• dedifferentiation
• neogenesis
• regeneration
• transdifferentiation
• β-cells

• 33301 MITACS

• diabetes
• differentiation
• heterogeneity
• pancreas
• proliferation
• regeneration
• β-cell

Insulin is a hormone secreted by pancreatic β cells. The concentration of glucose in circulation is proportional to the secretion of insulin by these cells. In target cells, insulin binds to its receptors and activates phosphatidylinositol-3-kinase/protein kinase B, inducing different mechanisms depending on the cell type. In the liver it activates the synthesis of glycogen, in adipose tissue and muscle it allows the capture of glucose, and in the hypothalamus, it regulates thermogenesis and appetite. Defects in insulin function [insulin resistance (IR)] are related to the development of neurodegenerative diseases in obese people. Furthermore, in obesity and diabetes, its role as an anorexigenic hormone in the hypothalamus is diminished during IR. Therefore, hyperphagia prevails, which aggravates hyper-glycemia and IR further, becoming a vicious circle in which the patient cannot regulate their need to eat. Uncontrolled calorie intake induces an increase in reactive oxygen species, overcoming cellular antioxidant defenses (oxidative stress). Reactive oxygen species activate stress-sensitive kinases, such as c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that induce phos-phorylation in serine residues in the insulin receptor, which blocks the insulin signaling pathway, continuing the mechanism of IR. The brain and pancreas are organs mainly affected by oxidative stress. The use of drugs that regulate food intake and improve glucose metabolism is the conventional therapy to improve the quality of life of these patients. Currently, the use of antioxidants that regulate oxidative stress has given good results because they reduce oxidative stress and inflammatory processes, and they also have fewer side effects than synthetic drugs.

• Insulin
• Pancreas
• Hypothalamus
• Hyperphagia
• Hyperglycemia
• Stress

• CP: Metabolism
• CP: Molecular biology
• RNAi screen
• SMNDC1
• alpha cells
• beta cells
• chromatin remodelers
• insulin transcription
• pancreatic islets
• splicing

• Animals
• Chromatin Assembly and Disassembly
• Glucagon-Secreting Cells/metabolism
• Humans
• Insulin/metabolism
• Insulin Secretion
• Insulin-Secreting Cells/metabolism
• Islets of Langerhans/metabolism
• Mice
• RNA Splicing/genetics
• RNA Splicing Factors/metabolism
• SMN Complex Proteins/metabolism
• Transcription Factors/metabolism

• U24 DK098085 NIDDK NIH HHS

• Animals
• Diabetes Mellitus, Experimental/metabolism
• Hypoxia/metabolism
• Insulin/metabolism
• Islets of Langerhans/metabolism
• Islets of Langerhans Transplantation/methods
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein/genetics
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

• cell fate
• co-regulator
• diabetes
• endocrine
• islets
• pancreatic development
• transcription
• transcription factor

Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.

• MAFA
• MAFB
• dedifferentiation
• diabetes mellitus
• insulin
• plasticity
• transcription factor
• β-cells

• MafA
• beta cell maturity
• diabetes
• pancreatic beta cells
• transcription factors

• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/metabolism
• Humans
• Insulin/metabolism
• Insulin Secretion
• Insulin-Secreting Cells/metabolism
• Maf Transcription Factors, Large/genetics
• Maf Transcription Factors, Large/metabolism

• R01 DK132661 NIDDK NIH HHS
• T32 DK007328 NIDDK NIH HHS
• T32DK00732 NIH HHS
• R01DK132661 NIH HHS

Diabetes mellitus is a significant cause of morbidity and mortality in the United States and worldwide. According to the CDC, in 2017, ∼34.2 million of the American population had diabetes. Also, in 2017, diabetes was the seventh leading cause of death and has become the number one biomedical financial burden in the United States. Insulin replacement therapy and medications that increase insulin secretion and improve insulin sensitivity are the main therapies used to treat diabetes. Unfortunately, there is currently no radical cure for the different types of diabetes. Loss of β cell mass is the end result that leads to both type 1 and type 2 diabetes. In the past decade, there has been an increased effort to develop therapeutic strategies to replace the lost β cell mass and restore insulin secretion. α cells have recently become an attractive target for replacing the lost β cell mass, which could eventually be a potential strategy to cure diabetes. This review highlights the advantages of using α cells as a source for generating new β cells, the various investigative approaches to convert α cells into insulin-producing cells, and the future prospects and problems of this promising diabetes therapeutic strategy.

