Metabolomic analysis of pancreatic beta cells following exposure to high glucose

Wallace, Martina; Whelan, Helena; Brennan, Lorraine

doi:10.1016/j.bbagen.2012.10.025

Cited by 28 publications

(24 citation statements)

References 56 publications

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“…Finally, chronic exposure to hyperglycemia caused glutamine concentrations and C4-glutamate labeling from U- 13 C-glucose to decrease, while GABA concentrations increased. These changes may indicate changes in flux through the GABA shunt pathway and glutamate dehydrogenase which have both been implicated in β-cell function [21]. While this study did not investigate the mechanism of these changes, the results partly align with another report that employed the GABA transaminase inhibitor gabaculine and succinic semialdehyde supplementation of the GABA shunt to link GABA metabolism to GSIS in rat islets [77].…”

Section: β-Cell Dysfunction and T2dsupporting

confidence: 78%

“…Cell numbers required for each analysis vary by method. For the studies included here, a typical GC–MS analysis uses 1.2–3.4 million cells [5,18], LC–MS 3.4–35 million [19,20], NMR 1.5–180 million [21–23], and lipidomics 9–94 million cells [24–26]. For context, 300–400 medium-to-large sized islets can be isolated from a single rat, with each islet comprised of 1000–1500 cells, yielding around 400,000 cells per animal.…”

Section: General Principles and Methodsmentioning

confidence: 99%

“…Multiple contributors to β-cell dysfunction have been proposed, including oxidative stress [69,70], ER stress [70], altered glucose metabolism [71] or impaired exocytosis mechanisms [72–75]. Several GC–MS-based metabolomics studies have been reported for insulinoma cell models of glucotoxicity, three of which were combined with 13 C-tracer and NMR experiments [21,22,36,64,76]. Despite similarities in methods used, significant variation in metabolite coverage remains.…”

Section: β-Cell Dysfunction and T2dmentioning

confidence: 99%

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Metabolomics applied to the pancreatic islet

Gooding

Jensen

Newgard

2016

Archives of Biochemistry and Biophysics

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Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to metabolic fuels, hormones, or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes gained from metabolomics studies.

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Section: β-Cell Dysfunction and T2dsupporting

confidence: 78%

Section: General Principles and Methodsmentioning

confidence: 99%

Section: β-Cell Dysfunction and T2dmentioning

confidence: 99%

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Metabolomics applied to the pancreatic islet

Gooding

Jensen

Newgard

2016

Archives of Biochemistry and Biophysics

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“…As shown previously [13,21], increased glucose levels affected the abundance of saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in membrane phospholipids. SFA incorporation following PA treatment was correlated positively to ambient glucose; the incremental SFA incorporation following treatment with 500 μmol/l PA increased from 24.0±0.6 ng/10 6 cells at 5 mmol/l glucose to 33.2±3.5 and 41.9±1.6 ng/10 6 cells at 11 and 25 mmol/l glucose, respectively.…”

Section: Resultsmentioning

confidence: 96%

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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Aims/hypothesis Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy-2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), which in turn augmented glucosestimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability. Methods INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 μmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly. Results PA was incorporated into membrane phospholipids in a concentration-and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARδ in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death. Conclusions/interpretation These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells.

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“…Chronic exposure of beta cells to high glucose (HG) causes detrimental effects on expression of genes related to insulin production and content, glucosestimulated insulin secretion (GSIS), and mitochondrial function (Wallace et al, 2013). In addition, oxidative stress may contribute to chronic hyperglycaemia-induced beta cell dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Uncoupling protein‐2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS‐1E cells and in diabetic mouse islets

Liu

Gao

et al. 2014

British J Pharmacology

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Background and PurposeUncoupling protein‐2 (UCP2) may regulate glucose‐stimulated insulin secretion. The current study investigated the effects of berberine, an alkaloid found in many medicinal plants, on oxidative stress and insulin secretion through restoration of UCP2 expression in high glucose (HG)‐treated INS‐1E cells and rat islets or in db/db mouse islets.Experimental ApproachMouse and rat pancreatic islets were isolated. Nitrotyrosine, superoxide dismutase (SOD)‐1 and UCP2 expression and AMPK phosphorylation were examined by Western blotting. Insulin secretion was measured by elisa. Mitochondrial reactive oxygen species (ROS) production was detected by confocal microscopy.Key ResultsIncubation of INS‐1E cells and rat islets with HG (30 mmol·L−1; 8 h) elevated nitrotyrosine level, reduced SOD‐1 and UCP2 expression and AMPK phosphorylation, and inhibited glucose‐stimulated insulin secretion. HG also increased mitochondrial ROS in INS‐1E cells. Co‐treatment with berberine inhibited such effects. The AMPK inhibitor compound C, the UCP2 inhibitor genipin and adenovirus ucp2 shRNA inhibited these protective effects of berberine. Furthermore, compound C normalized berberine‐stimulated UCP2 expression but genipin did not affect AMPK phosphorylation. Islets from db/db mice exhibited elevated nitrotyrosine levels, reduced expression of SOD‐1 and UCP2 and AMPK phosphorylation, and decreased insulin secretion compared with those from db/m+ mice. Berberine also improved these defects in diabetic islets and genipin blocked the effects of berberine.Conclusions and ImplicationsBerberine inhibited oxidative stress and restored insulin secretion in HG‐treated INS‐IE cells and diabetic mouse islets by activating AMPK and UCP2. UCP2 is an important signalling molecule in mediating anti‐diabetic effects of berberine.

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Metabolomic analysis of pancreatic beta cells following exposure to high glucose

Cited by 28 publications

References 56 publications

Metabolomics applied to the pancreatic islet

Metabolomics applied to the pancreatic islet

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Uncoupling protein‐2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS‐1E cells and in diabetic mouse islets

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