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

• Published in: Journal of proteome research 2017-06, Vol.16 (6), p.2294-2306
• Main Authors: Garcia-Contreras, Marta, Tamayo-Garcia, Alejandro, Pappan, Kirk L, Michelotti, Gregory A, Stabler, Cherie L, Ricordi, Camillo, Buchwald, Peter
• Format: Article
• Language: English
• Subjects: Biomarkers - analysis; Humans; Hyperglycemia; Hypoxia; Inflammation - diagnosis; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation; Kynurenic Acid - analysis; Kynurenine - analysis; Metabolomics - methods
• ISSN: 1535-3893; 1535-3907; 1535-3907
• DOI: 10.1021/acs.jproteome.7b00160

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.