Palmitoylation couples insulin hypersecretion with β cell failure in diabetes

Hyperinsulinemia often precedes type 2 diabetes. Palmitoylation, implicated in exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). APT1 biology was altered in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic islets caused insulin hypersecretion. APT1 knockout mice had islet autonomous increased glucose-stimulated insulin secretion that was associated with prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Scamp1 knockdown caused insulin hypersecretion. Expression of a mutated Scamp1 incapable of being palmitoylated in APT1-deficient cells rescued insulin hypersecretion and nutrient-induced apoptosis. High-fat-fed islet-specific APT1-knockout mice and global APT1-deficient db/db mice showed increased β cell failure. These findings suggest that APT1 is regulated in human islets and that APT1 deficiency causes insulin hypersecretion leading to β cell failure, modeling the evolution of some forms of human type 2 diabetes. [Display omitted] •APT1 shows altered expression in human pancreatic islets•APT1 deficiency causes insulin hypersecretion•Deficiency of the APT1 substrate Scamp1 causes insulin hypersecretion•APT1 deficiency promotes β cell failure in high-fat-fed mice and db/db mice The depalmitoylation enzyme acyl-protein thioesterase 1 (APT1) is altered in pancreatic islets from people with type 2 diabetes and in nondiabetic islets exposed to hyperglycemia. APT1 deficiency in mice increases insulin secretion that promotes β cell failure in the setting of metabolic stress, suggesting involvement of palmitoylation in diabetes pathogenesis.