Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By using the euglycemic glucose-clamp technique we have observed the effects of comparable low dose proinsulin and insulin infusions on isotopically determined glucose turnover in 20 anesthetized dogs. In each animal somatostatin (SRIF) infusion was used to suppress endogenous pancreatic hormone secretion and basal glucagon was replaced. Peripheral proinsulin (0.083 micrograms X kg-1 X min-1) and insulin (350 microU X kg-1 X min-1) levels 15- to 20-fold higher than insulin on a molar basis, based on previous observations that proinsulin has only 5-10% the biologic potency of insulin. Three groups of infusion studies were performed: SRIF and glucagon (n = 5); SRIF, glucagon, and proinsulin (n = 10); and SRIF, glucagon, and insulin (n = 5). The mean serum proinsulin level of 2.43 +/- 0.36 pmol/ml achieved represented a 17-fold excess compared with the mean serum insulin level of 0.14 +/- 0.03 pmol (20 +/- 4 microU/ml). At these concentrations, both hormones reduced hepatic glucose production rates by approximately 50% to 2.0 +/- 0.2 mg X kg-1 X min-1 and 1.8 +/- 0.5 mg X kg-1 X min-1, respectively. In contrast, proinsulin failed to stimulate peripheral glucose utilization, whereas insulin led to a 2.0 +/- 0.3 mg X kg-1 X min-1 increment (approximately 50% increase) in glucose uptake (P less than 0.05). Thus at low infusion rates proinsulin exerts its effect predominantly by suppressing hepatic glucose production without measurable stimulation of peripheral glucose disposal. In contrast, for a comparable degree of hepatic glucose output suppression, insulin also significantly stimulates glucose disposal.
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PMID:Selective suppression of hepatic glucose output by human proinsulin in the dog. 288 85

Biopsies of the pancreas head, tail, and uncinate regions of 6 Chacma baboons (Papio ursinus) were processed for ultrastructural and immunocytochemical (ICC) studies using avidin-biotin peroxidase label for light microscopy (LM) and immunogold for electron microscopy (EM). Survey 0.5 micron sections of Spurrs resin embedded tissue revealed areas of suitable islets. Thin 100-nm sections were then cut and stained from the osmicated blocks for ultrastructural studies. For ICC investigations, 1 micron sections were immunolabeled for LM before areas were selected for thin sectioning for ultrastructural immunolabeling. The baboon endocrine pancreas ultrastructure was found to be similar to that of other mammals with minor differences in islet and secretory granule size and shape and in electron opacity of the secretory granule cores. Insulin glucagon, somatostatin and pancreatic polypeptide (PP) producing cells were described. A small number of cells were seen to contain both glucagon and PP and some D cells were observed to contain a few granules with both the appearance and immunoreactivity of A cell secretory granules. Statistical analysis of 100 secretory granule diameters of each of the 4 cell types in 6 baboons revealed significant differences (p less than 0.001) in size between all but those of the A and D cells. The insulin precursor subunit, C-peptide, and the glucagon precursor, glicentin, were each found together with the final hormone product in their respective secretory granules. The precursors were often located toward the periphery of the secretory granule, suggesting that the conversion of precursor to active hormone may be membrane associated. A nonrandom topographical association was observed between A and D cells, suggesting a strong functional implication.
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PMID:Morphology and endocrine production of cells in the islets of Langerhans of the Chacma baboon. 288 75

RIN-m cells, cultured from a rat insulinoma, not only bind and secrete but also degrade insulin (Diabetes 1982; 31:521-31). The insulin-degrading activity resides in the cytosol and is similar to the insulin-specific proteases previously described in muscle and other tissues. It has an apparent Km of 0.15 microM for porcine insulin in crude cell-free extracts, a competitive inhibition constant for proinsulin that is close to the Km, and a lower but measurable affinity for glucagon. The enzyme is inactive at pHs below 6.0, indicating that it is not lysosomal, is completely inhibited by N-ethylmaleimide, and exhibits apparent competitive inhibition constants (microM) for the following peptides: desoctapeptide insulin, 0.043; guinea pig insulin, 0.048; proinsulin, 0.64; insulin B-chain, 1.17; glucagon, 7.0; and cyclic somatostatin, 8.6. Highly active insulin-degrading activity was found using cell suspensions of 22 cloned and 8 subcloned cell lines derived from RIN-m as well as 11 other continuous cell lines derived from a variety of nonislet tissues of rat, mouse, and human origin. Homogenates of the original rat islet tumor and cytosol of normal rat islets also contained insulin-degrading activity. Although insulin protease is present in a variety of tissues, it may have an additional regulatory function in cells that are actively synthesizing, storing, and secreting insulin.
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PMID:Cytosolic insulin-degrading activity in islet-derived tumor cell lines and in normal rat islets. 298 50

