Diabetic pdx1-mutant zebrafish show conserved responses to nutrient overload and anti-glycemic treatment

Kimmel, Robin A.; Dobler, Stefan; Schmitner, Nicole; Walsen, Tanja; Freudenblum, Julia; Meyer, Dirk

doi:10.1038/srep14241

Cited by 59 publications

(68 citation statements)

References 69 publications

(108 reference statements)

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“…Paired box 4 (Pax4) is a transcriptional regulator that is important in pancreatic islet beta cell differentiation and development [40]. An additional transcription factor that regulates pancreas development and particularly endocrine function and beta cell formation is Pancreatic and Duodenal Homeobox 1 (Pdx1) [41, 42]. Pdx1 is also a key player in glucose-dependent regulation of insulin gene expression.…”

Section: Resultsmentioning

confidence: 99%

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Beaver

Nkrumah‐Elie

Truong

et al. 2017

The Journal of Nutritional Biochemistry

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The high prevalence of zinc deficiency is a global public health concern, and suboptimal maternal zinc consumption has been associated with adverse effects ranging from impaired glucose tolerance to low birthweights. The mechanisms that contribute to altered development and poor health in zinc deficient offspring are not completely understood. To address this gap, we utilized the Danio rerio model and investigated the impact of dietary zinc deficiency on adults and their developing progeny. Zinc deficient adult fish were significantly smaller in size, and had decreases in learning and fitness. We hypothesized that parental zinc deficiency would have an impact on their offspring’s mineral homeostasis and embryonic development. Results from mineral analysis showed that parental zinc deficiency caused their progeny to be zinc deficient. Furthermore, parental dietary zinc deficiency had adverse consequences for their offspring including a significant increase in mortality and decreased physical activity. Zinc deficient embryos had altered expression of genes that regulate metal homeostasis including several zinc transporters (ZnT8, ZnT9) and the metal-regulatory transcription factor 1 (MTF-1). Zinc deficiency was also associated with decreased expression of genes related to diabetes and pancreatic development in the embryo (Insa, Pax4, Pdx1). Decreased expression of DNA methyltransferases (Dnmt4, Dnmt6) was also found in zinc deficient offspring, which suggests that zinc deficiency in parents may cause altered epigenetic profiles for their progeny. These data should inform future studies regarding zinc deficiency and pregnancy and suggest that supplementation of zinc deficient mothers prior to pregnancy may be beneficial.

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Section: Resultsmentioning

confidence: 99%

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Beaver

Nkrumah‐Elie

Truong

et al. 2017

The Journal of Nutritional Biochemistry

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show abstract

“…The supernatant was transferred to fresh eppendorfs and used directly for glucose measurement. The glucose assay was performed as described (Kimmel et al., 2015) on biological replicates, using 15 μL larvae extract per reaction. Sample buffer was added up to 25 μl, and combined with 25 μL reaction mix.…”

Section: Methodsmentioning

confidence: 99%

Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Li¹,

Casteels²,

Frogne³

et al. 2017

Cell

Self Cite

322

301

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SummaryType 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABAA receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic β cell mass from α cells.

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“…Studies in the zebrafish, Danio rerio , indicate that K ATP channels may be physiologically significant in fishes: treatment of larvae with pharmacological activators of mammalian K ATP channels or transgenic expression of mammalian K ATP channels with GOF mutations is sufficient to raise larval whole-body glucose [7]. Conversely, treatment of larvae with compounds that can close mammalian K ATP channels, or transgenic expression of mammalian K ATP channels with dominant-negative mutations, is sufficient to lower whole-larval glucose [7,8]. …”

Section: Introductionmentioning

confidence: 99%

Expression and function of ATP-dependent potassium channels in zebrafish islet β-cells

et al. 2017

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ATP-sensitive potassium channels (KATP channels) are critical nutrient sensors in many mammalian tissues. In the pancreas, KATP channels are essential for coupling glucose metabolism to insulin secretion. While orthologous genes for many components of metabolism–secretion coupling in mammals are present in lower vertebrates, their expression, functionality and ultimate impact on body glucose homeostasis are unclear. In this paper, we demonstrate that zebrafish islet β-cells express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. We further show that pharmacological activation of native zebrafish KATP using diazoxide, a specific KATP channel opener, is sufficient to disturb glucose tolerance in adult zebrafish. That β-cell KATP channel expression and function are conserved between zebrafish and mammals illustrates the evolutionary conservation of islet metabolic sensing from fish to humans, and lends relevance to the use of zebrafish to model islet glucose sensing and diseases of membrane excitability such as neonatal diabetes.

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Diabetic pdx1-mutant zebrafish show conserved responses to nutrient overload and anti-glycemic treatment

Cited by 59 publications

References 69 publications

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Expression and function of ATP-dependent potassium channels in zebrafish islet β-cells

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