Localization and biosynthesis of polyamines in insulin-producing cells

Hougaard, David M.; Nielsen, Jens Høiriis; Larsson, Lars‐Inge

doi:10.1042/bj2380043

Cited by 59 publications

(44 citation statements)

References 22 publications

(24 reference statements)

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“…GABA can be folaned both by decarboxylation of glutamate, catalyzed by glutamate decarboxylase and from putrescine, catalyzed by DAO and aldehyde dehydrogenase [11]. Previously, the putrescine pathway has been shown to exist in several tissues, including the liver, small intestine, spleen, kidney and pancreatic islets [11,14,17,18] DAO has previously been implicated in growth regu-…”

Section: Discussionmentioning

confidence: 99%

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Regulation of gastric mucosal diamine oxidase activity by gastrin

Hougaard

Larsson

1992

FEBS Letters

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The polyamines spermidine and spermin¢ are essential for cell proliferation, Most growth factors stimulate polyamine synthesis by inducing ornithine decarboxylase activity, which catalyzes the formation of putrescine from ornithine, Patrescine can then be utilized either for polyamine biosynthesis or may serve as a ~ubstrate for diamine oxidase (DAO), leading to formation of y-aminobutyrie acid (GABA). Growth of tbe oxyntic mueosa of the stomach is stimulated by feeding° by trophic hormones such a~ gastrin and by exogenous administration of patreseine. Conversely. fasting, as well as omithine decarboxylas¢ inhibition decrease oxyntic mucosal DNA synthesis. We now demonstrate that fasted rats show a high degree of [~H]GABA formation from ['~H]putrescine in the oxyntie mucosa and that feeding or injections ofgastrin, caerulein or the DAO.inhibitor aminoguunidine decrease such [~H]GABA formation and, instead, stimulate formation of ['~H]sl~rmidine, Moreover. gastrin injections reduced ox~,ntie mucosal DAO activity, Thus, oxyntic mueosal DAO activity is regulated by tropic factors and may be involved in growth regulation by controlling intramucosal putrescine metabolism.

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Section: Discussionmentioning

confidence: 99%

“…The oxynti¢ mueosu was rinsed in cold saline and homogenized at 4°C in 0.2 M HCIO~, The extracted polyamines and GABA were dansylated and separated by HPLC as previously described [14]. Fractions were collected and subjected to liquid scintillation counting [141.…”

Section: Pcdyantine Determination and Pol)amhtt/gaba Synthesismentioning

confidence: 99%

Regulation of gastric mucosal diamine oxidase activity by gastrin

Hougaard

Larsson

1992

FEBS Letters

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“…It has been shown that other nutrients also enhance insulin-gene expression (Welsh et al, 1986) and that the insulin mRNA contents often correlate well with the rate of islet ATP generation (Welsh et al, 1986;Spinas et al, 1987;Eizirik et al, 1988). Thus glucose may need to be metabolized in order to exert its effects on insulin-gene expression; however, the precise role of the putative factors produced by glucose metabolism in this mechanism remains unknown.Polyamines are ubiquitous aliphatic cations present at millimolar concentrations in pancreatic f-cells (Hougaard et al, 1986; Welsh & Sj6holm, 1988 (Howell & Taylor, 1968;Lernmark et al, 1976). The islets were subsequently picked free from exocrine tissue and maintained free-floating in tissue culture at 37°C under a humidified atmosphere of air/5 % CO2.…”

