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

Marta Garcia-Contreras, Alejandro Tamayo-Garcia, Kirk L. Pappan, Gregory A. Michelotti, Cherie L. Stabler, Camillo Ricordi, Peter Buchwald

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2294-2306
Number of pages13
JournalJournal of Proteome Research
Volume16
Issue number6
DOIs
StatePublished - Jun 2 2017

Fingerprint

Metabolomics
Islets of Langerhans
Insulin
Inflammation
Glucose
Kynurenic Acid
Kynurenine
N-Formylmethionine
Transplantation
Indoleamine-Pyrrole 2,3,-Dioxygenase
Islets of Langerhans Transplantation
Citrulline
Sorbitol
Biomarkers
Mannitol
Metabolites
Interleukin-1
Hypoglycemia
Lactic Acid
Hypoxia

Keywords

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

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry

Cite this

Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets. / Garcia-Contreras, Marta; Tamayo-Garcia, Alejandro; Pappan, Kirk L.; Michelotti, Gregory A.; Stabler, Cherie L.; Ricordi, Camillo; Buchwald, Peter.

In: Journal of Proteome Research, Vol. 16, No. 6, 02.06.2017, p. 2294-2306.

Research output: Contribution to journalArticle

Garcia-Contreras, Marta ; Tamayo-Garcia, Alejandro ; Pappan, Kirk L. ; Michelotti, Gregory A. ; Stabler, Cherie L. ; Ricordi, Camillo ; Buchwald, Peter. / Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets. In: Journal of Proteome Research. 2017 ; Vol. 16, No. 6. pp. 2294-2306.
@article{45bf86f14d2246ceb05623b24a0423f4,
title = "Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets",
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",
author = "Marta Garcia-Contreras and Alejandro Tamayo-Garcia and Pappan, {Kirk L.} and Michelotti, {Gregory A.} and Stabler, {Cherie L.} and Camillo Ricordi and Peter Buchwald",
year = "2017",
month = "6",
day = "2",
doi = "10.1021/acs.jproteome.7b00160",
language = "English (US)",
volume = "16",
pages = "2294--2306",
journal = "Journal of Proteome Research",
issn = "1535-3893",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - Metabolomics Study of the Effects of Inflammation, Hypoxia, and High Glucose on Isolated Human Pancreatic Islets

AU - Garcia-Contreras, Marta

AU - Tamayo-Garcia, Alejandro

AU - Pappan, Kirk L.

AU - Michelotti, Gregory A.

AU - Stabler, Cherie L.

AU - Ricordi, Camillo

AU - Buchwald, Peter

PY - 2017/6/2

Y1 - 2017/6/2

N2 - 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.

AB - 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.

KW - cytokines

KW - human islets

KW - hyperglycemia

KW - hypoxia

KW - insulin secretion

KW - metabolomics

KW - perifusion

UR - http://www.scopus.com/inward/record.url?scp=85020173180&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020173180&partnerID=8YFLogxK

U2 - 10.1021/acs.jproteome.7b00160

DO - 10.1021/acs.jproteome.7b00160

M3 - Article

C2 - 28452488

AN - SCOPUS:85020173180

VL - 16

SP - 2294

EP - 2306

JO - Journal of Proteome Research

JF - Journal of Proteome Research

SN - 1535-3893

IS - 6

ER -