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

Ohtani, Masahiro; Mizuno, Ikuko; Kojima, Yumiko; Ishikawa, Yuichi; Sodeno, Midori; Asakura, Yuka; Samejima, Keijiro; Oka, Takami

doi:10.1247/csf.09008

Cited by 14 publications

(8 citation statements)

References 30 publications

(38 reference statements)

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“…In general, human islets present with fewer b cells and more a cells than rodent islets (for further information see Steiner et al (2010)). Another important difference between human and rodent islets is the fact that human b cells do not express the key urea cycle enzyme ornithine transcarbamylase; thus, the ornithine produced from arginase activity may be converted to glutamate and GSH or used for polyamine synthesis, with profound implications for b-cell functional integrity (Ohtani et al 2009). …”

Section: Proposed Model For Pancreatic B-cell Dysfunction On the Timementioning

confidence: 99%

Reactive oxygen and nitrogen species generation, antioxidant defenses, and β-cell function: a critical role for amino acids

Newsholme¹,

Rebelato²,

Abdulkader³

et al. 2012

Journal of Endocrinology

129

118

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Growing evidence indicates that the regulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels is essential for maintaining normal β-cell glucose responsiveness. While long-term exposure to high glucose induces oxidative stress in β cells, conflicting results have been published regarding the impact of ROS on acute glucose exposure and their role in glucose stimulated insulin secretion (GSIS). Although β cells are considered to be particularly vulnerable to oxidative damage, as they express relatively low levels of some peroxide-metabolizing enzymes such as catalase and glutathione (GSH) peroxidase, other less known GSH-based antioxidant systems are expressed in β cells at higher levels. Herein, we discuss the key mechanisms of ROS/RNS production and their physiological function in pancreatic β cells. We also hypothesize that specific interactions between RNS and ROS may be the cause of the vulnerability of pancreatic β cells to oxidative damage. In addition, using a hypothetical metabolic model based on the data available in the literature, we emphasize the importance of amino acid availability for GSH synthesis and for the maintenance of β-cell function and viability during periods of metabolic disturbance before the clinical onset of diabetes.

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Section: Proposed Model For Pancreatic B-cell Dysfunction On the Timementioning

confidence: 99%

Reactive oxygen and nitrogen species generation, antioxidant defenses, and β-cell function: a critical role for amino acids

Newsholme¹,

Rebelato²,

Abdulkader³

et al. 2012

Journal of Endocrinology

129

118

View full text Add to dashboard Cite

show abstract

“…Because polyamines also regulate multiple cell functions, our findings of increased intracellular levels of polyamines may have diverse implications for BUC function. The relationship among intracellular polyamines, [Ca 2ϩ ] i , and release of ACh by BUC is reminiscent of what has been described in pancreatic ␤-islet cells (18). In these islet cells, decreasing intracellular polyamines decreased cellular release of insulin in response to glucose.…”

Section: Discussionmentioning

confidence: 53%

Elevated polyamines in urothelial cells from OAB subjects mediate oxotremorine-evoked rapid intracellular calcium rise and delayed acetylcholine release

Sun

Tomiya

et al. 2013

American Journal of Physiology-Renal Physiology

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Increased polyamine signaling in bladder urothelial cells (BUC) may play a role in the pathophysiology of overactive bladder (OAB). We quantitated intracellular polyamine levels in cultured BUC from OAB and asymptomatic (NB) subjects. We assessed whether polyamines modulated rapid intracellular calcium ([Ca(2+)]i) changes and delayed acetylcholine (ACh) release evoked by oxotremorine (OXO, a muscarinic agonist). BUC were cultured from cystoscopic biopsies. High-performance liquid chromatography (HPLC) quantitated intracellular putrescine, spermidine, and spermine levels. Five-millimeter difluoromethylornithine (DFMO), and one-millimeter methylglyoxalbisguanylhydrazone (MGBG) treatments were used to deplete intracellular polyamines. Ten micrometers of OXO were used to increase [Ca(2+)]i levels (measured by fura 2 microfluorimetry) and trigger extracellular ACh release (measured by ELISA). Polyamine levels were elevated in OAB compared with NB BUC (0.5 ± 0.15 vs. 0.16 ± 0.03 nmol/mg for putrescine, 2.4 ± 0.21 vs. 1.01 ± 0.13 nmol/mg for spermidine, and 1.90 ± 0.27 vs. 0.86 ± 0.26 nmol/mg for spermine; P < 0.05 for all comparisons). OXO evoked greater [Ca(2+)]i rise in OAB (205.10 ± 18.82% increase over baseline) compared with in NB BUC (119.54 ± 13.01%; P < 0.05). After polyamine depletion, OXO evoked [Ca(2+)]i rise decreased in OAB and NB BUC to 43.40 ± 6.45 and 38.82 ± 3.5%, respectively. OXO tended to increase ACh release by OAB vs. NB BUC (9.02 ± 0.1 vs. 7.04 ± 0.09 μM, respectively; P < 0.05). Polyamine depletion reduced ACh release by both OAB and NB BUC. In conclusion, polyamine levels were elevated twofold in OAB BUC. OXO evoked greater increase in [Ca(2+)]i and ACh release in OAB BUC, although these two events may be unrelated. Depletion of polyamines caused OAB BUC to behave similarly to NB BUC.

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“…Previous studies have shown that a depletion of polyamines led to reduced insulin content by inhibition of spermidine synthase. Spermidine synthase inhibition reduced endogenous spermidine levels leading to reduced Ca +2 levels and subsequently diminished insulin content 30 . An addition of exogenous spermidine reversed the Ca +2 levels and insulin content 30 .…”

Section: Discussionmentioning

confidence: 99%

The effect of spermidine on autoimmunity and beta cell function in NOD mice

Karacay

Prietl

Harer

et al. 2022

Sci Rep

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Spermidine is a natural polyamine which was shown to prolong lifespan of organisms and to improve cardiac and cognitive function. Spermidine was also reported to reduce inflammation and modulate T-cells. Autophagy is one of the mechanisms that spermidine exerts its effect. Autophagy is vital for β-cell homeostasis and autophagy deficiency was reported to lead to exacerbated diabetes in mice. The effect of spermidine in type 1 diabetes pathogenesis remains to be elucidated. Therefore, we examined the effect of spermidine treatment in non-obese diabetic (NOD) mice, a mouse model for type 1 diabetes. NOD mice were given untreated or spermidine-treated water ad libitum from 4 weeks of age until diabetes onset or 35 weeks of age. We found that treatment with 10 mM spermidine led to higher diabetes incidence in NOD mice despite unchanged pancreatic insulitis. Spermidine modulated tissue polyamine levels and elevated signs of autophagy in pancreas. Spermidine led to increased proportion of pro-inflammatory T-cells in pancreatic lymph nodes (pLN) in diabetic mice. Spermidine elevated the proportion of regulatory T-cells in early onset mice, whereas it reduced the proportion of regulatory T-cells in late onset mice. In summary spermidine treatment led to higher diabetes incidence and elevated proportion of T-cells in pLN.

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

Cited by 14 publications

References 30 publications

Reactive oxygen and nitrogen species generation, antioxidant defenses, and β-cell function: a critical role for amino acids

Reactive oxygen and nitrogen species generation, antioxidant defenses, and β-cell function: a critical role for amino acids

Elevated polyamines in urothelial cells from OAB subjects mediate oxotremorine-evoked rapid intracellular calcium rise and delayed acetylcholine release

The effect of spermidine on autoimmunity and beta cell function in NOD mice

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