Hexosamines stimulate apoptosis by altering SIRT1 action and levels in rodent pancreatic  -cells

Lafontaine-Lacasse, Mathieu; Doré, Geneviève; Picard, Frédéric

doi:10.1677/joe-10-0243

Cited by 23 publications

(13 citation statements)

References 50 publications

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“…Thus, HSP attenuates unresolved inflammation (Newsholme & de Bittencourt 2014). Amino acids, such as L-glutamine, are required for the optimal HSP70 response, through the HBP-induced activation of SIRT1/HUR (Lafontaine-Lacasse et al 2011, which was observed in our study (Fig. 5A and C respectively).…”

Section: Discussionsupporting

confidence: 74%

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

Cruzat¹,

Keane²,

Scheinpflug³

et al. 2014

Journal of Endocrinology

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Obesity-associated diabetes and concomitant inflammation may compromise pancreatic b-cell integrity and function. L-glutamine and L-alanine are potent insulin secretagogues, with antioxidant and cytoprotective properties. Herein, we studied whether the dipeptide L-alanyl-L-glutamine (Ala-Gln) could exert protective effects via sirtuin 1/HUR (SIRT1/HUR) signalling in b-cells, against detrimental responses following ex vivo stimulation with inflammatory mediators derived from macrophages (IMMs). The macrophages were derived from blood obtained from obese subjects. Macrophages were exposed (or not) to lipopolysaccharide (LPS) to generate a pro-inflammatory cytokine cocktail. The cytokine profile was determined following analysis by flow cytometry. Insulin-secreting BRIN-BD11 b-cells were exposed to IMMs and then cultured with or without Ala-Gln for 24 h. Chronic insulin secretion, the L-glutamineglutathione (GSH) axis, and the level of insulin receptor b (IR-b), heat shock protein 70 (HSP70), SIRT1/HUR, CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome c oxidase IV (COX IV) were evaluated. Concentrations of cytokines, including interleukin 1b (IL1b), IL6, IL10 and tumour necrosis factor alpha (TNFa) in the IMMs, were higher following exposure to LPS. Subsequently, when b-cells were exposed to IMMs, chronic insulin secretion, and IR-b and COX IV levels were decreased, but these effects were partially or fully attenuated by the addition of Ala-Gln. The glutamine-GSH axis and HSP70 levels, which were compromised by IMMs, were also restored by Ala-Gln, possibly due to protection of SIRT1/HUR levels, and a reduction of CHOP expression. Using an ex vivo inflammatory approach, we have demonstrated Ala-Gln-dependent b-cell protection mediated by coordinated effects on the glutamine-GSH axis, and the HSP pathway, maintenance of mitochondrial metabolism and stimulus-secretion coupling essential for insulin release.

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Section: Discussionsupporting

confidence: 74%

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

Cruzat¹,

Keane²,

Scheinpflug³

et al. 2014

Journal of Endocrinology

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“…Despite the fact that HSF1 can bind in the heat shock elements (HSEs) in the nuclei, promoting HSP expression (e.g., HSP72) its activation may occur by other mechanisms, such Sirtuin 1 (SIRT1)/HuR modulation (Gabai et al, 2012). SIRT1/HuR are mostly modulated by severe inflammation, oxidative stress situations, and nutrients (Kim et al, 2012;Lafontaine-Lacasse et al, 2011;Newsholme et al, 2014). Therefore, increased expression of HSF1, with or without HSP70 stimulation may improve the inflammation status, increasing the liver's ability to respond under harmful situations (e.g., chronic inflammation).…”

Section: Discussionmentioning

confidence: 99%

L-glutamine Supplementations Enhance Liver Glutamine-Glutathione Axis and Heat Shock Factor-1 Expression in Endurance-Exercise Trained Rats

Petry

Cruzat

Heck³

et al. 2015

International Journal of Sport Nutrition and Exercise Metabolism

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Liver L-glutamine is an important vehicle for the transport of ammonia and intermediary metabolism of amino acids between tissues, particularly under catabolic situations, such as high-intensity exercise. Hence, the aim of this study was to investigate the effects of oral supplementations with L-glutamine in its free or dipeptide forms (with L-alanine) on liver glutamine-glutathione (GSH) axis, and 70 kDa heat shock proteins (HSP70)/heat shock transcription factor 1 (HSF1) expressions. Adult male Wistar rats were 8-week trained (60 min/day, 5 days/week) on a treadmill. During the last 21 days, the animals were daily supplemented with 1 g of L-glutamine/kg body weight per day in either l-alanyl-L-glutamine dipeptide (DIP) form or a solution containing L-glutamine and l-alanine in their free forms (GLN+ALA) or water (controls). Exercise training increased cytosolic and nuclear HSF1 and HSP70 expression, as compared with sedentary animals. However, both DIP and GLN+ALA supplements enhanced HSF1 expression (in both cytosolic and nuclear fractions) in relation to exercised controls. Interestingly, HSF1 rises were not followed by enhanced HSP70 expression. DIP and GLN+ALA supplements increased plasma glutamine concentrations (by 62% and 59%, respectively) and glutamine to glutamate plasma ratio in relation to trained controls. This was in parallel with a decrease in plasma ammonium levels. Supplementations increased liver GSH (by 90%), attenuating the glutathione disulfide (GSSG) to GSH ratio, suggesting a redox state protection. In conclusion, oral administration with DIP and GLN+ALA supplements in endurance-trained rats improve liver glutamine-GSH axis and modulate HSF1 pathway.

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“…SIRT1 is susceptible to intracellular fluctuations in the NAD + -to-NADH ratio and may influence type 2 diabetes risk by its known epigenetic effects and β-cell apoptosis (4,7,8). Recently, Sandovici et al (9) showed that suboptimal nutrition in rats during early development led to epigenetic silencing and reduced the expression of the transcription factor Hnf4a, which is required for pancreatic β-cell differentiation and glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Variants in the SIRT1 Gene May Affect Diabetes Risk in Interaction With Prenatal Exposure to Famine

et al. 2012

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OBJECTIVETo investigate whether SIRT1, a nutrient-sensing histone deacetylase, influences fetal programming during malnutrition.RESEARCH DESIGN AND METHODSIn 793 individuals of the Dutch Famine Birth Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms (SNPs) and prenatal exposure to famine on type 2 diabetes risk.RESULTSIn the total population (exposed and unexposed), SIRT1 variants were not associated with type 2 diabetes. A significant interaction was found between two SIRT1 SNPs and exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2 diabetes only in individuals who had been exposed to famine prenatally (odds ratio for rs7895833 0.50 [95% CI 0.24–1.03], P = 0.06; for rs1467568 0.48 [0.25–0.91], P = 0.02).CONCLUSIONSSIRT1 may be an important genetic factor involved in fetal programming during malnutrition, influencing type 2 diabetes risk later in life.

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Hexosamines stimulate apoptosis by altering SIRT1 action and levels in rodent pancreatic -cells

Cited by 23 publications

References 50 publications

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

L-glutamine Supplementations Enhance Liver Glutamine-Glutathione Axis and Heat Shock Factor-1 Expression in Endurance-Exercise Trained Rats

Variants in the SIRT1 Gene May Affect Diabetes Risk in Interaction With Prenatal Exposure to Famine

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