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J Proteome Res. 2017 Jun 2;16(6):2294-2306. doi: 10.1021/acs.jproteome.7b00160. Epub 2017 May 9.

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

Author information

1
Diabetes Research Institute, Miller School of Medicine, University of Miami , Miami, Florida 33136, United States.
2
Ri.MED Foundation , Palermo 90133, Italy.
3
School of Medicine and Dentistry, Catholic University of Valencia , Valencia 46001, Spain.
4
Metabolon, Inc. , Durham, North Carolina 27713, United States.
5
Department of Biomedical Engineering, University of Florida , Gainesville 32611, Florida, United States.

Abstract

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 indoleamine-2,3-dioxygenase on the corresponding pathway could be a worthwhile therapeutic target to dampen inflammatory effects.

KEYWORDS:

cytokines; human islets; hyperglycemia; hypoxia; insulin secretion; metabolomics; perifusion

PMID:
28452488
PMCID:
PMC5557342
DOI:
10.1021/acs.jproteome.7b00160
[Indexed for MEDLINE]
Free PMC Article

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