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Pancreatic β cell–selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis
Jie Xu, … , Cheng Hu, Michael B. Wheeler
Jie Xu, … , Cheng Hu, Michael B. Wheeler
Published May 24, 2021
Citation Information: JCI Insight. 2021;6(10):e143037. https://doi.org/10.1172/jci.insight.143037.
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Research Article Endocrinology Metabolism

Pancreatic β cell–selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis

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Abstract

GWAS have shown that the common R325W variant of SLC30A8 (ZnT8) increases the risk of type 2 diabetes (T2D). However, ZnT8 haploinsufficiency is protective against T2D in humans, counterintuitive to earlier work in humans and mouse models. Therefore, whether decreasing ZnT8 activity is beneficial or detrimental to β cell function, especially under conditions of metabolic stress, remains unknown. In order to examine whether the existence of human islet amyloid polypeptide (hIAPP), a coresident of the insulin granule, affects the role of ZnT8 in regulating β cell function, hIAPP-expressing transgenics were generated with reduced ZnT8 (ZnT8B+/– hIAPP) or null ZnT8 (ZnT8B–/– hIAPP) expression specifically in β cells. We showed that ZnT8B–/– hIAPP mice on a high-fat diet had intensified amyloid deposition and further impaired glucose tolerance and insulin secretion compared with control, ZnT8B–/–, and hIAPP mice. This can in part be attributed to impaired glucose sensing and islet cell synchronicity. Importantly, ZnT8B+/– hIAPP mice were also glucose intolerant and had reduced insulin secretion and increased amyloid aggregation compared with controls. These data suggest that loss of or reduced ZnT8 activity in β cells heightened the toxicity induced by hIAPP, leading to impaired β cell function and glucose homeostasis associated with metabolic stress.

Authors

Jie Xu, Nadeeja Wijesekara, Romario Regeenes, Dana Al Rijjal, Anthony L. Piro, Youchen Song, Anne Wu, Alpana Bhattacharjee, Ying Liu, Lucy Marzban, Jonathan V. Rocheleau, Paul E. Fraser, Feihan F. Dai, Cheng Hu, Michael B. Wheeler

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Figure 7

β Cell ZnT8 haploinsufficient hIAPP mice have increased islet amyloidogenesis and β cell loss but normal β cell morphology.

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β Cell ZnT8 haploinsufficient hIAPP mice have increased islet amyloidoge...
(A) Thioflavin S staining (scale bar: 50 μm) with quantification of (B) amyloid severity, (C) amyloid prevalence, and (D) β cell area. (E) Transmission electron microscopy on isolated islets (scale bar: 500 nm). (F) Quantifications of the number of dense-core granules and (G) rod-like insulin granules. Data are represented as mean ± SEM. (A–D) Control (n = 4), ZnT8B–/– (n = 3), hIAPP (n = 6), and ZnT8B–/– hIAPP (n = 4). (E and G) Control (n = 2), hIAPP (n = 3), and ZnT8B+/– × hIAPP (n = 2). *P < 0.05, all groups compared with control; ##P < 0.01, ZnT8B+/– hIAPP compared with ZnT8B+/–. $P < 0.01, ZnT8B+/– hIAPP compared with hIAPP. One-way ANOVA with Tukey’s adjustment was used in B–D, F, and G.

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