• alpha cell
• diabetes
• gene therapy

• PPARγ
• SetD7 (Set7/9)
• gene transcription
• glucose homeostasis
• high-fat diet
• obesity
• partial pancreatectomy (Px);
• thiazolidinedione (TZD)
• type 2 diabetes (T2D)
• β-cell compensation
• β-cell mass

• Animals
• Cell Line
• Gene Expression Regulation, Enzymologic
• Histone-Lysine N-Methyltransferase/biosynthesis
• Histone-Lysine N-Methyltransferase/genetics
• Hyperglycemia/genetics
• Hyperglycemia/metabolism
• Insulin-Secreting Cells/metabolism
• Mice
• Mice, Transgenic
• PPAR gamma/genetics
• PPAR gamma/metabolism
• Rats
• Response Elements

• R01 DK056818 NIDDK NIH HHS
• R56 DK056818 NIDDK NIH HHS

• beta cell development and maturation
• diabetes
• pancreas development
• single-cell RNA sequencing
• stem cell pancreatic differentiation

Diabetes mellitus (DM) is one of the main causes of morbidity and mortality, with an increasing incidence worldwide. The impact of DM on public health in developing countries has triggered alarm due to the exaggerated costs of the treatment and monitoring of patients with this disease. Considerable efforts have been made to try to prevent the onset and reduce the complications of DM. However, because insulin-producing pancreatic β-cells progressively deteriorate, many people must receive insulin through subcutaneous injection. Additionally, current therapies do not have consistent results regarding the prevention of chronic complications. Leveraging the approval of real-time continuous glucose monitors and sophisticated algorithms that partially automate insulin infusion pumps has improved glycemic control, decreasing the burden of diabetes management. However, these advances are facing physiologic barriers. New findings in molecular and cellular biology have produced an extraordinary advancement in tissue development for the treatment of DM. Obtaining pancreatic β-cells from somatic cells is a great resource that currently exists for patients with DM. Although this therapeutic option has great prospects for patients, some challenges remain for this therapeutic plan to be used clinically. The purpose of this review is to describe the new techniques in cell biology and regenerative medicine as possible treatments for DM. In particular, this review highlights the origin of induced pluripotent cells (iPSCs) and how they have begun to emerge as a regenerative treatment that may mitigate the pathology of this disease.

• diabetes mellitus
• histone modification
• iPSC
• pancreatic β-cells
• regenerative medicine
• transcriptional regulation

• Algorithms
• Chronic Disease
• Diabetes Mellitus/metabolism
• Diabetes Mellitus/pathology
• Diabetes Mellitus/therapy
• Humans
• Induced Pluripotent Stem Cells/metabolism
• Induced Pluripotent Stem Cells/pathology
• Induced Pluripotent Stem Cells/transplantation
• Stem Cell Transplantation

• extracellular matrix
• human pluripotent stem cells
• islet cells
• maturation
• pathways
• signaling molecules

• Animals
• Cell Differentiation
• Cellular Reprogramming Techniques/methods
• Glucagon-Secreting Cells/cytology
• Glucagon-Secreting Cells/metabolism
• Humans
• Insulin-Secreting Cells/cytology
• Insulin-Secreting Cells/metabolism
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/metabolism
• Signal Transduction
• Stem Cell Niche

• R15 EB027391 NIBIB NIH HHS
• CBET1928855 National Science Foundation
• 1R15EB027391-01 NIH HHS

Next generation sequencing studies have highlighted discrepancies in β-cells which exist between mice and men. Numerous reports have identified MAF BZIP Transcription Factor B (MAFB) to be present in human β-cells postnatally, while its expression is restricted to embryonic and neo-natal β-cells in mice. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to β-cell development and function specifically in humans. Here we report that MAFB knockout hPSCs have normal pancreatic differentiation capacity up to the progenitor stage, but favor somatostatin- and pancreatic polypeptide–positive cells at the expense of insulin- and glucagon-producing cells during endocrine cell development. Our results describe a requirement for MAFB late in the human pancreatic developmental program and identify it as a distinguishing transcription factor within islet cell subtype specification. We propose that hPSCs represent a powerful tool to model human pancreatic endocrine development and associated disease pathophysiology.

The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification.

• Arsenic
• Hyperglycemia
• PDX1
• miR-2909 RNomics
• β-cells

• Animals
• Arsenic/pharmacology
• Cell Line, Tumor
• Homeodomain Proteins/metabolism
• Insulin-Secreting Cells
• Mice
• Mice, Inbred BALB C
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Pancreas/drug effects
• Pancreas/metabolism
• Trans-Activators/metabolism

Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1), Neurogenin-3 (NEUROG3), and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) are transcription factors critical for beta cell development and maturation. NEUROG3 is expressed in endocrine progenitor cells and controls islet differentiation and regeneration. PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the insulin gene and drives insulin expression in response to glucose. In addition to those natural roles in beta cell development and maturation, ectopic expression of PDX1, NEUROG3, and/or MAFA has been successfully used to reprogram various cell types into insulin-producing cells in vitro and in vivo, such as pancreatic exocrine cells, hepatocytes, and pluripotent stem cells. Here, we review biological properties of PDX1, NEUROG3, and MAFA, and their applications and limitations for beta cell regenerative approaches. The primary source literature for this review was acquired using a PubMed search for articles published between 1990 and 2017. Search terms include diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine.

