal and diabetic (host) rats contained numerous NPY-immunopositive varicose nerve fibres located in the wall of blood vessels. SP was demonstrated in neurons located in the interlobular areas of normal tissue and in fine varicose nerve fibres of the interacinar region of the pancreas of STZ-induced diabetic rats with SPTG. In normal pancreatic tissue, VIP-immunopositive nerve fibres were observed in all areas of the pancreas. VIP-positive nerve fibres were still discernible especially in the interacinar regions of the pancreas of host rats. In conclusion, the pattern of distribution and density of NPY, SP and VIP in the pancreas of STZ-induced diabetic rats with SPTG is similar to that observed in normal pancreas, but the expression of CGRP and CCK-8 seemed to have increased as a result of transplantation and or diabetes.
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PMID:Effect of subcutaneous pancreatic tissue transplants on streptozotocin-induced diabetes in rats. III. Distribution of neuropeptides in normal and diabetic (host) pancreas. 1036 89

The aim of this work was to study cholecystokinin-octapeptide (CCK-8)-stimulated pancreatic secretion after the induction of pancreatitis with L-arginine (ARG) in rats with or without streptozotocin (STZ) diabetes. One, 3, 7, and 14 days after pancreatitis induction, rats were surgically prepared with pancreatic duct and femoral vein cannulae under urethane anesthesia. Graded doses of CCK-8 ranging from 9 to 2,400 ng/kg/30 min were administered intravenously. In the control group, the step-wise increasing doses of CCK-8 resulted in a characteristic dose-response curve for the pancreatic volume, protein and amylase secretion (maximal volume, protein and amylase output at 600 ng/kg/30 min of CCK-8: 157 +/- 20.2 microl/30 min, 28.3 +/- 1.18 mg/30 min, and 3,750 +/- 92 IU/30 min, respectively). In rats with pancreatitis, the pancreatic volume (both basal and maximal) and amylase secretion were significantly elevated on day 1 versus the control group; then on days 3,7, and 14, the pancreatic secretory volume and amylase were progressively and significantly decreased versus the control group. However, the protein output was continuously decreased versus the control group on days 1, 3, 7, and 14. In diabetic rats, the maximal volume and protein and amylase output were all significantly decreased versus the control group throughout the experiment. In the diabetes + pancreatitis group, the maximal volume and protein and amylase output were all significantly increased versus the diabetes group on days 1, 3, 7, and 14. These results indicate that in the early phase of ARG-induced pancreatitis, the pancreatic secretion is characterized by increases in secretory volume and amylase, with a simultaneous decrease in protein output. Simultaneous diabetes seems to moderate the CCK-8-stimulated secretory changes in both the early and late phases after ARG-induced pancreatitis.
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PMID:Pancreatic secretory responses in L-arginine-induced pancreatitis: comparison of diabetic and nondiabetic rats. 1043 64

Although relatively frequent. diabetic involvement of digestive tract motility has not been investigated extensively in different organs. The authors studied esophageal, gastric, and gallbladder motor function in 35 type 2 (noninsulin-dependent) diabetic patients to determine the extent of gut involvement. Of these patients, 27 (77%) had peripheral neuropathy, 12 (34%) had both peripheral and autonomic neuropathy, and 22 (63%) had gastrointestinal symptoms. Esophageal manometric abnormalities were recorded in 18 patients, and delayed radionuclide emptying of the esophagus was documented in 16 patients, with a 83% concordance between the two tests. Scintigraphic gastric emptying of solids was delayed in 56% of patients, whereas gallbladder emptying after cholecystokinin stimulation was reduced in 69% of them. In 74% of patients at least one of the viscera under investigation showed abnormal motor function; however, only 36% of patients displayed involvement of the three organs. Gastrointestinal symptoms, duration and therapy of diabetes, previous poor glycemic control, and retinopathy did not correlate with the presence or the extent of motor disorders. Neuropathy was not predictive of gastrointestinal involvement and its extent; however, when motor abnormalities were present in patients with neuropathy, these were usually more severe. Gastrointestinal motor disorders are frequent and widespread in type 2 diabetics, regardless of symptoms. Autonomic neuropathy has a poor predictive value on motor disorders (0.75 for the esophagus, 0.5 for the stomach, 0.8 for the gallbladder), thus suggesting the coexistence of other pathophysiologic mechanisms.
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PMID:Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus. 1047 80

