The effective delivery of antioxidants to the cells is hindered by their high metabolization rate. In this work, quercetin was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. They were characterized in terms of its physicochemical properties (particle size distribution, ζ-potential, encapsulation efficiency, quercetin release and biological interactions with cardiac cells regarding nanoparticle association, and internalization and protective capability against relevant challenges). A better delivery of quercetin was achieved when encapsulated versus free. When the cells were challenged with antimycin A, it resulted in lower mitochondrial O2- (4.65- vs. 5.69- fold) and H2O2 rate production (1.15- vs. 1.73- fold). Similarly, under hypoxia-reoxygenation injury, a better maintenance of cell viability was found (77 vs. 65%), as well as a reduction of thiol groups (~70 vs. 40%). Therefore, the delivery of encapsulated quercetin resulted in the preservation of mitochondrial function and ATP synthesis due to its improved oxidative stress suppression. The results point to the potential of this strategy for the treatment of oxidative stress-based cardiac diseases.

Close ties have been made among certain nutrients, obesity, type 2 diabetes and circadian clocks. Among nutrients, taurine has been documented as being effective against obesity and type 2 diabetes. However, the impact of taurine on circadian clocks has not been elucidated. We investigated whether taurine can modulate or correct disturbances in daily rhythms caused by a high-fat diet in mice. Male C57BL/6 mice were divided in four groups: control (C), control + taurine (C+T), high-fat diet (HFD) and HFD + taurine (HFD+T). They were administered 2% taurine in their drinking water for 10 weeks. Mice were euthanized at 6:00, 12:00, 18:00, and 24:00. HFD mice increased body weight, visceral fat and food intake, as well as higher levels of glucose, insulin and leptin, throughout the 24 h. Taurine prevented increments in food intake, body weight and visceral fat, improved glucose tolerance and insulin sensitivity and reduced disturbances in the 24 h patterns of plasma insulin and leptin. HFD downregulated the expression of clock genes Rev-erbα, Bmal1, and Per1 in pancreatic islets. Taurine normalized the gene and protein expression of PER1 in beta-cells, which suggests that it could be beneficial for the correction of daily rhythms and the amelioration of obesity and diabetes.

Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α–independent peroxisome proliferator–activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by β cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.

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The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes.

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing β cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create β-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts. In light of the therapeutic benefits of choosing an accessible cell type as the cell of origin, in this study we set out to analyze the feasibility of transforming human skin fibroblasts into β-like cells. We describe how the timed-introduction of five developmental transcription factors (Neurog3, Pdx1, MafA, Pax4, and Nkx2-2) promotes conversion of fibroblasts toward a β-cell fate. Reprogrammed cells exhibit β-cell features including β-cell gene expression and glucose-responsive intracellular calcium mobilization. Moreover, reprogrammed cells display glucose-induced insulin secretion in vitro and in vivo. This work provides proof-of-concept of the capacity to make insulin-producing cells from human fibroblasts via transcription factor-mediated direct reprogramming.

Direct lineage reprogramming of one somatic cell into another bypassing an intermediate pluripotent state has emerged as an alternative to embryonic or induced pluripotent stem cell differentiation to generate clinically relevant cell types. One cell type of clinical interest is the pancreatic β cell that secretes insulin and whose loss and/or dysfunction leads to diabetes. Generation of functional β-like cells from developmentally related somatic cell types (pancreas, liver, gut) has been achieved via enforced expression of defined sets of transcription factors. However, clinical applicability of these findings is challenging because the starting cell types are not easily obtainable. Skin fibroblasts are accessible and easily manipulated cells that could be a better option, but available studies indicate that their competence to give rise to β cells through similar direct reprogramming approaches is limited. Here, using human skin fibroblasts and a protocol that ensures high and consistent expression of adenovirus-encoded reprogramming factors, we show that the transcription factor cocktail consisting of Pdx1, Ngn3, MafA, Pax4 and Nkx2-2 activates key β cell genes and down-regulates the fibroblast transcriptional program. The converted cells produce insulin and exhibit intracellular calcium responses to glucose and/or membrane depolarization. Furthermore, they secrete insulin in response to glucose in vitro and after transplantation in vivo. These findings demonstrate that transcription factor-mediated direct reprogramming of human fibroblasts is a feasible strategy to generate insulin-producing cells.