Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells

Low, Blaise Su Jun; Lim, Chang Siang; Ding, Shirley Suet Lee; Tan, Yaw Sing; Ng, Natasha Hui Jin; Krishnan, Vidhya G.; Ang, Su Fen; Neo, Claire Wen Ying; Verma, Chandra; Hoon, Shawn; Lim, Su Chi; Tai, E Shyong; Teo, Adrian Kee Keong

doi:10.1038/s41467-021-22843-4

Cited by 42 publications

(48 citation statements)

References 97 publications

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“…Typical consensus sites for N-glycosylation, i.e., the Asn-X-(Thr/Ser) motif, were detected at N 166 and N 545 in the long Prss53 isoform, whereas only one N-glycosylation site (N 166 ) was detected in the short Prss53 isoform. Signal P ( http://www.cbs.dtu.dk/services/SignalP/ ), a program developed by Nielsen et al, 21 was used to predict the presence of a cleavage site for the signal peptide between Ala (A) 17 and Ala (A) 18 for mouse Prss53, or Gly (G) 19 and Gln (Q) 20 for human Prss53 (Figure S2B). the presence of a cleavage site for the signal peptide between Ala (A) 17 and Ala (A) 18 for mouse Prss53, or Gly (G) 19 and Gln (Q) 20 for human Prss53 (Figure S2B).…”

Section: Resultsmentioning

confidence: 99%

“…Signal P ( http://www.cbs.dtu.dk/services/SignalP/ ), a program developed by Nielsen et al, 21 was used to predict the presence of a cleavage site for the signal peptide between Ala (A) 17 and Ala (A) 18 for mouse Prss53, or Gly (G) 19 and Gln (Q) 20 for human Prss53 (Figure S2B). the presence of a cleavage site for the signal peptide between Ala (A) 17 and Ala (A) 18 for mouse Prss53, or Gly (G) 19 and Gln (Q) 20 for human Prss53 (Figure S2B).…”

Section: Resultsmentioning

confidence: 99%

“… Characterization of Prss53 expression in COS7 cells. a. Molecular sizes of in vitro- translated Prss53 in the presence of 20 S methionine. Both the short (51.5 kDa) and long (59.0 kDa) isoforms of Prss53 were synthesized with (myc-tag) or without (No tag) a myc-epitope tag.…”

Section: Resultsmentioning

confidence: 99%

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Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells

Mizusawa

Harada

Iwata

et al. 2021

Islets

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The aim of this study was to identify genes that are specifically expressed in pancreatic islet β-cells (hereafter referred to as β-cells). Large-scale complementary DNA-sequencing analysis was performed for 3,429 expressed sequence tags derived from murine MIN6 β-cells, through homology comparisons using the GenBank database. Three individual ESTs were found to code for protease serine S1 family member 53 ( Prss53 ). Prss53 mRNA is processed into both a short and long form, which encode 482 and 552 amino acids, respectively. Transient overexpression of myc-tagged Prss53 in COS-7 cells showed that Prss53 was strongly associated with the luminal surfaces of organellar membranes and that it underwent signal peptide cleavage and N-glycosylation. Immunoelectron microscopy and western blotting revealed that Prss53 localized to mitochondria in MIN6 cells. Short hairpin RNA-mediated Prss53 knockdown resulted in Ppargc1a downregulation and Ucp2 and Glut2 upregulation. JC-1 staining revealed that the mitochondria were depolarized in Prss53 -knockdown MIN6 cells; however, no change was observed in glucose-stimulated insulin secretion. Our results suggest that mitochondrial Prss53 expression plays an important role in maintaining the health of β-cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells

Mizusawa

Harada

Iwata

et al. 2021

Islets

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“…Although there was no change in glucose content in serum in female offspring, it was found that glucose tolerance increased in ZnD-HF female offspring at 30 min after insulin intervention. Moreover, paternal Zn deficiency also increased ZnD-HF glucose tolerance when these female offspring were fasted for 6 h, which was manifested as the up-regulated expression of Glut2 in female offspring ( Low et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Paternal Zn-deficiency abolishes metabolic effects in offspring induced by diet type

Dong

Yue

et al. 2022

Animal Nutrition

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Accumulating evidence implicates that offspring are susceptible to paternal alterations in numerous fetal disorders, such as growth and metabolic defects. However, less study has been conducted to define the relationship between paternal zinc deficiency (ZnD) and energy metabolism of offspring. In the present study, we used a paternal ZnD exposure (Zn at 0.3 μg/g) model to test energy metabolism of male and female offspring with the intervention of diet type (high-fat diet and low-fat diet). Our results demonstrated that paternal ZnD decreased body weight (BW) gain per week ( P < 0.01) and ME intake per week ( P < 0.05) at 11 weeks in male offspring with high-fat diet intervention but not in female offspring. Further, anabolism and catabolism of hepatic energy products also exhibited alterations. ZnD attenuated liver glucose but increased lipids content accompanied with elevated adiponectin and reduction in leptin level in serum, which exhibited lipid metabolic disturbance and smaller ratio of liver weight to BW in male but not female offspring. The qRT-PCR and liver energy metabolites analysis revealed that paternal ZnD mainly induced reduction in glucose tolerance and lowered glucose uptaking ability in male offspring and thereby alleviated glycolysis and the tricarboxylic acid cycle (TCA) cycle, which displayed a male gender-dependency. Therefore, we propose that paternal ZnD abolishes metabolic effects in male offspring induced by diet type intervention. Our findings reveal a novel link between paternal Zn-D and offspring energy metabolism.

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“…A more recent report was provided by Teo and colleagues ( 110 ). These researchers used MODY3 patient-derived hiPSCs to study the impact of a recently reported patient-specific heterozygous HNF1A +/H126D mutation ( 140 ).…”

Section: Modeling Monogenic Diabetes With Human Pluripotent Stem Cellsmentioning

confidence: 99%

Monogenic Diabetes Modeling: In Vitro Pancreatic Differentiation From Human Pluripotent Stem Cells Gains Momentum

2021

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The occurrence of diabetes mellitus is characterized by pancreatic β cell loss and chronic hyperglycemia. While Type 1 and Type 2 diabetes are the most common types, rarer forms involve mutations affecting a single gene. This characteristic has made monogenic diabetes an interesting disease group to model in vitro using human pluripotent stem cells (hPSCs). By altering the genotype of the original hPSCs or by deriving human induced pluripotent stem cells (hiPSCs) from patients with monogenic diabetes, changes in the outcome of the in vitro differentiation protocol can be analyzed in detail to infer the regulatory mechanisms affected by the disease-associated genes. This approach has been so far applied to a diversity of genes/diseases and uncovered new mechanisms. The focus of the present review is to discuss the latest findings obtained by modeling monogenic diabetes using hPSC-derived pancreatic cells generated in vitro. We will specifically focus on the interpretation of these studies, the advantages and limitations of the models used, and the future perspectives for improvement.

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Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells

Cited by 42 publications

References 97 publications

Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells

Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells

Paternal Zn-deficiency abolishes metabolic effects in offspring induced by diet type

Monogenic Diabetes Modeling: In Vitro Pancreatic Differentiation From Human Pluripotent Stem Cells Gains Momentum

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