Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis

Abstract

An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may protect against glucotoxicity are poorly understood. We investigated whether Lin28a overexpression can improve glucotoxicity-induced β-cell dysregulation in INS-1 and primary rat islet cells. INS-1, a rat insulinoma cell line was cultured and primary rat islet cells were isolated from SD-rats. To define the effect of Lin28a in chronic high glucose-induced β-cell dysregulation, we performed several in vitro and ex-vivo experiments. Chronic exposure to high glucose led to a downregulation of Lin28a mRNA and protein expression, followed by a decrease in insulin mRNA expression and secretion in β-cells. The mRNA and protein expression levels of PDX-1 and BETA2, were reduced; The levels of apoptotic factors, including c-caspase3 and the Bax/Bcl-2 ratio, were increased due to glucotoxicity. Adenovirus-mediated Lin28a overexpression in β-cells reversed the glucotoxicity-induced reduction of insulin secretion and insulin mRNA expression via regulation of β-cell-enriched transcription factors such as PDX-1 and BETA2. Adenovirus-mediated overexpression of Lin28a downregulated the glucotoxicity-induced upregulation of c-caspase3 levels and the Bax/Bcl-2 ratio, while inhibition of endogenous Lin28a by small interfering RNA resulted in their up-regulation. Lin28a counteracted glucotoxicity-induced downregulation of p-Akt and p-mTOR. Our results suggest that Lin28a protects pancreatic β-cells from glucotoxicity through inhibition of apoptotic factors via the PI3 kinase/Akt/mTOR pathway.

Advances in the study of RNA-binding proteins in diabetic complications

“…As all these above-mentioned mechanisms are downstream effectors, more researchers are looking for the common 'keys' to these mechanisms, namely their upstream regulators, that acts as a master regulatory factor to the development and progression of DM and its complications. Recent studies have then found that RNA binding proteins (RBPs) such as human antigen R (HuR) and TTP (Tristetraprolin) are directly involved in vasculopathy in diabetes or diabetic complications by regulating the expression and stability of vascular endothelial growth factor (VEGF) mRNA [ [16] , [17] , [18] ], while LIN28 mediates the handling and ripening of let7 microRNA (miRNA), which promotes the uptake of blood glucose by tissue cells to inhibit the progression of DM and its complications [ [19] , [20] , [21] ].…”

Identifying miRNA Signatures Associated with Pancreatic Islet Dysfunction in a FOXA2-Deficient iPSC Model

“…The most upregulated DEGs involved in this process, RELN, was predicted to be targeted by hsa-miR-429. Also, one of the most important DEGs for the neuron proliferation is LIN28A [38], which has been reported to ameliorate β-cell dysfunction and apoptosis [39]. LIN28A was targeted in our study by several DEmiRs such as hsa-let-7d-5p, hsa-miR-4510, hsa-miR-329-3p, hsa-miR-296-5p, and hsa-miR-181c-5p, which were downregulated in FOXA2 −/− islets.…”

Exploring the mechanism of Jinlida granules against type 2 diabetes mellitus by an integrative pharmacology strategy

“…CASP3 is a key zymogen in cell apoptosis. It has been reported to be increased in glucotoxicity-induced β-cell apoptosis 45 . All these targets have verified link with the pathogenesis of T2DM.…”