scholarly journals Reinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christos Karampelias ◽  
Habib Rezanejad ◽  
Mandy Rosko ◽  
Likun Duan ◽  
Jing Lu ◽  
...  
Keyword(s):  
Folic Acid ◽  
Cell Differentiation ◽  
Folinic Acid ◽  
Carbon Metabolism ◽  
Cell Mass ◽  
Cell Regeneration ◽  
Β Cell ◽  
Ductal Cells ◽  
Neonatal Pig ◽  
One Carbon Metabolism

AbstractDiabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells.

scholarly journals Gastrin Treatment Stimulates β-Cell Regeneration and Improves Glucose Tolerance in 95% Pancreatectomized Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2580-2588 ◽  
Author(s):  
Noèlia Téllez ◽  
Géraldine Joanny ◽  
Jéssica Escoriza ◽  
Marina Vilaseca ◽  
Eduard Montanya
Keyword(s):  
Glucose Tolerance ◽  
Cell Mass ◽  
Cell Regeneration ◽  
Β Cells ◽  
Β Cell ◽  
Ductal Cells ◽  
Treatment Of Diabetes

β-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost β-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on β-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px+G and S+G) or vehicle (Px+V and S+V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 ± 52 mg vs. 436 ± 51 mg/dl, P < 0.05), and increased β-cell mass (1.15 ± 0.15 mg)) compared with vehicle-treated rats (0.67 ± 0.15 mg, P < 0.05). Gastrin treatment induced β-cell regeneration by enhancing β-cell neogenesis (increased number of extraislet β-cells in Px+G: 0.42 ± 0.05 cells/mm2vs. Px+V: 0.27 ± 0.07 cells/mm2, P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px+G: 1.21 ± 0.38% vs. Px+V: 0.23 ± 0.10%, P < 0.05) and replication (Px+G: 1.65 ± 0.26% vs. S+V: 0.64 ± 0.14%; P < 0.05). In addition, reduced β-cell apoptosis contributed to the increased β-cell mass in gastrin-treated rats (Px+G: 0.07 ± 0.02%, Px+V: 0.23 ± 0.05%; P < 0.05). Gastrin action on β-cell regeneration and survival increased β-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes.

scholarly journals Cross Talk between One-Carbon Metabolism, Eph Signaling, and Histone Methylation Promotes Neural Stem Cell Differentiation

Cell Reports ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2864-2873.e7 ◽  
Author(s):  
Mohamad-Ali Fawal ◽  
Thomas Jungas ◽  
Anthony Kischel ◽  
Christophe Audouard ◽  
Jason S. Iacovoni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Neural Stem Cell ◽  
Cross Talk ◽  
Histone Methylation ◽  
Carbon Metabolism ◽  
Stem Cell Differentiation ◽  
One Carbon Metabolism

scholarly journals Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into β cells in mice with reversal of diabetes

2016 ◽  
Vol 113 (3) ◽  
pp. 650-655 ◽  
Author(s):  
Mingfeng Zhang ◽  
Qing Lin ◽  
Tong Qi ◽  
Tiankun Wang ◽  
Ching-Cheng Chen ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Low Dose ◽  
Mixed Chimerism ◽  
High Dose ◽  
Β Cells ◽  
Β Cell ◽  
Ductal Cells ◽  
Ductal Cell ◽  
Term Administration

We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9+ (Sox9+) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9+ ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9+ ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300–450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9+ ductal cell differentiation into β cells in adult mice.

scholarly journals Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

2014 ◽  
Vol 223 (1) ◽  
pp. 67-78 ◽  
Author(s):  
Noèlia Téllez ◽  
Eduard Montanya
Keyword(s):  
Cell Mass ◽  
Β Cell ◽  
Neurogenin 3 ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Blood Glucose Levels ◽  
Morphometric Analyses ◽  
Underlying Mechanisms ◽  
Mass Expansion

