Inhibition of SNAT5 induces incretin-responsive state from incretin-unresponsive state in pancreatic B-cells: Study of B-cell spheroid clusters as a model

Mahira Hashim, Norihide Yokoi, Harumi Takahashi, Ghupurjan Gheni, Oduori S. Okechi, Tomohide Hayami, Naoya Murao, Shihomi Hidaka, Kohtaro Minami, Akira Mizoguchi, Susumu Seino

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

B-Cell-b-cell interactions are required for normal regulation of insulin secretion. We previously found that formation of spheroid clusters (called K20-SC) from MIN6-K20 clonal b-cells lacking incretin-induced insulin secretion (IIIS) under monolayer culture (called K20-MC) drastically induced incretin responsiveness. Here we investigated the mechanism by which an incretin-unresponsive state transforms to an incretin-responsive state using K20-SC as a model. Glutamate production by glucose through the malate-aspartate shuttle and cAMP signaling, both of which are critical for IIIS, were enhanced in K20-SC. SC formed from b-cells deficient for aspartate aminotransferase 1, a critical enzyme in the malate-aspartate shuttle, exhibited reduced IIIS. Expression of the sodium-coupled neutral amino acid transporter 5 (SNAT5), which is involved in glutamine transport, was downregulated in K20-SC and pancreatic islets of normal mice but was upregulated in K20-MC and islets of rodent models of obesity and diabetes, both of which exhibit impaired IIIS. Inhibition of SNAT5 significantly increased cellular glutamate content and improved IIIS in islets of these models and in K20-MC. These results suggest that suppression of SNAT5 activity, which results in increased glutamate production, and enhancement of cAMP signaling endows incretin-unresponsive b-cells with incretin responsiveness.

Original languageEnglish
Pages (from-to)1795-1806
Number of pages12
JournalDiabetes
Volume67
Issue number9
DOIs
Publication statusPublished - 01-09-2018

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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