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confidence: 99%

A role for polyamines in glucose-stimulated insulin-gene expression

Welsh

1990

Biochemical Journal

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The aim of the present study was to evaluate the possible role for polyamines in the glucose regulation of the metabolism of insulin mRNA of pancreatic islet cells. For this purpose islets were prepared from adult mice and cultured for 2 days in culture medium RPMI 1640 containing 3.3 mm-or 16.7 mM-glucose with or without the addition of the inhibitors of polyamine biosynthesis difluoromethylornithine (DFMO) and ethylglyoxal bis(guanylhydrazone) (EGBG). Culture at the high glucose concentration increased the islet contents of both insulin mRNA and polyamines. The synthesis of total RNA, total islet polyamines and polyamines associated with islet nuclei was also increased. When the combination of DFMO and EGBG was added in the presence of 16.7 mM-glucose, low contents of insulin mRNA, spermine and spermidine were observed. Total islet polyamine synthesis was also depressed by DFMO + EGBG, unlike islet biosynthesis of polyamines associated with nuclei, which was not equally decreased by the polyamine-synthesis inhibitors. Total RNA synthesis and turnover was not affected by DFMO + EGBG. Finally, actinomycin D attenuated the glucoseinduced enhancement of insulin mRNA, and cycloheximide counteracted the insulin-mRNA attenuation induced by inhibition of polyamine synthesis. It is concluded that the glucose-induced increase in insulin mRNA is paralleled by increased contents and rates of polyamine biosynthesis and that an attenuation of the increase in polyamines prevents the increase in insulin mRNA. In addition, the results are compatible with the view that polyamines exert their effects on insulin mRNA mainly by increasing the stability of this messenger. INTRODUCTIONIt is generally agreed that glucose is the principal regulator of the insulin gene (Welsh, 1989). This nutrient is thought to increase insulin mRNA contents both in vitro and in vivo, and increases of as much as 10-fold have been observed on glucose stimulation (Brunstedt & Chan, 1982). The glucose effect is mediated by a combination of increased transcription of the insulin gene and a selective stabilization of insulin mRNA against degradation . The stimulatory effect of glucose on insulin-gene transcription may, in part, be mediated by cyclic AMP Welsh et al., 1985). It has been shown that other nutrients also enhance insulin-gene expression (Welsh et al., 1986) and that the insulin mRNA contents often correlate well with the rate of islet ATP generation (Welsh et al., 1986;Spinas et al., 1987;Eizirik et al., 1988). Thus glucose may need to be metabolized in order to exert its effects on insulin-gene expression; however, the precise role of the putative factors produced by glucose metabolism in this mechanism remains unknown.Polyamines are ubiquitous aliphatic cations present at millimolar concentrations in pancreatic f-cells (Hougaard et al., 1986; Welsh & Sj6holm, 1988 (Howell & Taylor, 1968;Lernmark et al., 1976). The islets were subsequently picked free from exocrine tissue and maintained free-floating in tissue culture at 37°C under a humidifi...

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“…In addition, methylglyoxal bis(guanylhydrazone) (MGBG), an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), which produces decarboxylated S-adenosylmethionine, a substrate for spermidine and sperimine synthases, has also been used (Marton and Pegg, 1995). Earlier studies have shown that high concentrations of polyamines are present in pancreatic islets (Hougaard et al, 1986) and studies using DFMO suggested that polyamines play a role in the synthesis and release of insulin (Welsh and Sjöholm, 1988;Sjöholm, 1993). However, since DFMO reduces the intracellular levels of polyamines including putrescine, spermidine and spermine, the functional role of each polyamine has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Spermidine Regulates Insulin Synthesis and Cytoplasmic Ca2+ in Mouse Beta-TC6 Insulinoma Cells

Ohtani

Mizuno

Kojima

et al. 2009

Cell Struct. Funct.

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ABSTRACT. In order to assess the functional role of the polyamines spermidine and spermine in pancreatic betacells, we examined the effect of spermidine and spermine synthase inhibitors, trans-4-methylcyclohexylamine (MCHA) and N-(3-aminopropyl)cyclohexylamine (APCHA), on cellular polyamine and insulin contents, insulin secretion, and cytoplasmic Ca 2+ concentration ([Ca 2+ ]i) in mouse insulin-secreting Beta-TC6 cells. The cellular spermidine and spermine contents were reduced 90% and 64% by cultivation of cells in the presence of MCHA and APCHA for 3 days, respectively. Addition of spermidine or spermine reversed the polyamine level reduced by MCHA or APCHA, respectively. Insulin secretion was decreased 40~60% in the cells treated with MCHA or APCHA. The reduction by MCHA was reversed to the untreated level by adding spermidine exogenously, while the effect of APCHA was not reversed by treatment with spermine. The cellular insulin content was also reduced by treatment with MCHA but not the expression of insulin 1 and 2 genes, suggesting that spermidine was involved in the translation of insulin mRNAs. The elevation of [Ca 2+ ]i, a key event triggering insulin secretion induced by glucose, was reduced in Beta-TC6 cells by MCHA treatment. The spermidine synthase inhibitor also augmented the sustained [Ca 2+ ]i rise induced by carbamylcholine but not by a high concentration of KCl or nicotine. These results suggested that spermidine rather than spermine plays an important role in the regulation of insulin synthesis and the glucose-induced [Ca 2+ ]i rise in Beta-TC6 cells.

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Localization and biosynthesis of polyamines in insulin-producing cells

Cited by 59 publications

References 22 publications

Regulation of gastric mucosal diamine oxidase activity by gastrin

Regulation of gastric mucosal diamine oxidase activity by gastrin

A role for polyamines in glucose-stimulated insulin-gene expression

Spermidine Regulates Insulin Synthesis and Cytoplasmic Ca2+ in Mouse Beta-TC6 Insulinoma Cells

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