Palmitoylation couples insulin hypersecretion with ß 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 ß cell failure. These findings suggest that APT1 is regulated in human islets and that APT1 deficiency causes insulin hypersecretion leading to ß cell failure, modeling the evolution of some forms of human type 2 diabetes.

Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome.

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.