• Diabetes
• Embryonic stem cells
• Induced pluripotent stem cells
• Regenerative medicine
• Trans-differentiation

• Animals
• Cell Enlargement
• Diet, High-Fat/adverse effects
• Gene Expression/physiology
• Glucose/metabolism
• Glucose Intolerance/genetics
• Homeostasis/physiology
• Insulin/metabolism
• Insulin-Secreting Cells/cytology
• Insulin-Secreting Cells/metabolism
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Mice
• Mice, Transgenic
• Multiprotein Complexes/metabolism
• Protein Kinases/deficiency
• Signal Transduction
• TOR Serine-Threonine Kinases/metabolism

• R01 DK046409 NIDDK NIH HHS
• K01 DK103823 NIDDK NIH HHS
• R01 DK084236 NIDDK NIH HHS
• R01 DK073716 NIDDK NIH HHS
• P30 DK020572 NIDDK NIH HHS
• T32 GM007315 NIGMS NIH HHS
• National Institutes of Health
• National Institute of Diabetes and Digestive and Kidney Diseases

• Foxa2
• Pdx1
• Trans-differentiation
• β-Cell identity
• β-Cell maturation

• Cis-regulatory function
• Lineage diversification
• Mouse
• Pancreatic endocrine progenitors
• Pdx1 enhancer Area II

• diabetes mellitus
• differentiation
• gene expression
• insulin producing cells
• microRNAs

Synthetic biology has advanced the design of standardized transcription control devices that programme cellular behaviour. By coupling synthetic signalling cascade- and transcription factor-based gene switches with reverse and differential sensitivity to the licensed food additive vanillic acid, we designed a synthetic lineage-control network combining vanillic acid-triggered mutually exclusive expression switches for the transcription factors Ngn3 (neurogenin 3; OFF-ON-OFF) and Pdx1 (pancreatic and duodenal homeobox 1; ON-OFF-ON) with the concomitant induction of MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A; OFF-ON). This designer network consisting of different network topologies orchestrating the timely control of transgenic and genomic Ngn3, Pdx1 and MafA variants is able to programme human induced pluripotent stem cells (hIPSCs)-derived pancreatic progenitor cells into glucose-sensitive insulin-secreting beta-like cells, whose glucose-stimulated insulin-release dynamics are comparable to human pancreatic islets. Synthetic lineage-control networks may provide the missing link to genetically programme somatic cells into autologous cell phenotypes for regenerative medicine.

Synthetic biology offers the potential for the design and implementation of rationally designed, complex genetic programmes. Here the authors design a genetic network to trigger the differentiation of patient derived IPSCs into beta-like cells.

• Diabetes
• Islets of Langerhans
• Mouse
• Pancreatic development
• Regeneration
• β-Cell

Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes¹, but despite the growing diabetes epidemic the molecular mechanisms involved have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a critical factor involved in beta-cell biology and showed that beta-cell TXNIP was upregulated in diabetes, whereas TXNIP deficiency protected against diabetes by preventing beta-cell apoptosis^2–3. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MafA, a known insulin transcription factor. After discovering miR-204 to be induced by TXNIP in a microRNA microarray, we confirmed the findings using INS-1 beta-cells, islets of TXNIP-deficient mice, diabetic mouse models and primary human islets. We further discovered that TXNIP induces miR-204 by controlling the activity of STAT3, a transcription factor involved in miR-204 regulation^4–5 and identified MafA as a novel target downregulated by miR-204. Taken together, our results demonstrate for the first time that TXNIP controls microRNA expression and insulin production, and that miR-204 is involved in beta-cell function. The identified novel TXNIP/miR-204/MafA/insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.

During embryonic development, multipotent endodermal cells differentiate to form the pancreas. Islet cell clusters arising from the pancreatic bud form the acini tissue and exocrine ducts whilst pancreatic islets form around the edges of the clusters. The successive steps of islet differentiation are controlled by a complex network of transcription factors and signals that influence cell differentiation, growth and lineage. A Westernized lifestyle has led to an increased consumption of a high saturated fat diet, and an increase in maternal obesity. The developing fetus is highly sensitive to the intrauterine environment, therefore any alteration in maternal nutrition during gestation and lactation which affects the in-utero environment during the key developmental phases of the pancreas may change the factors controlling β-cell development and β-cell mass. Whilst the molecular mechanisms behind the adaptive programming of β-cells are still poorly understood it is established that changes arising from maternal obesity and/or over-nutrition may affect the ability to maintain fetal β-cell mass resulting in an increased risk of type 2 diabetes in adulthood.

• developmental programming
• maternal over-nutrition
• obesity
• pancreas
• transcription factors

• Cell Differentiation/physiology
• Embryonic Stem Cells/cytology
• Humans
• Organogenesis/genetics
• Organogenesis/physiology
• Pancreas/cytology

• U01 DK089570 NIDDK NIH HHS
• U19 DK042502 NIDDK NIH HHS
• 1 UO1 DK089570-01 NIDDK NIH HHS