1822-P: Overexpression of Acyl-Protein Thioesterase 1 in Pancreatic Islets Preserves Beta-Cell Function

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Introduction and Objective:Protein S-palmitoylation is a reversible modification involved in the β cell dysfunction that characterizes type 2 diabetes. Palmitate linked to cysteine is removed mostly through the activity of the depalmitoylase acyl-protein thioesterase 1 (APT1), an event important for intracellular trafficking and signaling. APT1 enzyme activity is decreased by hyperglycemia, and mice with islet-specific APT1 deficiency have insulin hypersecretion that promotes β cell failure in two models: high fat diet and db/db mice. We tested the hypothesis that APT1 activity preserves β cell function.Methods:We generated mice bearing a cassette at the ROSA locus with APT1 engineered to resist inhibition by high glucose followed by a floxed stop signal. These mice were crossed with tamoxifen inducible Pdx1 Cre mice to yield APT1 overexpression (OE) mice.Results:Islet APT1 enzyme activity was ~95% higher in islets from APT1 OE as compared to control islets. There was no effect of APT1 OE in female or male chow diet mice on body weight, glucose or insulin tolerance, insulin levels after glucose challenge, or β cell mass, but C-peptide responses to glucose were increased in APT1 OE females and males. In females and males on high fat diet, APT1 OE mice had improved glucose tolerance and increased insulin and C-peptide following glucose challenge without effects on body weight, insulin tolerance, or β cell mass compared to controls. In female and male db/db mice, APT1 OE animals had improved glucose tolerance associated with increased levels of C-peptide and insulin without effects on body weight or severe insulin resistance measured in insulin tolerance tests. Palmitoylation proteomics comparing APT1 OE and control INS-1 cells identified substrates with decreased palmitoylation implicated in insulin secretion including GAPDH and clathrin.Conclusion:These findings suggest that increasing APT1 enzyme activity in islets may preserve β cell function.

Disclosure

G. Dong: None. S. Adak: None. W. Zhang: None. M.S. Remedi: None. X. Wei: None. C.F. Semenkovich: Advisory Panel; Alnylam Pharmaceuticals, Inc. Other Relationship; AirSeal CardioVascular.



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