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Transcription factor EB (TFEB) is considered the master transcriptional regulator of autophagy and lysosomal biogenesis, which regulates target gene expression through binding to CLEAR motifs. TFEB dysregulation has been linked to the development of numerous pathological conditions; however, several other lines of evidence show that TFEB might be a point of convergence of diverse signaling pathways and might therefore modulate other important biological processes such as cellular senescence, DNA repair, ER stress, carbohydrates, and lipid metabolism and WNT signaling-related processes. The regulation of TFEB occurs predominantly at the post-translational level, including phosphorylation, acetylation, SUMOylating, PARsylation, and glycosylation. It is noteworthy that TFEB activation is context-dependent; therefore, its regulation is subjected to coordinated mechanisms that respond not only to nutrient fluctuations but also to stress cell programs to ensure proper cell homeostasis and organismal health. In this review, we provide updated insights into novel post-translational modifications that regulate TFEB activity and give an overview of TFEB beyond its widely known role in autophagy and the lysosomal pathway, thus opening the possibility of considering TFEB as a potential therapeutic target.

To identify when during fetal development connexins (Cxs) 26 (Cx26) 32 (Cx32), and 36 (Cx36) begin to be expressed, as well as to characterize their spatial distribution, real time polymerase chain reaction and immunolabeling studies were performed. Total RNA from mouse pancreases at 13 and 18 days postcoitum (dpc) and 3 days postpartum (dpp) was analyzed. In addition, pancreatic sections of mouse at 13, 14, 15, 16, 18 dpc and 3 dpp and of rat at term were double labeled with either anti-insulin or anti-a-amylase and anti-Cx26 or -Cx32 or -Cx36 antibodies and studied with confocal microscopy. From day 13 dpc, Cxs 26, 32, and 36 transcripts were identified and their levels increased with age. At 13-14 dpc, Cxs 26 and 32 were localized in few acinar cells, whereas Cx36 was distributed in small beta cell clumps. From day 14 dpc onwards, the number of labeled cells and relative immunofluorescent reactivity of all three Cxs at junctional membranes of the respective cell types increased. Cxs 26 and 32 colocalized in fetal acinar cells. In rat pancreas at term, a similar connexin distribution was found. Relative Cxs levels evaluated by immunoblotting also increased (two-fold) in pancreas homogenates from day 18 dpc to 3 dpp. The early cell specific, wide distribution, and age dependent expression of Cxs 26, 32, and 36 during fetal pancreas ontogeny suggests their possible involvement in pancreas differentiation and prenatal maturation. Anat Rec, 295:980-990, 2012. V C 2012 Wiley Periodicals, Inc.

Nowadays, connexin (Cx) 36 is considered the sole gap junction protein expressed in pancreatic beta cells. In the present research we investigated the expression of Cx30.2 mRNA and protein in mouse pancreatic islets. Cx30.2 mRNA and protein were identified in isolated islet preparations by qRT-PCR and Western blot, respectively. Immunohistochemical analysis showed that insulin-positive cells were stained for Cx30.2. Confocal images from double-labeled pancreatic sections revealed that Cx30.2 and Cx36 fluorescence co-localize at junctional membranes in islets from most pancreases. Abundant Cx30.2 tiny reactive spots were also found in cell cytoplasms. In beta cells cultured with stimulatory glucose concentrations, Cx30.2 was localized in both cytoplasms and cell membranes. In addition, Cx30.2 reactivity was localized at junctional membranes of endothelial or cluster of differentiation 31 (CD31) positive cells. Moreover, a significant reduction of Cx30.2 mRNA was found in islets preparations incubated for 24h in 22mM as compared with 3.3mM glucose. Therefore, it is concluded that Cx30.2 is expressed in beta and vascular endothelial cells of mouse pancreatic islets.

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Autophagy is a crucial mechanism for the functioning and survival of pancreatic beta cells. Its dysregulation has been associated with obesity, insulin resistance, and glucose intolerance. Furthermore, decreased autophagy in insulin-secret ing beta cells has been reported to contribute to the devel opment of type 2 diabetes mellitus (T2DM), which constitutes about 95% of all diabetes cases and is a chronic metabolic disease that it currently affects millions of people around the world. In different models of rodents, whether diabetic or obese, it has been observed that treatment with autophagy enhancers lowers glucose levels, increases insulin sensitivity, and protects beta cells from apoptosis. As stated above, it has recently been proposed to carry out an early intervention in patients with T2DM, using drugs that promote autophagy, which could help preserve the mass of beta cells and prevent the progression of the disease. This review provides an over view of the importance of the physiological process of auto phagy and its imminent role in the development of T2DM. Keywords: Pancreatic beta cells; autophagy; cell death; diabetes mellitus type 2