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Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.

Generation of three-dimensional (3D)-structured functional human islets is expected to be an alternative cell source for cadaveric human islet transplantation for the treatment of insulin-dependent diabetes. Human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer infinite resources for newly synthesized human islets. Recent advancements in hPSCs technology have enabled direct differentiation to human islet-like clusters, which can sense glucose and secrete insulin, and those islet clusters can ameliorate diabetes when transplanted into rodents or non-human primates (NHPs). However, the generated hPSC-derived human islet-like clusters are functionally immature compared with primary human islets. There remains a challenge to establish a technology to create fully functional human islets in vitro , which are functionally and transcriptionally indistinguishable from cadaveric human islets. Understanding the complex differentiation and maturation pathway is necessary to generate fully functional human islets for a tremendous supply of high-quality human islets with less batch-to-batch difference for millions of patients. In this review, I summarized the current progress in the generation of 3D-structured human islets from pluripotent stem cells and discussed the importance of adapting physiology for in vitro functional human islet organogenesis and possible improvements with environmental cues.

During the past few decades, it has been widely recognized that Reduction-Oxidation (redox) responses occurring at the intra- and extra-cellular levels are one of most important biological phenomena and dysregulated redox responses are involved in the initiation and progression of multiple diseases. Thioredoxin1 (Trx1) and Thioredoxin2 (Trx2), mainly located in the cytoplasm and mitochondria, respectively, are ubiquitously expressed in variety of cells and control cellular reactive oxygen species by reducing the disulfides into thiol groups. Thioredoxin interacting protein (Txnip/thioredoxin binding protein-2/vitamin D3 upregulated protein) directly binds to Trx1 and Trx2 (Trx) and inhibit the reducing activity of Trx through their disulfide exchange. Recent studies have revealed that Trx1 and Txnip are involved in some critical redox-dependent signal pathways including NLRP-3 inflammasome activation in a redox-dependent manner. Therefore, Trx/Txnip, a redox-sensitive signaling complex is a regulator of cellular redox status and has emerged as a key component in the link between redox regulation and the pathogenesis of diseases. Here, we review the novel functional concept of the redox-related protein complex, named \"Redoxisome,\" consisting of Trx/Txnip, as a critical regulator for intra- and extra-cellular redox signaling, involved in the pathogenesis of various diseases such as cancer, autoimmune disease, and diabetes.

Pharmacological fibroblast growth factor 1 (FGF1) normalizes blood glucose in diabetic mice by means of an FGF receptor signalling pathway that is independent of its mitogenic activity. Glucose-lowering activity of 'endocrine' FGF1 As a non-endocrine member of the fibroblast growth factor (FGF) family, FGF1 is known as a classic growth factor with mitogenic and angiogenic activity. This study identifies FGF1 as a powerful metabolic regulator. Injection of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice, but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. This work raises the possibility that FGF1 could have therapeutic potential for the treatment of insulin resistance and type 2 diabetes. Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation 1 , 2 . Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis 3 , 4 . Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

Human pancreatic islets regulate organ development and metabolic homeostasis, with dysfunction leading to diabetes. Human pluripotent stem cells (hPSCs) provide a potential alternative source to cadaveric human pancreatic islets for replacement therapy in diabetes. However, human islet-like organoids (HILOs) generated from hPSCs in vitro often exhibit heterogeneous immature phenotypes such as aberrant gene expression and inadequate insulin secretion in response to glucose. Here we show that FXYD Domain Containing Ion Transport Regulator 2 (FXYD2) marks and regulates functional maturation and heterogeneity of generated HILOs, by controlling the β cell transcriptome necessary for glucose-stimulated insulin secretion (GSIS). Despite its presence in mature β cells, FXYD2 is diminished in hPSC-derived β-like cells. Mechanistically, we find that FXYD2 physically interacts with SRC proto-oncogene, non-receptor tyrosine kinase (SRC) protein to regulate FXYD2-SRC-TEAD1 signaling to modulate β cell transcriptome. We demonstrate that FXYD2 HILOs significantly outperform FXYD2 counterparts to improve hyperglycemia in STZ-induced diabetic immune deficient mice. These results suggest that FXYD2 marks and regulates human β cell maturation via channel-sensing signal transduction and that it can be used as a selection marker for functional heterogeneity of stem cell derived human islet organoids.

