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)

Islet amyloid polypeptide (IAPP) or amylin is a hormone candidate predominantly expressed in insulin cells. A role for IAPP in the regulation of glucose homeostasis and the development of non-insulin-dependent diabetes mellitus has been proposed. IAPP is structurally related to the sensory neuropeptide calcitonin gene-related peptide. In the present study, using in situ hybridization, immunocytochemistry, and immunochemistry, the expression of IAPP in sensory neurons in the rat was investigated. IAPP was expressed in a population of small- to medium-sized nerve cell bodies in dorsal root ganglia from all levels and in the jugular-nodose and trigeminal ganglion; IAPP-expressing nerve cell bodies constituted a subpopulation of those expressing calcitonin gene-related peptide. In addition, IAPP-like immunoreactivity occurred in nerve cell bodies storing substance P and pituitary adenylate cyclase-activating polypeptide. IAPP-immunoreactive nerve fibers were encountered in the dorsal horns of the spinal cord, and to a lesser extent in peripheral tissues receiving sensory innervation; IAPP-immunoreactive fibers constituted a subpopulation of those containing calcitonin gene-related peptide and/or substance P. The immunochemical determinations demonstrated a low level of IAPP-like immunoreactivity in the dorsal root ganglia and spinal cord, which chromatographically coeluted with authentic rat IAPP. We conclude that IAPP is expressed in sensory neurons, thus being a novel sensory neuropeptide candidate for which a physiological role remains to be identified.
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PMID:Islet amyloid polypeptide (amylin) is expressed in sensory neurons. 747 13

The 38 amino acid peptide pituitary adenylate cyclase activating polypeptide (PACAP) induced a dose dependent increase of catecholamine secretion in cultures of bovine chromaffin cells. This secretagogue activity of PACAP was strictly dependent on the presence of calcium in the culture medium. If calcium was omitted from the medium no effect of PACAP on catecholamine secretion could be detected during an incubation of 20 min. Preincubation of cells with 1 nM PACAP for 5 min facilitated the subsequent nicotine stimulated catecholamine secretion during a 20 min incubation without addition of the peptide. PACAP induced catecholamine secretion was clearly accompanied by a dose dependent increase of intracellular cAMP concentrations. The percentage of cells responding to PACAP with increased catecholamine secretion was assessed by immunocytochemistry of the transient appearance of dopamine-beta-hydroxylase, associated with the membranes of the chromaffin granules on the cell surface during the secretory process. About 70% of adrenal medullary cells responded to 100 nM PACAP with enhanced secretory activity. Though PACAP stimulated catecholamine secretion, we did not observed major effects on intracellular free calcium concentrations ([Ca2+]i) as determined with fura-2 by single cell fluorescence microscopy. In maximally 20% of the cells a rise in [Ca2+]i in response to a challenge with 500 nM PACAP was observed. Lower concentrations of PACAP were without an effect on [Ca2+]i. These data indicate that the stimulatory action of PACAP on in vitro catecholamine secretion from bovine chromaffin cells is linked to a rise of intracellular cAMP.
Exp Clin Endocrinol Diabetes 1995
PMID:Enhanced cAMP production mediates the stimulatory action of pituitary adenylate cyclase activating polypeptide (PACAP) on in vitro catecholamine secretion from bovine adrenal chromaffin cells. 755 79

