Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction

Abstract

The increasing incidence of type 2 diabetes mellitus is partially due to the rising obesity rates and the elevated levels of free fatty acids (FFAs). It is known that FFAs are putative mediators of beta-cell dysfunction, which is characterized with impaired glucose-stimulated insulin secretion and increased apoptosis, being defined as lipotoxicity. To date, many factors and their related signal pathways have been reported to be involved in FFA-induced beta-cell dysfunction. However, the entire blueprint is still not obtained. Some essential and newfound effectors, including the sterol regulatory element-binding protein (SREBP)-1c, farnesoid X receptor (FXR), forkhead box-containing protein O (FoxO) 1, ubiquitin C-terminal hydrolase L (UCHL) 1, N-myc downstream-regulated gene (NDRG) 2, perilipin family proteins, silent information regulator 2 protein 1 (Sirt1), pituitary adenylate cyclase-activating polypeptide (PACAP), and ghrelin are described in this review, which may help to further understand the molecular network for lipotoxicity.

FIG. 1.

Schematic diagram of effector intercrossing network under physiological condition. Sterol regulatory element-binding protein (SREBP)-1c is involved in multiple gene regulation, including insulin receptor substrate (IRS)-2, pancreatic and duodenal homeobox (Pdx-1), granuphilin, uncoupling protein (UCP) 2, and ion channels. Pituitary adenylate cyclase-activating polypeptide (PACAP) and silent information regulator 2 protein 1 (Sirt1) could regulate the expression of UCP2 as well. Farnesoid X receptor (FXR) upregulates the expression of Pdx-1, NeuroD1, and MafA. Forkhead box-containing protein O1 (FoxO1) is the downstream mediator of phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which could modulate the activity and/or expression of Pdx-1 and BAX. N-myc downstream-regulated gene (NDRG2) (substrate of Akt) and deubiquitinating enzyme ubiquitin C-terminal hydrolase L (UCHL1) are both involved in beta-cell survival. Perilipin and adipocyte differentiation-related protein (ADFP) can regulate the triglycerides (TG) storage in beta cells. The function of ghrelin includes the activation of PI3K/Akt pathway, the nuclear exclusion of FoxO1, the reduction in cytoplasmic TG synthesis, and the downregulation of BAX, SREBP-1c, and CHOP-10. Frame in bold line, direct target of lipid stress; ⊕, enhance; ⊖, inhibit.

FIG. 2.

Expression/activity of effectors under lipotoxic conditions. Lipid stress elevates the expression/activity of SREBP-1c and UCHL1, but downregulates the activity of NDRG2. The regulation of FXR, FoxO1, perilipin, ADFP, PACAP, Sirt1, and ghrelin under lipid stress needs to be further verified. Solid arrows stand for events that have been confirmed and dashed arrows for the events requiring substantiation.