Pancreatic β‐cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β‐cell apoptosis; however, the mechanisms of progression and suppression are not yet fully understood. Here, we report that the autocrine/paracrine function of insulin reduces ER stress‐induced β‐cell apoptosis. Insulin reduced the ER‐stress inducer tunicamycin‐ and thapsigargin‐induced cell viability loss due to apoptosis in INS‐1 β‐cells. Moreover, the effect of insulin was greater than that of insulin‐like growth factor‐1 at physiologically relevant concentrations. Insulin did not attenuate the ER stress‐induced increase in unfolded protein response genes. ER stress did not induce cytochrome c release from mitochondria. Mitochondrial hyperpolarization was induced by ER stress and prevented by insulin. The protonophore/mitochondrial oxidative phosphorylation uncoupler, but not the antioxidants N‐acetylcysteine and α‐tocopherol, exhibited potential cytoprotection during ER stress. Both procaspase‐12 and cleaved caspase‐12 levels increased under ER stress. The caspase‐12 inhibitor Z‐ATAD‐FMK decreased ER stress‐induced apoptosis. Caspase‐12 overexpression reduced cell viability, which was diminished in the presence of insulin. Insulin decreased caspase‐12 levels at the post‐translational stages. These results demonstrate that insulin protects against ER stress‐induced β‐cell apoptosis in this cell line. Furthermore, mitochondrial hyperpolarization and increased caspase‐12 levels are involved in ER stress‐induced and insulin‐suppressed β‐cell apoptosis.

Transforming growth factor beta (TGF-β) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. TGF-β-induced EMT is an important step during carcinoma progression to invasion state. Thioredoxin binding protein-2 (TBP-2, also called Txnip or VDUP1) is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. However, it remains unclear how TBP-2 suppresses the invasion and metastasis of cancer. In this study, we demonstrated that TBP-2 deficiency increases the transcriptional activity in response to TGF-β and also enhances TGF-β-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-β-responsive expression of Snail and Slug, transcriptional factors related to TGF-β-mediated induction of EMT, and promoted TGF-β-induced spindle-like morphology consistent with the depletion of E-Cadherin in A549 cells. Our results indicate that TBP-2 deficiency enhances TGF-β signaling and promotes TGF-β-induced EMT. The control of TGF-β-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-β signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression.

Direct conversions offer an alternative approach to generate insulin-producing cells for cell therapy in diabetes. A study reports a method to convert human stomach-derived gastric stem cells into functional insulin-producing cells through a unique differentiation path.

Since the discovery of insulin a century ago, insulin injection has been a primary treatment for both type 1 (T1D) and type 2 diabetes (T2D). T2D is a complicated disea se that is triggered by the dysfunction of insulin-producing β cells and insulin resistance in peripheral tissues. Insulin injection partially compensates for the role of endogenous insulin which promotes glucose uptake, lipid synthesis and organ growth. However, lacking the continuous, rapid, and accurate glucose regulation by endogenous functional β cells, the current insulin injection therapy is unable to treat the root causes of the disease. Thus, new technologies such as human pluripotent stem cell (hPSC)-derived islets are needed for both identifying the key molecular and genetic causes of T2D and for achieving a long-term treatment. This perspective review will provide insight into the efficacy of hPSC-derived human islets for treating and understanding T2D. We discuss the evidence that β cells should be the primary target for T2D treatment, the use of stem cells for the modeling of T2D and the potential use of hPSC-derived islet transplantation for treating T2D.