Abstract
Alström syndrome 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). We previously published data supporting the alms1 loss-of-function zebrafish mutant as a monogenic model for mechanistic interrogation of T2DM phenotypes. Both adult and larval alms1-/- animals exhibit reduced insulin+ areas alongside defective peripheral glucose uptake and concomitant hyperinsulinemia in larval alms1-/- animals. Gene expression changes in beta-cells isolated from alms1-/- mutants revealed changes consistent with insulin hyperproduction, insulin hypersecretion and glucose sensing failure. Therefore, we used this model, in which hyperinsulinemia is the primary and causative defect underlying generation of T2DM, in a high-throughput screen to examine small molecule compounds effecting pancreatic mass in vivo. The external development, simple growing conditions, and large number of progeny in the zebrafish allow for rapid screening with parallel elimination of lethal compounds. We examined the Microsource Spectrum Collection 2000, a library of 2,560 compounds, for those which increase beta-cell mass in wildtype, alms1-/- animals or both. These identified compounds are indicated in future studies for beta-cell proliferation pathways, T2DM diabetes-specific interactions, and potential targets for future therapeutic development. Disclosure J. Dunleavey: None. D.A. Annis: None. T.L. Hostelley: None. N.A. Zaghloul: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases
Published Version
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