Metabolomic analysis of pancreatic β-cell insulin release in response to glucose

Huang, Mei; Joseph, Jamie W.

doi:10.4161/isl.20141

Cited by 35 publications

(50 citation statements)

References 74 publications

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“…We observed the significant elevation of several metabolites, both in the cell and the media samples, following high glucose exposure. Elevation of some of these metabolites (e.g., fructose) under high glucose has also been observed in previous studies using the β-cell line 832/13 59, 60 . Furthermore, imidazole lactate, a metabolite involved in the histidine metabolism, was also upregulated in high glucose conditions.…”

Section: Discussionsupporting

confidence: 81%

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

et al. 2017

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The transplantation of human pancreatic islets is a therapeutic possibility for a subset of type 1 diabetic patients who experience severe hypoglycemia. Pre- and post-transplantation loss in islet viability and function, however, is a major efficacy-limiting impediment. To investigate the effects of inflammation and hypoxia, the main obstacles hampering the survival and function of isolated, cultured, and transplanted islets, we conducted a comprehensive metabolomics evaluation of human islets in parallel with dynamic glucose-stimulated insulin release (GSIR) perifusion studies for functional evaluation. Metabolomics profiling of media and cell samples identified a total of 241 and 361 biochemicals, respectively. Metabolites that were altered in highly significant manner in both included, for example, kynurenine, kynurenate, citrulline, and mannitol/sorbitol under inflammation (all elevated) plus lactate (elevated) and N-formylmethionine (depressed) for hypoxia. Dynamic GSIR experiments, which capture both first- and second-phase insulin release, found severely depressed insulin-secretion under hypoxia, whereas elevated baseline and stimulated insulin-secretion was measured for islet exposed to the inflammatory cytokine cocktail (IL-1β, IFN-γ, and TNF-α). Because of the uniquely large changes observed in kynurenine and kynurenate, they might serve as potential biomarkers of islet inflammation, and IDO on the corresponding pathway could be a worthwhile therapeutic target to dampen inflammatory effects.

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Section: Discussionsupporting

confidence: 81%

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

et al. 2017

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“…The contributions of glycogen synthesis and the pentose phosphate pathway (PPP) to total glucose utilization are thought to be low in β-cells, and >90% of glucose molecules entering β-cells are estimated to engage in glycolysis and subsequent mitochondrial metabolism [33,34]. In agreement with this, unbiased metabolomics analysis of 832/13 cells has demonstrated a significant glucose-induced increment of all glycolytic intermediates measured (glucose-6-phosphate, fructose 1,6-bisphosphate, dihydroxyactone phosphate, 2/3-phosphoglycerate, phosphoenolpyruvate and pyruvate) [18,20]. Furthermore, targeted as well as unbiased metabolomics analyses have revealed a robust increase in TCA intermediates ((iso)citrate, aconitate, α-ketoglutarate, succinate, fumarate and malate) in response to 45–120 min of glucose stimulation [18–20,35,36].…”

Section: Healthy Islet Functionmentioning

confidence: 86%

“…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%

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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“…With this proviso, metabolomic studies reveal 5-to 20-fold increases in metabolites such as citrate, 2-oxoglutarate, and malate during the period following a low to high glucose transition (FIGURE 7B), although absolute quantitation is rarely applied (188,230,490). It should be noted that while the low to high glucose transition has attracted a vast range of papers, the reverse process, the depletion of metabolites on the return to basal glucose, has been largely neglected.…”

Section: A Citric Acid Cycle Derived Coupling Factors Pyruvate Carbmentioning

confidence: 99%

The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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The pancreatic ␤-cell secretes insulin in response to elevated plasma glucose. This review applies an external bioenergetic critique to the central processes of glucose-stimulated insulin secretion, including glycolytic and mitochondrial metabolism, the cytosolic adenine nucleotide pool, and its interaction with plasma membrane ion channels. The control mechanisms responsible for the unique responsiveness of the cell to glucose availability are discussed from bioenergetic and metabolic control standpoints. The concept of coupling factor facilitation of secretion is critiqued, and an attempt is made to unravel the bioenergetic basis of the oscillatory mechanisms controlling secretion. The need to consider the physiological constraints operating in the intact cell is emphasized throughout. The aim is to provide a coherent pathway through an extensive, complex, and sometimes bewildering literature, particularly for those unfamiliar with the field.

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Metabolomic analysis of pancreatic β-cell insulin release in response to glucose

Cited by 35 publications

References 74 publications

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

Metabolomics applied to the pancreatic islet

The Pancreatic β-Cell: A Bioenergetic Perspective

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