Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish

Jurczyk, Agata; Roy, Nicole M.; Bajwa, Rabia; Gut, Philipp; Lipson, Kathryn L.; Yang, Chyun-Yu; Covassin, Laurence; Racki, Waldemar J.; Rossini, Aldo A.; Phillips, Nancy E.; Stainier, Didier Y. R.; Greiner, Dale L.; Brehm, Michael A.; Bortell, Rita; Diiorio, Philip J.

doi:10.1016/j.ygcen.2010.10.010

Cited by 105 publications

(110 citation statements)

References 72 publications

(102 reference statements)

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“…In agreement with previous observations, free glucose levels appeared to diminish after 2 dpf, increasing again from 3 to 5 dpf (Jurczyk et al 2011, Gut et al 2013). This could correspond to an initial increase in glucose levels that might drive the maturation of beta pancreatic cells as observed in mammals (Hellerstrom & Swenne 1991, et al 2004), dropping at 3dpf and increasing afterwards, coinciding with the functional onset of the hepatic gluconeogenesis (Gut et al 2013).…”

Section: Figuresupporting

confidence: 93%

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GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

Jiménez-Amilburu¹,

Jong-Raadsen²,

Bakkers³

et al. 2014

Journal of Endocrinology

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Cardiomyopathies-associated metabolic pathologies (e.g., type 2 diabetes and insulin resistance) are a leading cause of mortality. It is known that the association between these pathologies works in both directions, for which heart failure can lead to metabolic derangements such as insulin resistance. This intricate crosstalk exemplifies the importance of a fine coordination between one of the most energy-demanding organs and an equilibrated carbohydrate metabolism. In this light, to assist in the understanding of the role of insulinregulated glucose transporters (GLUTs) and the development of cardiomyopathies, we have developed a model for glut12 deficiency in zebrafish. GLUT12 is a novel insulin-regulated GLUT expressed in the main insulin-sensitive tissues, such as cardiac muscle, skeletal muscle, and adipose tissue. In this study, we show that glut12 knockdown impacts the development of the embryonic heart resulting in abnormal valve formation. Moreover, glut12-deficient embryos also exhibited poor glycemic control. Glucose measurements showed that these larvae were hyperglycemic and resistant to insulin administration. Transcriptome analysis demonstrated that a number of genes known to be important in cardiac development and function as well as metabolic mediators were dysregulated in these larvae. These results indicate that glut12 is an essential GLUT in the heart where the reduction in glucose uptake due to glut12 deficiency leads to heart failure presumably due to the lack of glucose as energy substrate. In addition, the diabetic phenotype displayed by these larvae after glut12 abrogation highlights the importance of this GLUT during early developmental stages.

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Section: Figuresupporting

confidence: 93%

“…Metformin was added to the water. Glucose measurements were performed using a fluorescence-based enzymatic detection kit (Biovision, Mountain View, CA, USA) as previously described (Jurczyk et al 2011).…”

Section: Insulin and Metformin Administration And Glucose Measurementsmentioning

confidence: 99%

GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

Jiménez-Amilburu¹,

Jong-Raadsen²,

Bakkers³

et al. 2014

Journal of Endocrinology

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“…Most importantly, we identified that activation of glucagon is required for β cell regeneration from both precursor pools. Furthermore, our results demonstrate that key physiological actions of glucagon in regulating blood glucose are conserved with mammals, just as for insulin (Kinkel and Prince, 2009;Jurczyk et al, 2011;Andersson et al, 2012); in particular, we found that in zebrafish glucagon activity is correlated with blood glucose levels, and that glucagon expression is upregulated in the absence of β cells. These findings further validate zebrafish as a model for studying human metabolic disease.…”

Section: Discussionsupporting

confidence: 55%

“…The zebrafish is an attractive and useful model for studying mechanisms of pancreas formation and disease repair because of its conserved architecture, composition, development, and attributes that permit rapid loss-of-function analyses (Biemar et al, 2001;Field et al, 2003;Kinkel and Prince, 2009;Jurczyk et al, 2011). In addition, the heightened regenerative capacity of the zebrafish facilitates the discovery of novel organ repair mechanisms that might be present, but dormant, in mammals (Aguirre et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

et al. 2015

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The interconversion of cell lineages via transdifferentiation is an adaptive mode of tissue regeneration and an appealing therapeutic target. However, its clinical exploitation is contingent upon the discovery of contextual regulators of cell fate acquisition and maintenance. In murine models of diabetes, glucagon-secreting alpha cells transdifferentiate into insulin-secreting beta cells following targeted beta cell depletion, regenerating the form and function of the pancreatic islet. However, the molecular triggers of this mode of regeneration are unknown. Here, using lineage-tracing assays in a transgenic zebrafish model of beta cell ablation, we demonstrate conserved plasticity of alpha cells during islet regeneration. In addition, we show that glucagon expression is upregulated after injury. Through gene knockdown and rescue approaches, we also find that peptides derived from the glucagon gene are necessary for alpha-to-beta cell fate switching. Importantly, whereas beta cell neogenesis was stimulated by glucose, alpha-to-beta cell conversion was not, suggesting that transdifferentiation is not mediated by glucagon/GLP-1 control of hepatic glucose production. Overall, this study supports the hypothesis that alpha cells are an endogenous reservoir of potential new beta cells. It further reveals that glucagon plays an important role in maintaining endocrine cell homeostasis through feedback mechanisms that govern cell fate stability.

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“…Glucose measurements were done using a fluorescencebased enzymatic detection kit (Biovision, Inc., Mountain View, CA, USA) as described previously (Jurczyk et al 2011).…”

Section: Glucose Measurementsmentioning

confidence: 99%

Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

Marín-Juez¹,

Jong-Raadsen²,

Yang³

et al. 2014

Journal of Endocrinology

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Type 2 diabetes, obesity, and metabolic syndrome are pathologies where insulin resistance plays a central role, and that affect a large population worldwide. These pathologies are usually associated with a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia), which diminishes the concentration of key downstream elements, causing insulin resistance. The complexity of the study of insulin resistance arises from the heterogeneity of the metabolic states where it is observed. To contribute to the understanding of the mechanisms triggering insulin resistance, we have developed a zebrafish model to study insulin metabolism and its associated disorders. Zebrafish larvae appeared to be sensitive to human recombinant insulin, becoming insulin-resistant when exposed to a high dose of the hormone. Moreover RNA-seq-based transcriptomic profiling of these larvae revealed a strong downregulation of a number of immune-relevant genes as a consequence of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator protein tyrosine phosphatase nonreceptor type 6 (ptpn6) appeared to be upregulated in insulin-resistant larvae. Knockdown of ptpn6 was found to counteract the observed downregulation of the immune system and insulin signaling pathway caused by hyperinsulinemia. These results indicate that ptpn6 is a mediator of the metabolic switch between insulin-sensitive and insulin-resistant states. Our zebrafish model for hyperinsulinemia has therefore demonstrated its suitability for discovery of novel regulators of insulin resistance. In addition, our data will be very useful in further studies of the function of immunological determinants in a non-obese model system.

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Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish

Cited by 105 publications

References 72 publications

GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

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