Conflicting reports on the direction and magnitude of the effect of somatostatin on (pro)insulin synthesis prompted our investigation. Two assays for proinsulin synthesis were designed in which [4,5-3H]-L-leucine incorporation into proinsulin was normalized on the basis of postincubation insulin levels rather than on the number of islets incubated. Somatostatin at a concentration of 10 micrograms/ml inhibited 300 mg/dl glucose-stimulated proinsulin synthesis by 25% from 448 +/- 25 dpm/microunits insulin to 336 +/- 25 dpm/microunits insulin (disintegrations per minute in the proinsulin peak per microunit extractable insulin) (p less than 0.05). Glucagon (10 micrograms/ml) reversed the inhibitory effect of somatostatin on proinsulin synthesis from 336 +/- 25 dpm/microunits insulin to 480 +/- 44 dpm/microunits insulin (p less than 0.02). Somatostatin (10 micrograms/ml) had no significant effect on proinsulin synthesis in the presence of 70 mg/dl or 150 mg/dl glucose. Insulin release in 300 mg/dl glucose was inhibited 38% by 10 micrograms/ml somatostatin from 3.05 +/- 0.40 mU medium/mU tissue to 1.90 +/- 0.10 mU medium/mU tissue (p less than 0.01) over a 45-minute incubation period. These data suggest that somatostatin may act on glucose signal transduction on a level at which both insulin synthesis and secretion are affected. Further, the results are consistent with the hypothesis that cyclic AMP participates in mediating somatostatin effects on B-cell metabolism.
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PMID:Evidence that somatostatin inhibits proinsulin synthesis and insulin release by isolated pancreatic islets of the rat. 610 96

Many small biologicaly active peptides are derived from larger precursor forms which fulfil a variety of roles in the synthesis, segregation and intracellular migration of secretory products. Limited proteolysis may occur at several stages during this process, giving rise to products that are either degraded (e.g. the prepeptides) or discharged coordinately from their cells of origin during exocytosis (e.g. insulin and C-peptide). Molecular defects have recently been found to occur at cleavage sites in proinsulin as well as in other proproteins, and these point mutations may, in some instances, be responsible for familial metabolic disorders. The nature and cell specificity of the proteolytic enzymes involved in the conversion of the various precursor forms remains unresolved. Recent studies in our laboratory have led to the identification of precursors of glucagon and somatostatin in rat islets of Langerhans. Analysis of tryptic maps of these precursors has shown that a trypsin-like enzyme would be sufficient to cleave the C-terminally located somatostatin sequence from its precursor (relative molecular mass 12,500), but that both trypsin-like and carboxypeptidase B-like enzymes would be necessary to cleave the internal glucagon sequence from its prohormone (relative molecular mass 18,000). Molecular cloning techniques have provided valuable new approaches to analysing the structures of a variety of precursor forms, including those for insulin, gastrin, growth hormone, adrenocorticotropic hormone and the endorphins, and in the future will undoubtedly shed more light on the structures of their chromosomal genes, the mechanisms regulating their expression, and their evolutionary origins.
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PMID:Formation of biologically active peptides. 610 30

Binding sites of isolated rat pancreatic islets have been shown to interact with insulin. Employing various species-insulins, insulin analogues and substances not being structurally related to insulin, structure-specificity as well as pH- and temperature-dependence of insulin binding to rat pancreatic islets have been studied. Rat insulin displaced 125 I-insulin from its binding sites in the same concentration-dependent manner as pork insulin did, whereas the insulin analogue des-(phe-val-asp)B1-3-p-glu B4-insulin was less effective. Pork C-peptide hardly competed for binding and pork proinsulin did not compete at all. Both the species' insulins inhibited glucose (16.7 mM)-induced insulin secretion. The inhibitory effect was less when des-(phe-val-asp)B1-3-p-glu B4-insulin was employed and no inhibition of insulin secretion was observed by the use of pork C-peptide or proinsulin. Glucagon and somatostatin did not affect insulin binding. pH optimum of insulin binding appears to be in the range between 7.0 and 8.0. Binding was augmented with increasing temperature up to 37 degrees C. It is concluded that rat pancreatic islets possess insulin because binding and biological potency of substances related to insulin were in harmony. Moreover pH- and temperature-optimum of insulin binding are in a physiological range.
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PMID:Insulin receptors on rat pancreatic islets: specificity of 125 I-insulin binding. 612 93

Rat islet cell tumours induced by injection of streptozotocin and nicotinamide have been studied in vivo and after the establishment of monolayer cultures of tumour cells. During an intravenous glucose tolerance test, tumour-bearing rats had increased release of immunoreactive insulin, with a high proportion of proinsulin, as well as accelerated glucose disposal relative to control rats. The tumours were rich in immunoreactive insulin and somatostatin, poor in glucagon. Non-tumour pancreatic tissue or isolated islets contained 10% or less of the corresponding normal amounts of insulin whereas the islet content of somatostatin was unchanged and that of glucagon increased. This is best interpreted as a selective suppression of non-tumour B cells, further supported by the observation that the initially reduced insulin release and content of non-tumour islets were partially restored after 2 days in tissue culture. In monolayer culture, tumour cells maintained insulin production and acute responsiveness to glucose for prolonged periods. There was no sign of cell proliferation. It is concluded that primary, chemically-induced insulin-producing pancreatic islet cell tumours retain several features characteristic to normal B cells and continue to influence glucose homeostasis in vivo.
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PMID:Studies in vivo and in vitro on chemically-induced primary islet cell tumours and non-tumour endocrine pancreatic tissue. 613 Oct 5

