Glutamine deprivation induces metabolic adaptations associated with beta cell dysfunction and exacerbate lipotoxicity

Studies have reported that plasma glutamine is reduced in type 2 diabetes (T2D) patients. Glutamine supplementation improves glycaemic control, however the mechanisms are unclear. Here, we evaluated in vitro the pancreatic beta cell bioenergetic and insulin secretory responses to various levels of g...

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Veröffentlicht in:Molecular and cellular endocrinology Jg. 491; S. 110433
Hauptverfasser: Carlessi, Rodrigo, Rowlands, Jordan, Ellison, Gaewyn, Helena de Oliveira Alves, Heloisa, Newsholme, Philip, Mamotte, Cyril
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Ireland Elsevier B.V 01.07.2019
Schlagworte:
Animals
Apoptosis
Beta cell dysfunction
Blood Glucose - metabolism
Energy Metabolism
ER stress
glucose
Glutamine
Glutamine - deficiency
glycemic control
insulin
Insulin - metabolism
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - metabolism
Insulin-Secreting Cells - pathology
islets of Langerhans
Lipotoxicity
Male
Metabolic flux
mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - pathology
noninsulin-dependent diabetes mellitus
Oxidative Stress
palmitates
Palmitates - toxicity
patients
phenotype
Rats
Rats, Wistar
saturated fatty acids
secretion
Signal Transduction
Unfolded protein response
viability
ER stress
Metabolic flux
Lipotoxicity
Beta cell dysfunction
Glutamine
Unfolded protein response
ISSN:0303-7207, 1872-8057, 1872-8057
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Zusammenfassung:Studies have reported that plasma glutamine is reduced in type 2 diabetes (T2D) patients. Glutamine supplementation improves glycaemic control, however the mechanisms are unclear. Here, we evaluated in vitro the pancreatic beta cell bioenergetic and insulin secretory responses to various levels of glutamine availability, or treatment in the presence of an inhibitor of intracellular glutamine metabolism. The impact of glutamine deprivation to the pathological events induced by the saturated fatty acid palmitate was also investigated. Glutamine deprivation induced a reduction in mitochondrial respiration and increase in glucose uptake and utilization. This phenotype was accompanied by impairment in beta cell function, as demonstrated by diminished insulin production and secretion, and activation of the unfolded protein response pathway. Palmitate led to insulin secretory dysfunction, loss of viability and apoptosis. Importantly, glutamine deprivation significantly exacerbated these phenotypes, suggesting that low glutamine levels could participate in the process of beta cell dysfunction in T2D. •Glutamine availability determines metabolic flux in BRIN-BD11 clonal beta cells.•Decrease in glutamine induces glycolysis and suppresses oxidative phosphorylation.•Glutamine deprivation triggers the UPR and leads to insulin secretory dysfunction.•Lipotoxicity is exacerbated in the absence of glutamine.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0303-7207
1872-8057
1872-8057
DOI:10.1016/j.mce.2019.04.013