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

1. The distribution and effects of pituitary adenylate cyclase-activating polypeptide (PACAP-27 and -38), helospectin (Hel-1 and Hel-2), and vasoactive intestinal polypeptide (VIP), were investigated in isolated preparations of human corpus cavernosum (CC). 2. Immunohistochemistry revealed coinciding profiles of nerve structures that showed immunoreactivities for VIP and PACAP, and VIP and Hel. Confocal microscopy showed the co-existence of VIP- and PACAP-immunoreactivities, and VIP- and Hel-immunoreactivities in most (90%) varicose nerve structures. 3. As determined by radioimmunoassay, the amounts of VIP, PACAP-27, and PACAP-38 in the preparations were 61.7 +/- 11.6, 0.1 +/- 0.05, and 3.7 +/- 0.5 pmol g-1 wet weight of tissue (pmol g-1 wet wt.), respectively. In tissue from patients with diabetes, the content of VIP was lower (13.7 +/- 0.5 pmol g-1 wet wt.), whereas that of PACAP (-27 and -38) was unchanged. 4. Cyclic nucleotide levels were determined in preparations exposed to PACAP-27, PACAP-38, Hel-1, Hel-2, and VIP. All the peptides, but Hel-2, significantly increased the concentrations of cyclic AMP, whereas the levels of cyclic GMP were unchanged. 5. The peptides concentration-dependently relaxed noradrenaline-contracted preparations. The order of potency was VIP > PACAP 27 > Hel-1 > Hel-2 > PACAP-38. 6. Hel-1, VIP and PACAP-27 effectively counteracted electrically induced contractions. At 10(-6) M, the highest peptide concentration used, the inhibitory effects obtained reached 96 +/- 3%, 87 +/- 6%, and 80 +/- 3%, respectively. 7. The results suggest that PACAP and Hel-1 are co-localized with VIP in nerve structures within the human cavernous tissue, and that the peptides are effective relaxants of CC preparations in vitro. The role of the investigated peptides for penile erection remains to be established.
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PMID:Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum. 856 57

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterised by an early age of onset and an autosomal dominant mode of inheritance. Only a proportion of cases are due to mutations in the glucokinase gene. We have studied five Caucasian MODY families, including the first MODY family to be described, with five candidate genes implicated in regulation of insulin secretion. The affected subjects showed more marked hyperglycaemia than that found in subjects with glucokinase mutations. We assessed polymorphic markers close to the genes for glucokinase, hexokinase II, adenosine deaminase, pituitary adenylate cyclase-activating polypeptide receptor, and glucagon-like peptide-1 receptor. Linkage analysis with diabetes gave cumulative log of the odds (LOD) scores of less than -3, implying that mutations in these genes are unlikely to provide a major genetic contribution to this form of MODY.
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PMID:Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase. 859 19

The effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on LH and FSH secretion by human pituitary gonadotrophinomas in cell culture was studied. PACAP (1-38 peptide, 0.2-20 nmol/L) dose-dependently stimulated both LH and FSH secretion after 24 hours incubation. Of 11 tumours studied, PACAP (20 nmol/L) stimulated LH and/or FSH secretion by 1.7-4 fold in 9 cases. Two tumours did not respond to PACAP, although LHRH was stimulatory in these. None of the 11 tumours contained gsp mutations, excluding the possibility that these were the cause of the occassionally observed non-responsiveness to PACAP. A combination of PACAP (20 nmol/L) together with TRH (25 nmol/L) resulted in greater stimulatory effects on LH and FSH secretion than exerted by either peptide alone, but this was not observed with LHRH. In 3 tumours tested, PACAP stimulated cAMP production 2-3 fold by cultured human pituitary gonadotrophinomas but had no effect on rate of phosphatidylinositol (PI) turnover. These results indicate that PACAP can directly stimulate LH and FSH secretion by human pituitary gonadotrophs and that PACAP-receptors in gonadotrophin-secreting tumours are coupled with adenylate cyclase but not the PI second messenger system. We conclude that PACAP may play a role in controlling gonadotroph function in the human pituitary gland.
Exp Clin Endocrinol Diabetes 1996
PMID:Pituitary adenylate cyclase-activating polypeptide directly stimulates LH and FSH secretion by human pituitary gonadotrophinomas. 881 43

Pituitary adenylate cyclase activating polypeptide (PACAP), which was isolated from ovine hypothalamic extract, has been shown to have a physiological role in the regulation of insulin or islet functions. In streptozotocin (STZ)-induced diabetic rats, we examined the content of PACAP immunoreactivity and gene expression of three specific receptors. Four weeks after administration of STZ (50 mg/kg), plasma glucose levels increased 3.3-fold, and plasma insulin levels decreased to one-tenth as compared with the control. The content of PACAP immunoreactivity in the pancreas potently increased by 30%, but the content of vasoactive intestinal polypeptide (VIP) immunoreactivity was not changed. In the other tissues, the content of PACAP immunoreactivity did not significantly change except in the hypothalamus, which showed a 10% increment. In the expression level of PACAP/VIP receptors, semi-quantitative RT-PCR analysis revealed that VIP1/PACAP receptor mRNA significantly increased as compared with the other two types of receptors in the pancreas of STZ-induced diabetic rats. These findings suggest that PACAP and VIP1/PACAP receptor might be involved in the pathophysiology of diabetes mellitus.
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PMID:The augmentation of pituitary adenylate cyclase-activating polypeptide (PACAP) in streptozotocin-induced diabetic rats. 986 55

