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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 <i>SLC30A8</i> 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

<i>SLC30A8</i> 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 <i>SLC30A8</i> 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 <i>SLC30A8</i>, R138X. The R138X mice had normal body weight, glucose tolerance, and pancreatic β-cell mass. Interes  ...[more]

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