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)

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

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

Abnormality of pancreatic exocrine secretion has been observed in patients with diabetes mellitus. Troglitazone is a novel insulin-sensitizing agent that improves hyperglycemia and hyperinsulinemia in insulin-resistant diabetes mellitus. We investigated the effect of troglitazone on exocrine pancreas in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ (25 mg/kg), and then 0.2% troglitazone containing rat chow was given for 2 weeks. Control diabetic animals received normal rat chow for 2 weeks. Glucose tolerance tests were performed before and after the administration of troglitazone. Pancreas weight, enzyme, protein, and insulin contents in the pancreas were measured. For the exocrine secretory study, pure pancreatic juice was collected hourly. Plasma glucose concentrations stimulated by the oral administration of 2.5 g/kg glucose in the troglitazone-treated group were significantly lower than those in the control group, but not plasma insulin concentrations. Pancreas weight in diabetic rats was less than that in normal rats. Administration of troglitazone resulted in a significant increase in pancreas weight and amylase and trypsin output. However, protein and insulin contents were not affected by the treatment with troglitazone. Both basal and cholecystokinin (CCK-8; 26 pmol/kg/h) stimulated exocrine secretion in juice volume, amylase, and trypsin output were markedly decreased in diabetic rats, compared with those in normal rats. Impaired basal and CCK-stimulated pancreatic exocrine secretion in diabetic rats recovered to the normal levels when troglitazone was given. In conclusion, troglitazone might be effective to restore exocrine pancreatic insufficiency in STZ-diabetic rats.
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PMID:Effect of troglitazone on exocrine pancreas in rats with streptozotocin-induced diabetes mellitus. 1107 98

Protein tyrosine phosphatase 1B (PTP1B) attenuates insulin signaling by catalyzing dephosphorylation of insulin receptors (IR) and is an attractive target of potential new drugs for treating the insulin resistance that is central to type II diabetes. Several analogues of cholecystokinin(26)(-)(33) (CCK-8) were found to be surprisingly potent inhibitors of PTP1B, and a common N-terminal tripeptide, N-acetyl-Asp-Tyr(SO(3)H)-Nle-, was shown to be necessary and sufficient for inhibition. This tripeptide was modified to reduce size and peptide character, and to replace the metabolically unstable sulfotyrosyl group. This led to the discovery of a novel phosphotyrosine bioisostere, 2-carboxymethoxybenzoic acid, and to analogues that were >100-fold more potent than the CCK-8 analogues and >10-fold selective for PTP1B over two other PTP enzymes (LAR and SHP-2), a dual specificity phosphatase (cdc25b), and a serine/threonine phosphatase (calcineurin). These inhibitors disrupted the binding of PTP1B to activated IR in vitro and prevented the loss of tyrosine kinase (IRTK) activity that accompanied PTP1B-catalyzed dephosphorylation of IR. Introduction of these poorly cell permeant inhibitors into insulin-treated cells by microinjection (oocytes) or by esterification to more lipophilic proinhibitors (3T3-L1 adipocytes and L6 myocytes) resulted in increased potency, but not efficacy, of insulin. In some instances, PTP1B inhibitors were insulin-mimetic, suggesting that in unstimulated cells PTP1B may suppress basal IRTK activity. X-ray crystallography of PTP1B-inhibitor complexes revealed that binding of an inhibitor incorporating phenyl-O-malonic acid as a phosphotyrosine bioisostere occurred with the mobile WPD loop in the open conformation, while a closely related inhibitor with a 2-carboxymethoxybenzoic acid bioisostere bound with the WPD loop closed, perhaps accounting for its superior potency. These CCK-derived peptidomimetic inhibitors of PTP1B represent a novel template for further development of potent, selective inhibitors, and their cell activity further justifies the selection of PTP1B as a therapeutic target.
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PMID:Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action. 1134 29