We describe a screen for new imprinted human genes, and the identification in this way of ZAC (zinc finger protein which regulates apoptosis and cell cycle arrest)/ PLAGL1 (pleomorphicadenoma of the salivary gland gene like 1) as a strong candidate gene for transient neonatal diabetes mellitus (TNDM). To screen for imprinted genes, we compared parthenogenetic DNA from the chimeric patient FD and androgenetic DNA from hydatidiform mole, using restriction landmark genome scanning for methylation. This resulted in identification of two novel imprinted loci, one of which (NV149) we mapped to the TNDM region of 6q24. From analysis of the corresponding genomic region, it was determined that NV149 lies approximately 60 kb upstream of the ZAC / PLAGL1 gene. RT-PCR analysis was used to confirm that this ZAC / PLAGL1 is expressed only from the paternal allele in a variety of tissues. TNDM is known to result from upregulation of a paternally expressed gene on chromosome 6q24. The paternal expression, map position and known biological properties of ZAC / PLAGL1 make it highly likely that it is the TNDM gene. In particular, ZAC / PLAGL1 is a transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide, which is the most potent known insulin secretagog and an important mediator of autocrine control of insulin secretion in the pancreatic islet.
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PMID:The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes. 1065 56

Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardiotonic peptide, has a potential role for CGRP in diverse physiologic and pathophysiologic situations such as congestive heart failure, diabetes, migraine, and neurogenic inflammation. Although a peptide CGRP receptor antagonist, CGRP(8-37,) is available, its utility presents significant limitations for these indications. Here, we describe the properties of SB-(+)-273779 [N-methyl-N-(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl)nitrobenzanilide], a selective nonpeptide antagonist of CGRP(1) receptor. SB-(+)-273779 inhibited (125)I-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and human cloned CGRP(1) receptor with K(i) values of 310 +/- 40 and 250 +/-15 nM, respectively. SB-(+)-273779 also inhibited CGRP (3 nM)-activated adenylyl cyclase in these systems with IC(50) values of 390 +/-10 nM (in SK-N-MC) and 210 +/-16 nM (recombinant human CGRP receptors). Prolonged treatment (>30 min) of SK-N-MC cells with SB-(+)-273779 followed by extensive washing resulted in reduction in maximum CGRP-mediated adenylyl cyclase activity, suggesting that this compound has irreversible binding characteristics. In addition, SB-(+)-273779 antagonized CGRP-mediated 1) stimulation of intracellular Ca(2+) in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of insulin-stimulated [(14)C]deoxyglucose uptake in L6 cells, 3) vasodilation in rat pulmonary artery, and 4) decrease in blood pressure in anesthetized rats. SB-(+)-273779 tested at 3 microM had no significant affinity for calcitonin, endothelin, angiotensin II, and alpha-adrenergic receptors under standard ligand binding assays. SB-(+)-273779 also did not inhibit forskolin and pituitary adenylate cyclase-activating polypeptide. These results suggest that SB-(+)-273779 is a valuable tool for studying CGRP-mediated functional responses in complex biological systems.
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PMID:Pharmacology of SB-273779, a nonpeptide calcitonin gene-related peptide 1 receptor antagonist. 1118 5

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is ubiquitously distributed in both the central and peripheral nervous systems and exerts a variety of effects. PACAP is a neuropeptide in pancreatic islets, where it has been suggested as a parasympathetic and sensory neurotransmitter. PACAP stimulates insulin secretion in a glucose-dependent manner, by an effect executed mainly through augmenting the formation of cAMP and stimulating the uptake of calcium. Accumulating evidence in animal studies points to a physiological importance of PACAP in the regulation of the insulin response to feeding. This review summarizes the current knowledge of islet actions and mechanisms and the function of PACAP.
Diabetes 2001 Sep
PMID:The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function. 1152 60


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