Some long non-coding RNAs (lncRNAs) participate in physiological processes that maintain cellular and tissue homeostasis, and thus, the dysregulated expression of lncRNAs is involved in the onset and progression of many pathological conditions. Research has indicated that the genetic knockout of some lncRNAs in mice resulted in peri-or postnatal lethality or developmental defects. Diabetes mellitus (DM) is a major cause of peripheral neuropathy. Our studies showed that the expression levels of lncRNA uc.48+ in the diabetic rat dorsal root ganglia (DRG) and the DM patients' serum samples were increased. It suggested that lncRNA uc.48+ was involved in the pathophysiological process of DM. The aim of this study was to investigate the effects of lncRNA uc.48+ small interfering RNA (siRNA) on diabetic neuropathic pain (DNP) mediated by the P2X 3 receptor in the DRG. The values of the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured by the von Frey test and Hargreaves' test, respectively. The levels of P2X 3 protein and messenger RNA (mRNA) in the DRG were detected by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and western blotting. The experiments showed that the MWT and TWL values in DM rats were lower than those in the control rats. The MWT and TWL values in DM rats treated with lncRNA uc.48+ siRNA were increased compared to those in DM rats, but there was no significant difference between the DM rat group and the DM + scramble siRNA group. The levels of P2X 3 protein and mRNA in the DM DRG were higher than those in the control, while the levels of P2X 3 protein and mRNA in the DG of DM rats treated with uc.48+ siRNA were significantly decreased compared to those in DM rats. The expression levels of TNF-α in the DRG of DM rats treated with uc.48+ siRNA were significantly decreased compared to those in the DM group. The phosphorylation and activation of ERK1/2 in the DM DRG were decreased by uc.48+ siRNA treatment. Therefore, uc.48+ siRNA treatment may alleviate the DNP by inhibiting the excitatory transmission mediated by the P2X 3 receptor in DRG.

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High-glucose level exerts deleterious effects on pancreatic β cells, but the mechanisms remain unclear. Calcium/calmodulin-dependent serine protein kinase (CASK) plays a vital role in neural development and release of neurotransmitters, and probably plays a role in the anchoring of insulin on pancreatic β cell membrane. Hypoxia-inducible factor 1α (HIF1α) is involved in β-cell dysfunction. The aim of this study was to provide some basic evidence that CASK could be involved in glucotoxicity-induced insulin secretion dysfunction mediated by HIF1α in INS-1E cells. CASK overexpression plasmid, HIF1α agonist (CoCl2), and HIF1α selective inhibitor (KC7F2) were used. The results showed that chronic stimulation with high glucose could induce insulin secretion dysfunction in INS-1E β cells. Overexpression of CASK partially reversed the effects of high glucose on insulin secretion. CoCl2 reduced the expression of CASK, but KC7F2 reversed the glucotoxicity-induced CASK level reduction. These results suggested that glucotoxicity-induced insulin secretion defects in INS-1E cells could be mediated by HIF1α via the down-regulation of CASK.

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The current study revealed a new in vivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the Cask gene in mouse β-cells (βCASKKO), and glucose metabolism was evaluated in βCASKKO mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared with HFD-fed wild-type mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-fed βCASKKO mice. These results indicated that knockout of the Cask gene in β-cells had a diverse effect on glucose homeostasis; it reduced insulin secretion in ND-fed mice but improved insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

Islet inflammation is the hallmark of all types of diabetes mellitus (DM). 1,2 Accumulated evidence indicates that chronic islet inflammation exerts a strong role in pancreatic β-cell dysfunction, including impaired insulin secretion function and diminished mass of islet β-cells. 3 IL-1β has been identified as a main inflammatory mediator of eliciting islet β-cell injury in diabetes, 4 and animal studies and clinical trials blocking IL-1β signalling pathway have proved to ameliorate β-cell function and improve glucose homeostasis in DM, 5,6 yet the mechanism by which IL-1β impairs islet β-cell biology is not completely understood.