LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes

The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult β-cell within the pancreatic islets. The repression of...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2021-09, Vol.568, p.158-166
Main Authors: Sanchez, Paulina Karen Mendoza, Khazaei, Mona, Gatineau, Eva, Geravandi, Shirin, Lupse, Blaz, Liu, Huan, Dringen, Ralf, Wojtusciszyn, Anne, Gilon, Patrick, Maedler, Kathrin, Ardestani, Amin
Format: Article
Language:English
Subjects:
Beta-cell
Cells, Cultured
Diabetes
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Glucagon-Secreting Cells - cytology
Glucagon-Secreting Cells - metabolism
Glucose - metabolism
Humans
Insulin Secretion
Islets
L-Lactate Dehydrogenase - analysis
L-Lactate Dehydrogenase - genetics
L-Lactate Dehydrogenase - metabolism
Lactate
LDH
LDHA
RNA, Messenger - analysis
RNA, Messenger - genetics
Up-Regulation
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Summary:The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult β-cell within the pancreatic islets. The repression of LDHA under normal physiological condition and its inappropriate upregulation under a diabetogenic environment is well-documented in rodent islets/β-cells but little is known about LDHA expression in human islet cells and whether its abundance is altered under diabetic conditions. Analysis of public single-cell RNA-seq (sc-RNA seq) data as well as cell type-specific immunolabeling of human pancreatic islets showed that LDHA was mainly localized in human α-cells while it is expressed at a very low level in β-cells. Furthermore, LDHA, both at mRNA and protein, as well as lactate production is upregulated in human pancreatic islets exposed to chronic high glucose treatment. Microscopic analysis of stressed human islets and autopsy pancreases from individuals with type 2 diabetes (T2D) showed LDHA upregulation mainly in human α-cells. Pharmacological inhibition of LDHA in isolated human islets enhanced insulin secretion under physiological conditions but did not significantly correct the deregulated secretion of insulin or glucagon under diabetic conditions. LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes. [Display omitted] •LDHA is localized in α-cells and only minimally in β-cells in human islets.•LDHA expression and lactate production are upregulated by glucotoxicity.•LDHA is upregulated in α-cells in T2D.•LDHA inhibition stimulates insulin secretion.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2021.06.065