Induction of β-cell mass regeneration is a potentially curative treatment for diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and β-cell mass expansion in 95% pancreatectomised (Px) rats. In this study, we investigated the underlying mechanisms of gastrin-induced β-cell mass expansion after Px. After 90%-Px, rats were treated with gastrin (Px+G) or vehicle (Px+V), pancreatic remnants were harvested on days 1, 3, 5, 7, and 14 and used for gene expression, protein immunolocalisation and morphometric analyses. Gastrin- and vehicle-treated Px rats showed similar blood glucose levels throughout the study. Initially, after Px, focal areas of regeneration, showing mesenchymal cells surrounding ductal structures that expressed the cholecystokinin B receptor, were identified. These focal areas of regeneration were similar in size and cell composition in the Px+G and Px+V groups. However, in the Px+G group, the ductal structures showed lower levels of keratin 20 and β-catenin (indicative of duct dedifferentiation) and higher levels of expression of neurogenin 3 and NKX6-1 (indicative of endocrine progenitor phenotype), as compared with Px+V rats. In Px+G rats, β-cell mass and the number of scattered β-cells were significantly increased compared with Px+V rats, whereas β-cell replication and apoptosis were similar in the two groups. These results indicate that gastrin treatment-enhanced dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased β-cell neogenesis and fostered β-cell mass expansion.

scholarly journals Early administration of keratinocyte growth factor improves β-cell regeneration in rat with streptozotocin-induced diabetes

2007 ◽  
Vol 195 (2) ◽  
pp. 333-340 ◽  
Author(s):  
Jamileh Movassat ◽  
Bernard Portha
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
Wistar Rats ◽  
Keratinocyte Growth Factor ◽  
Cell Mass ◽  
Duct Cell ◽  
Cell Regeneration ◽  
Cell Replication ◽  
Β Cell ◽  
Old Rats

The aim of our study was to investigate the ability of keratinocyte growth factor (KGF; palifermin) in regulating β-cell growth in normal newborn rats and in rats with neonatal diabetes. Wistar rats were injected with streptozotocin (STZ) to induce diabetes on the dayof birth. From days 2 to 6 after birth, animals received a daily s.c. injection of KGF (STZ/KGF group) and at the dose of 3 mg/kg body weight or saline solution (STZ groups). A group of non-diabetic Wistar rats was treated either with saline (Wistar group) or with KGF from days 2 to 6 after birth at the dose of 3 mg/kg body weight (Wistar/KGF group). β-cell mass was measured at day 7 after birth in all groups. β- and ductal cells replication were measured in all groups and apoptosis was assessed in the pancreas of 2-, 4-, and 7-day-old STZ and STZ/KGF rats. The total β-cell mass of the 7-day-old KGF/STZ neonates was significantly increased compared with that of age-matched STZ rats. β-cell replication rate was decreased at day 2 in the STZ/KGF group and was similar in the 4- and 7-day-old rats from STZ and STZ/KGF groups. Duct cell replication was significantly increased in the pancreas of 2- and 4-day-old KGF/STZ neonates when compared with that of age-matched rats from STZ control group. The rate of apoptosis in the neonatal pancreases of STZ and KGF/STZ groups was not significantly different. In non-diabetic Wistar rats, KGF treatment led to a slight but significant increase in duct cell proliferation at day 2 without significant changes in the total β-cell mass in the 7-day-old rats. We provide evidence for a growth-promoting effect of KGF during β-cell regeneration in neonatal diabetic rats. KGF exerts strong mitogenic effect on the pancreatic duct cells, thus expanding the population of precursor cells that subsequently differentiate into insulin-producing β-cells.

scholarly journals Dynamics of β-cell turnover: evidence for β-cell turnover and regeneration from sources of β-cells other than β-cell replication in the HIP rat

2009 ◽  
Vol 297 (2) ◽  
pp. E323-E330 ◽  
Author(s):  
Erica Manesso ◽  
Gianna M. Toffolo ◽  
Yoshifumi Saisho ◽  
Alexandra E. Butler ◽  
Aleksey V. Matveyenko ◽  
...  
Keyword(s):  
Cell Mass ◽  
Cell Formation ◽  
Cell Regeneration ◽  
Cell Turnover ◽  
Cell Replication ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid

Type 2 diabetes is characterized by hyperglycemia, a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). These characteristics are recapitulated in the human IAPP transgenic (HIP) rat. We developed a mathematical model to quantify β-cell turnover and applied it to nondiabetic wild type (WT) vs. HIP rats from age 2 days to 10 mo to establish 1) whether β-cell formation is derived exclusively from β-cell replication, or whether other sources of β-cells (OSB) are present, and 2) to what extent, if any, there is attempted β-cell regeneration in the HIP rat and if this is through β-cell replication or OSB. We conclude that formation and maintenance of adult β-cells depends largely (∼80%) on formation of β-cells independent from β-cell duplication. Moreover, this source adaptively increases in the HIP rat, implying attempted β-cell regeneration that substantially slows loss of β-cell mass.

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