Results from recent studies have indicated that pancreatic islet prohormone converting enzymes are membrane-associated in islet microsomes and secretory granules. This observation, along with the demonstration that proglucagon is topologically segregated to the periphery within alpha cell secretory granules in several species, led us to investigate the possibility that newly synthesized islet prohormones might be associated with intracellular membranes. Anglerfish islets were incubated with [3H]tryptophan and [14C]isoleucine for 3 h, then fractionated by differential and density gradient centrifugation. Microsome (M) and secretory granule (SG) fractions were halved, sedimented, and resuspended in the presence or absence of dissociative reagents. After membrane lysis by repeated freezing and thawing, the membranous and soluble components were separated by centrifugation. Extracts of supernatants and pellets were chromatographed by gel filtration; fractions were collected and counted. A high proportion (77-79%) of the newly synthesized proinsulin and insulin was associated with both M and SG membranes. Most of the newly synthesized proglucagons and prosomatostatins (12,000-mol-wt precursors) were also membrane-associated (86-88%) in M and SG. In contrast, glucagon- and somatostatin-related peptides exhibited much less membrane-association in SG (24-31%). Bacitracin, bovine serum albumin EDTA, RNAse, alpha-methylmannoside, N-acetylglucosamine, and dithiodipyridine had no effect on prohormone association with membranes. However, high salt (1 M KCl) significantly reduced membrane-association of prohormones. Binding of labeled prohormones to SG membranes from unlabeled tissue increased with incubation time and was inhibited by unlabeled prohormones. The pH optimum for prohormone binding to both M and SG membranes was 5.2. It is suggested that association of newly synthesized prohormones with intracellular membranes could be related to the facilitation of proteolytic processing of prohormones and/or transport from their site of synthesis to the secretory granules.
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PMID:Association of newly synthesized islet prohormones with intracellular membranes. 614 27

Reversed-phase high-performance liquid chromatography (HPLC) is examined as a method for separating pancreatic peptides. The method was based on gradient elution with acetonitrile in an acid phosphate buffer (pH 3.10). Apart from human and porcine insulin all the other peptide standards tested (thyrotropin-releasing factor, vaso-active intestinal polypeptide, human C-peptide, porcine C-peptide, somatostatin, porcine glucagon, porcine proinsulin and porcine pancreatic polypeptide) could be separated simultaneously in 40 minutes with a binary gradient composed of five linear segments and increasing from 0 to 60% acetonitrile. Human and porcine insulin could be almost completely resolved by a minimal reduction in the steepness of the acetonitrile gradient. Repeated injections of human C-peptide and porcine insulin resulted in a coefficient of variation of less than 1.5% in the retention times. The use of 125I-labelled peptides gave recoveries exceeding 90%. HPLC of acid ethanol extracts of autopsy pancreases from three infants showed that the immunoreactivity of the peptides measured remained unaffected by the chromatography. Both immunoreactive C-peptide and immunoreactive insulin (IRI) were recovered in two peaks, the second common peak representing proinsulin and amounting to 6.5 to 8.4% of total IRI. Immunoreactive glucagon was eluted in a single peak. Chromatography of plasma extracts from two infants of diabetic mothers demonstrated that proinsulin accounted for 59-63% of total IRI, while insulin was separated into two peaks corresponding to the standards of human insulin and porcine insulin. These results indicate that reversed -phase HPLC is a method with a good reproducibility and a high recovery applicable to the rapid and effective separation of pancreatic peptides from biological extracts.
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PMID:Analysis of pancreatic peptide hormones by reversed-phase high-performance liquid chromatography. 614 91

A clonal hamster beta cell line (HIT) was established by simian virus 40 transformation of Syrian hamster pancreatic islet cells. Cytoplasmic insulin was detected in all cells by indirect fluorescent antibody staining, and membrane-bound secretory granules were observed ultrastructurally. Acidified-ethanol extracts of HIT cell cultures contained hamster insulin as determined by radioimmunoassay, radioreceptor assay, and bioassay. One subclone at passage 39 contained 2.6 micrograms of insulin per mg of cell protein. [3H]Leucine-labeled HIT insulin and proinsulin were identical to islet-derived proteins when compared by NaDodSO4/polyacrylamide gel electrophoresis of immunoprecipitates. HIT cell insulin secretion was stimulated by glucose, glucagon, and 3-isobutyl-1-methylxanthine. Insulin secretion at optimal glucose concentration (7.5 mM) was 2.4 milliunits per 10(6) cells per hr. Somatostatin and dexamethasone markedly inhibited HIT insulin secretion. The HIT cell line represents a unique in vitro system for studying beta cell metabolism and insulin biosynthesis.
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PMID:Insulin synthesis in a clonal cell line of simian virus 40-transformed hamster pancreatic beta cells. 627 Jun 73


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