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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   β  -cells isolated from  alms1 −/−   mutants revealed changes consistent with insulin hypersecretion and glucose sensing failure, which were corroborated in cultured murine  β -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.

Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes