The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing

Luu, Lemieux; Dai, Feihan F.; Prentice, Kacey J.; Huang, Xiaohang; Hardy, Alexandre B.; Hansen, Jakob Bondo; Liu, Yonggang; Joseph, Jamie W.; Wheeler, Michael B.

doi:10.1007/s00125-013-2946-5

Cited by 74 publications

(75 citation statements)

References 45 publications

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“…5B). In contrast, SIRT1 can suppress inflammation and stimulate HSP responses; however, in response to chronic inflammation, similar to that in obesity-associated diabetes, the SIRT1/HUR axis is repressed (Kotas et al 2013), contributing to the unresolved inflammation (LafontaineLacasse et al 2011, Luu et al 2013. In this study, using our in vitro model to mimic in vivo inflammation, we observed that Ala-Gln maintained the HSP70 levels via the SIRT1/HUR axis.…”

Section: Discussionmentioning

confidence: 48%

“…On the other hand, SIRT1 downstream pathways may be suppressed in chronic inflammatory situations, contributing to chronic low-grade inflammation and impaired insulin secretion (Luu et al 2013). Hence, L-glutamine together with L-alanine supplied as the L-alanyl-L-glutamine dipeptide (Ala-Gln) may benefit the antioxidant system, attenuating inflammation, and may modulate the HSP response in catabolic situations (Cruzat et al 2014a,b, Newsholme et al 2014.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

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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“…Repression of Sirt 1 in cells is responsible for major intracellular defects and caffeine induced mitochondrial apoptosis relevant to adipogenesis defects [31,32] related to NAFLD with NAFLD to reach 30% of the developing world [159][160][161][162]. Defective hepatic caffeine clearance rates in the developing world may be connected to pancreatic [163][164][165][166][167][168][169][170] and thyroid disease [171][172][173] but xenobiotics may also be the inducing factor in these chronic diseases. LPS induced Sirt 1 repression may involve both caffeine and xenobiotic toxic effects with the induction of NAFLD, NAFLD linked to gall bladder disease [174][175][176][177] and cardiovascular disease [107][108][109].…”

Section: Bacterial Lps and Caffeine Metabolism With Relevance To Naflmentioning

confidence: 99%

Nutrition Therapy Regulates Caffeine Metabolism with Relevance to NAFLD and Induction of Type 3 Diabetes

Martins¹

2017

DMD

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“…In addition to regulating glucose metabolism at the level of insulin-target cells, preclinical studies documented that VEGF and SIRT-1 genes act directly on pancreatic beta cells, facilitating insulin release (66, 67). Moreover, a preclinical study demonstrated a direct link between miR-29 and pancreatic insulin release, further connecting this miR with the metabolic adverse effects of APDs (68).…”

Section: Cvae and Metabolic Adverse Effects Of Apds: Same Pathogenesimentioning

confidence: 99%

The Ticking of the Epigenetic Clock: Antipsychotic Drugs in Old Age

et al. 2016

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BackgroundExposed to antipsychotic drugs (APDs), older individuals with dementing illness are at risk of cerebrovascular adverse effects (CVAE), including sudden death. Transient microvascular dysfunctions are known to occur in younger persons exposed to APDs; however, they seldom progress to CVAE, suggesting that APDs alone are insufficient for engendering this untoward effect. It is, therefore, believed that a preexistent microvascular damage is necessary for CVAE to take place, but the exact nature of this lesion remains unclear. CNS small vessel disease (SVD) is a well-known age-related risk factor for strokes, dementia, and sudden death, which may constitute the initial CVAE-predisposing pathology. Therefore, we propose the two strikes CVAE paradigm, in which SVD represents the first strike, while exposure to APDs, the second. In this model, both strikes must be present for CVAE to take place, and the neuroimaging load of white matter hyperintensities may be directly proportional with the CVAE risk. To investigate this hypothesis at the molecular level, we focused on a seemingly unrelated phenomenon: both APDs and SVD were found protective against a similar repertoire of cancers and their spread to the brain (1–4). Since microRNA-29 has shown efficacy against the same malignancies and has been associated with small vessels pathology, we narrowed our search down to this miR, hypothesizing that the APDs mechanism of action includes miR-29 upregulation, which in turn facilitates the development of SVD.AimTo assess whether miR-29 can be utilized as a peripheral blood biomarker for SVD and CVAE risk.MethodWe conducted a search of experimentally verified miR-29 target genes utilizing the public domain tools miRanda, RNA22 and Weizemann Institute of Science miRNA Analysis. We identified in total 67 experimentally verified target genes for miR-29 family, 18 of which correlate with microvascular integrity and may be relevant for CVAE.ConclusionUpregulated microRNA-29 silences the expression of 18 genes connected with capillary stability, engendering a major vulnerability for SVD (first strike) which in turn increases the risk for CVAE after exposure to APDs (second strike).

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The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing

Abstract: Taken together, these findings indicate that in beta cells the deacetylase SIRT1 regulates the expression of specific mitochondria-related genes that control metabolic coupling, and that a decrease in beta cell Sirt1 expression impairs glucose sensing and insulin secretion.

Cited by 74 publications

References 45 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

Nutrition Therapy Regulates Caffeine Metabolism with Relevance to NAFLD and Induction of Type 3 Diabetes

The Ticking of the Epigenetic Clock: Antipsychotic Drugs in Old Age

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