Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response

Natalicchio, Annalisa; Biondi, Giuseppina; Marrano, Nicola; Labarbuta, Rossella; Tortosa, Federica; Spagnuolo, Rosaria; D’Oria, Rossella; Carchia, Emanuele; Leonardini, Anna; Cignarelli, Angelo; Perrini, Sebastio; Laviola, Luigi

doi:10.1210/en.2015-2003

Cited by 24 publications

(21 citation statements)

References 50 publications

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“…1 , insulin release in response to 2.5 and 16.7 mM glucose was not apparently influenced by culture in palmitate-containing medium for 6 and 14 h. However, after 24 h exposure to the fatty acid, INS-1E β cells showed increased basal secretion and impaired ability to proportionately augment the release of insulin at higher glucose concentration; in addition, compared to control samples, palmitate-treated samples showed reduced cell survival (−32.0 ± 9.4%, p < 0.05). These results confirm what reported in previous studies on β cell deleterious effects of palmitate 27 , 28 . Then, in another set of experiments, INS-1E β cells were exposed for 24 h to a combination of deacetylase inhibitors (trichostatin A and nicotinamide).…”

Section: Resultssupporting

confidence: 93%

Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets

Ciregia

Bugliani²,

Ronci

et al. 2017

Sci Rep

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Type 2 diabetes is characterized by progressive β cell dysfunction, with lipotoxicity playing a possible pathogenetic role. Palmitate is often used to examine the direct effects of lipotoxicity and it may cause mitochondrial alterations by activating protein acetylation. However, it is unknown whether palmitate influences protein acetylation in β cells. We investigated lysine acetylation in mitochondrial proteins from INS-1E β cells (INS-1E) and in proteins from human pancreatic islets (HPI) after 24 h palmitate exposure. First, we confirmed that palmitate damages β cells and demonstrated that chemical inhibition of deacetylation also impairs INS-1E function and survival. Then, by 2-D gel electrophoresis, Western Blot and Liquid Chromatography-Mass Spectrometry we evaluated the effects of palmitate on protein acetylation. In mitochondrial preparations from palmitate-treated INS-1E, 32 acetylated spots were detected, with 13 proteins resulting over-acetylated. In HPI, 136 acetylated proteins were found, of which 11 were over-acetylated upon culture with palmitate. Interestingly, three proteins, glutamate dehydrogenase, mitochondrial superoxide dismutase, and SREBP-1, were over-acetylated in both INS-1E and HPI. Therefore, prolonged exposure to palmitate induces changes in β cell protein lysine acetylation and this modification could play a role in causing β cell damage. Dysregulated acetylation may be a target to counteract palmitate-induced β cell lipotoxicity.

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Section: Resultssupporting

confidence: 93%

Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets

Ciregia

Bugliani²,

Ronci

et al. 2017

Sci Rep

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“…Using rodent islets, Hashemitabar and associates have demonstrated beneficial effects of metformin [15 μM] on insulin gene expression, insulin secretion and islet cell viability [38]. Natalichhio and coworkers have shown significant restoration of GLP-1 receptor impairment by metformin [0.5–1.0 mM] in murine islets following exposure to palmitate [39]. Together, the above studies provide supporting evidence for beneficial/protective effects of metformin against gluco-, or lipotoxicity and ER stress.…”

Section: Discussionmentioning

confidence: 99%

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

et al. 2017

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Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic [HG; glucotoxic] conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed.

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“…In our laboratory, we have recently exploited 1.1B4 cells to assess the effects of PYY, NPY and pancreatic polypeptide and demonstrated beneficial effects on beta‐cell function and survival, thus providing a basis for the potential use of these and related agents for the treatment and/or prevention of diabetes . Additionally, the cells have been used for human translational studies such as the in vitro evaluation of mechanisms of lipotoxicity and assessment of novel peptide analogues for potential use as antidiabetic agents …”

Section: Human Beta‐cell Line Development and Potential For Therapeutmentioning

confidence: 99%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

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Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response

Cited by 24 publications

References 50 publications

Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets

Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

Cellular models for beta‐cell function and diabetes gene therapy

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