Gastrin (G) and cholecystokinin (CCK) are gastrointestinal neuropeptides that are released into circulation during a meal. G is also transiently expressed during embryogenic and early ontogenic development of the pancreas and is believed to act on islet-cell development. Both peptides act on pancreatic endocrine function; however, the effects are dependent on the species and on cellular and molecular underlying mechanisms that remain poorly characterized. Since CCK-B/G subtype receptor is predominant over the CCK-A subtype in the human pancreas, we hypothesized that it could be expressed by islet cells. Here we present reverse transcription-polymerase chain reaction and immunohistochemistry data demonstrating that the CCK-B/G receptor is expressed in islet cells and that islet glucagon-producing cells are the major site of CCK-B/G receptor expression in adult and fetal pancreas. Moreover, G immunoreactivity was detected in the fetal human pancreas at embryogenic week 22. G- and CCK-stimulated glucagon are released from purified human islets. Concentration of CCK and G eliciting a half-maximal level of glucagon secretion were 13 +/- 6 and 8 +/- 5 pmol/l, respectively. Maximal glucagon secretion was achieved in the presence of 30 pmol/l peptides and was similar to that obtained in the presence of 10 mmol/l L-arginine (1.6 pmol x ml(-1) x 90 min(-1)). The nonpeptide antagonist of the CCK-B/G receptor, RPR-101048, fully inhibited CCK- and G-stimulated glucagon secretion at 100 nmol/l concentration. These data are consistent with the view that the CCK-B/G receptor is involved in glucose homeostasis in adult humans and mediates the autocrine effects of G on islet differentiation and growth in the fetal pancreas.
Diabetes 1999 Oct
PMID:Evidence for a functional role of the cholecystokinin-B/gastrin receptor in the human fetal and adult pancreas. 1051 67

Diagnostic work-up in patients with diabetes mellitus, in whom gastrointestinal involvement is suspected comprises the assessment of gastrointestinal transit times, endoscopy, esophageal pH-metry or manometry, sonography and lactulose- or glucose-H2-breath tests. Prokinetic agents such as metoclopramide, cisapride or erythromycin and substances like loperamide, octreotide or clonidine are used to improve gastrointestinal dysfunction. Furthermore, in recent trials which aimed for the modulation of gastrointestinal transit times, cholecystokinin, proteinase inhibitors or amylin were administered in patients with diabetes mellitus. Nonpharmacological interventions include pancreas and kidney transplantation, gastric pacemakers and biofeedback training.
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PMID:Gastrointestinal involvement in patients with diabetes mellitus: Part II (second of two parts). Diagnostic procedures, pharmacological and nonpharmacological therapy. 1052 68

Neuropeptides and peptides are particularly important in the co-ordination of pancreatic exocrine and endocrine secretions. In diabetes mellitus, pancreatic endocrine secretion is particularly impaired. This study investigates whether there is a change in the pattern of distribution of neuropeptides including calcitonin-gene-related peptide (CGRP), neuropeptide-Y (NPY), vasoactive intestinal polypeptide (VIP), cholecystokinin-octapeptide (CCK-8), substance P (SP), and islet peptides including insulin (INS), glucagon (GLU), somatostatin (SOM) and pancreatic polypeptide (PP) in the pancreas of streptozotocin (STZ)-diabetic rats. After the onset of diabetes, the pattern of distribution of INS, GLU, SOM and PP cells was deranged. CGRP was demonstrated in ganglion cells of both normal and diabetic pancreas. CGRP was also localized in nerve fibres innervating the blood vessels of both normal and diabetic pancreas. The pancreata of both normal and diabetic rats contained numerous NPY-immunopositive varicose nerve fibres in the wall of blood vessels. In normal pancreatic tissue, VIP-immunopositive nerve fibres were observed in all areas of the pancreas. After the onset of diabetes, VIP-positive nerve fibres were still discernible in the interacinar regions of the pancreas. CCK-8 was identified in nerve fibres innervating both the normal and diabetic rat pancreata. These CCK-8-immunopositive nerves were varicose in nature and distributed in the wall of blood vessels. SP was demonstrated in neurons located in the interlobular areas of normal tissue and in fine varicose nerve fibres of the interacinar region of STZ-induced diabetic pancreas. In conclusion, CGRP, NPY, VIP, CCK-8 and SP are well distributed in both normal and diabetic pancreas.
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PMID:Distribution of calcitonin-gene-related peptide, neuropeptide-Y, vasoactive intestinal polypeptide, cholecystokinin-8, substance P and islet peptides in the pancreas of normal and diabetic rats. 1065 96

The investigation was performed in 96 Wistar rats. Diabetes mellitus was induced by single injection of 50 mg/kg of streptozotocin. Cholecystokinin (CCK) synthesizing neurons were identified in hypothalamic structures using indirect immunofluorescence. In latent period of diabetes (2 wks) number of CCK--immunopositive neurons increases, especially in paraventricular and suprachiasmatic nuclei, while in ventrolateral subnucleus of arcuate nucleus and parvicellular subnucleus of paraventricular nucleus areas occupied by immunoreactive material in neurons and their CCK content are reduced. By the end of wk 5 of the disease increase in number of CCK immunopositive neurons was registered only in medial parvicellular subnucleus of paraventricular nucleus whereas in other structures their number was reduced. The administration of CCK to intact animals causes increase of insulin content in endocrinocytes of pancreatic islets, but does not affect the level of hypoglycemia. The administration of the peptide to animals with diabetes leads to destruction of pancreatic islets, decline in endocrinocyte number and insulin content and marked hypoglycemia. Thus, the data obtained indicate the significant role of hypothalamic peptidergic system and CCK in regulation of beta-endocrinocyte function.
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PMID:[Changes in the cholecystokinin-synthetizing hypothalamic system during experimental diabetes mellitus in rats]. 1076 83


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