Dataset Information

Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity.

ABSTRACT: SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In ?-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a knockin mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X. The R138X mice had normal body weight, glucose tolerance, and pancreatic ?-cell mass. Interestingly, in hyperglycemic conditions induced by the insulin receptor antagonist S961, the R138X mice showed a 50% increase in insulin secretion. This effect was not associated with enhanced ?-cell proliferation or mass. Our data suggest that the SLC30A8 R138X LOF mutation may exert beneficial effects on glucose metabolism by increasing the capacity of ?-cells to secrete insulin under hyperglycemic conditions.

SUBMITTER: Kleiner S

PROVIDER: S-EPMC6094147 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity.

Kleiner Sandra S Gomez Daniel D Megra Bezawit B Na Erqian E Bhavsar Ramandeep R Cavino Katie K Xin Yurong Y Rojas Jose J Dominguez-Gutierrez Giselle G Zambrowicz Brian B Carrat Gaelle G Chabosseau Pauline P Hu Ming M Murphy Andrew J AJ Yancopoulos George D GD Rutter Guy A GA Gromada Jesper J

Proceedings of the National Academy of Sciences of the United States of America 20180723 32

SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In β-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a knockin mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X. The R138X mice had normal body weight, glucose tolerance, and pancreatic β-cell mass. Interes ...[more]

PMID: 30038024

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Project description:TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.

Dataset Information

Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity.

Publications

Mice harboring the human <i>SLC30A8</i> R138X loss-of-function mutation have increased insulin secretory capacity.

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