Targeting of dorsal root ganglia by diabetes could account for the selective sensory abnormalities that patients with early diabetic polyneuropathy develop. In this work, we addressed survival, phenotype and gene expression in sensory neurones in lumbar dorsal root ganglia in a long-term model of experimental streptozotocin-induced diabetes in rats, designed to reflect human disease. Motor and sensory conduction slowing developed early, by the 2-month time point. At 2 months, sensory neurones had no detectable alterations in their calibre or gene expression, assessed using quantitative in situ hybridization studies for mRNA markers that included alpha CGRP, beta CGRP, NFM, t alpha 1-tubulin, SP, VIP, B50 (GAP43), galanin, somatostatin, PACAP, HSP27, c-jun, SNAP 25, p75, TrkA, TrkB and TrkC. By 12 months, however, diabetics had developed neurone perikaryal and distal axon atrophy, accompanied by generalized downregulation of mRNA expression, particularly of CGRP transcripts, PACAP, SP, NFM, p75, trkA and trkC. With the exception of HSP-27, no elevation in mRNAs that increase after injury, such as VIP, galanin, CCK, PACAP, B50 and t alpha 1-tubulin, was observed and constitutive levels, when detectable, trended towards lower rather than increased levels. There was relative preservation of neurone numbers at 12 months; only a non-significant trend towards fewer diabetic neurones was detected using a rigorous and systematic physical dissector counting approach through the entire L5 ganglia. There was no change in the relative populations of CGRP- and SP-immunoreactive neurones. Our findings indicate that even long-term experimental diabetes is associated with relative preservation of sensory neurone populations, but the neurones are atrophic and their gene expression is altered. This pattern of change differs from that following axotomy, implies a degenerative rather than an injury phenotype and has important implications for how such neurones might be rescued.
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PMID:Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes. 1167 32

The aim of the present study was to investigate the spontaneous and cholecystokinin-octapeptide (CCK-8)-promoted laboratory changes and morphological alterations in rats with arginine (Arg)-induced pancreatitis in which diabetes had been induced with streptozotocin (STZ). Male Wistar rats were used in our experiments. Pancreatitis was induced by arginine, diabetes by STZ and regeneration was promoted by CCK-8. The serum amylase, glucose and insulin levels, the pancreatic contents of protein, DNA, amylase, trypsinogen and lipase, the pancreatic weight/body- weight ratio (pw/bw) and the plasma glucagon level were examined 1, 3, 7, 14 and 28 days after pancreatitis induction. Pancreatic tissue samples were examined by light microscopy and immunostaining on paraffin-embedded sections. The insulin and glucagon-containing cells were visualized by using monoclonal antibodies. The administration of low doses of CCK-8 accelerated the processes of regeneration following Arg-induced pancreatitis, but in rats that were also diabetic, pancreatic regeneration was not observed. The administration of low doses of CCK-8 seems to reduce the pancreatic beta -cell number and function in diabetic rats. The pancreatic endocrine function was further deteriorated by simultaneous Arg-induced pancreatitis. The diabetic state appeared to shift the normal pancreatic enzyme content (decreased amylase and increased trypsinogen) in this study.
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PMID:Cholecystokinin fails to promote pancreatic regeneration in diabetic rats following the induction of experimental pancreatitis. 1171 66

