Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes.
Hum Mol Genet
; 28(13): 2212-2223, 2019 07 01.
Article
en En
| MEDLINE
| ID: mdl-31220269
ABSTRACT
Alström syndrome (OMIM #203800) is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early-onset type 2 diabetes mellitus (T2DM). To investigate the underlying mechanisms of T2DM phenotypes, we generated a loss-of-function deletion of alms1 in the zebrafish. We demonstrate conservation of hallmark clinical characteristics alongside metabolic syndrome phenotypes, including a propensity for obesity and fatty livers, hyperinsulinemia and glucose response defects. Gene expression changes in ß-cells isolated from alms1-/- mutants revealed changes consistent with insulin hypersecretion and glucose sensing failure, which were corroborated in cultured murine ß-cells lacking Alms1. We also found evidence of defects in peripheral glucose uptake and concomitant hyperinsulinemia in the alms1-/- animals. We propose a model in which hyperinsulinemia is the primary and causative defect underlying generation of T2DM associated with alms1 deficiency. These observations support the alms1 loss-of-function zebrafish mutant as a monogenic model for mechanistic interrogation of T2DM phenotypes.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Degeneración Retiniana
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Pez Cebra
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Resistencia a la Insulina
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Diabetes Mellitus Tipo 2
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Insuficiencia Renal
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Síndrome de Alstrom
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2019
Tipo del documento:
Article