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

Paulina Karen Mendoza Sanchez, Mona Khazaei, Eva Gatineau, Shirin Geravandi, Blaz Lupse, Huan Liu, Ralf Dringen, Anne Wojtusciszyn, Patrick Gilon, Kathrin Maedler, Amin Ardestani

Journal: Biochemical and biophysical research communications 2021;568():158-166

PMID: 34217973

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Abstract

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.

Address: Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.; Pole of Endocrinology, Diabetes, and Nutrition (EDIN), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCLouvain), 1200, Brussels, Belgium.; Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.; Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany. Electronic address: [email protected].; Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany; Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected].

DOI: 10.1016/j.bbrc.2021.06.065

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https://medlineplus.gov/diabetestype2.html

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https://assays.cancer.gov/CPTAC-91

MeSH Terms: Cells, Cultured, Diabetes Mellitus, Type 2, Glucagon-Secreting Cells, Glucose, Humans, Insulin Secretion, L-Lactate Dehydrogenase, RNA, Messenger, Up-Regulation