This study investigates the effects of the islet hormones insulin (Ins), glucagon (Glu), and somatostatin (Som) with nerve stimulation (EFS) acetylcholine (ACh) and cholecytokinin-octapeptide (CCK-8) on amylase secretion and intracellular free calcium concentration [Ca(2+)](i) in the pancreas of age-matched control and diabetic rats. Either Ins, Glu or Som elicited small increases in amylase secretion from the pancreas of age-matched control animals compared to a much larger increase in amylase secretion with either EFS, ACh or CCK-8. Combining the islet hormones with either EFS, ACh or CCK-8 resulted in marked potentiation of amylase output. In the diabetic pancreas, the islet hormones had no effect on amylase secretion compared to diabetic control. Moreover, either EFS, ACh or CCK-8 evoked a much smaller increase in amylase output compared to age-matched control. In addition, the islet hormones failed to potentiate the secretory effects of either EFS, ACh or CCK-8. In fura-2 loaded acinar cells from age-matched control pancreas either Ins or Glu elicited a small increase in [Ca(2+)](i) whereas Som had no effect. Both ACh and CCK-8 evoked large increases in [Ca(2+)](i) compared to control. Combining either Ins, Glu or Som with either ACh or CCK-8 resulted in a marked elevation in [Ca(2+)](i) compared to the responses obtained with either the islet hormones, ACh or CCK-8 alone. In diabetic fura-2 loaded pancreatic acinar cells, the islet hormones had no effect on [Ca(2+)](i) compared to control and moreover, the responses were much smaller than those obtained in acinar cells from age-matched control. Both ACh and CCK-8 induced large increases in [Ca(2+)]( i) in diabetic acinar cells. However, combining the islet hormones with either ACh or CCK-8 failed to enhance [Ca(2+)](i) compared to the reponses obtained in acinar cells from age-matched control. The results suggests that [Ca(2+)](i) homeostasis is deranged during diabetes mellitus and this in turn is probably associated with reduced pancreatic amylase secretion.
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PMID:Involvement of cellular calcium in exocrine pancreatic insufficiency during streptozotocin-induced diabetes mellitus. 1188 Sep 30

Gastroparesis is a common complication of diabetes attributed to autonomic neuropathy. This study investigated whether acute hyperglycemia influences central thyrotropin-releasing hormone (TRH), a well-established brain medullary vagal stimulus, induced gastric acid secretion in overnight fasted, urethane-anesthetized rats. Intravenous infusion of D-glucose (20%, 30% and 40%) dose dependently reduced intracisternal TRH-induced gastric acid secretion (71+/-28 micromol/90 min) by 39%, 90% and 100% respectively. Pretreatment with cholecystokinin(A) (CCK(A)) receptor antagonist devazepide (1 mg/kg) did not influence the inhibitory effect of intravenous glucose (30%). These results indicate that hyperglycemia may have a central effect to antagonize medullary TRH stimulation of vagal outflow to the stomach.
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PMID:Intravenous glucose infusion decreases intracisternal thyrotropin-releasing hormone induced vagal stimulation of gastric acid secretion in anesthetized rats. 1264 56

Cholecystokinin-8 (CCK-8), the small peptide initially described as a gastric factor involved in the regulation of feeding behavior, is today recognized as one of the most abundant neurotransmitters/ neuropeptides in brain and is an important signal factor for the peripheral and central nervous systems. In the past twenty years, many studies have focused on possible clinical applications of this peptide and its receptor ligands in psychiatric diseases and gastrointestinal pathologies. Recently it has been suggested that CCK-8 may also have a neuroprotective role, thus opening a new field of interest around the physiology and the pharmacology of this neuropeptide and its receptors. It has been demonstrated that CCK-8 counteracts neuronal deficit following chemical or surgical lesions in both the central and peripheral nervous systems and that Nerve Growth factor (NGF) is involved in the CCK-induced recovery process. By using selective CCK receptor antagonists it has been demonstrated that CCK-8, when injected intraperitoneally, has the ability to stimulate NGF synthesis in brain and peripheral organs by a mechanism that involves the activation of CCK receptors. As has been widely reported, NGF is an essential survival and differentiative factor for selective neuronal populations of the PNS and CNS and plays a role in the events of degeneration and repair of the nervous system in diseases with different etiologies, e.g. neurodegenerative and autoimmune diseases as well as diabetes-associated pathologies. The possibility of using NGF in therapy has been evaluated and systemic and intracerebral NGF treatment have been tested in patients and animal models. Although the results of these studies are encouraging, the difficulty to predict and/or eliminate the side effects of NGF/NGF antibody treatment has made it difficult to fully evaluate the potential of the beneficial effects. In this context recent results obtained in our laboratories may offer a new prospective for the pharmacological approaches to the diseases associated with altered NGF production and functions. The data of our recent observations on NGF and CCK-8 is covered in this review.
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PMID:Cholecystokinin-8 and nerve growth factor: two endogenous molecules working for the upkeep and repair of the nervous system. 1276 2


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