α-Cell TXNIP Deletion Improves Hyperglucagonemia

Brian Lu, Junqin Chen, Guanlan Xu, Truman B Grayson, Gu Jing, SeongHo Jo, Anath Shalev
Endocrinology, Volume 163, Issue 11, November 2022, bqac133
https://doi.org/10.1210/endocr/bqac133

Abstract

Thioredoxin-interacting protein (TXNIP) has emerged as a key factor in pancreatic β-cell biology, and its upregulation by glucose and diabetes contributes to the impairment in functional β-cell mass and glucose homeostasis. In addition, β-cell deletion of TXNIP protects against diabetes in different mouse models. However, while TXNIP is ubiquitously expressed, its role in pancreatic α cells has remained elusive. We generated an α-cell TXNIP knockout (aTKO) mouse and assessed the effects on glucose homeostasis. While no significant changes were observed on regular chow, after a 30-week high-fat diet, aTKO animals showed improvement in glucose tolerance and lower blood glucose levels compared to their control littermates. Moreover, in the context of streptozotocin (STZ)-induced diabetes, aTKO mice showed significantly lower blood glucose levels compared to controls. While serum insulin levels were reduced in both control and aTKO mice, STZ-induced diabetes significantly increased glucagon levels in control mice, but this effect was blunted in aTKO mice. Moreover, glucagon secretion from aTKO islets was >2-fold lower than from control islets, while insulin secretion was unchanged in aTKO islets. At the same time, no change in α-cell or β-cell numbers or mass was observed, and glucagon and insulin expression and content were comparable in isolated islets from aTKO and control mice. Thus together the current studies suggest that downregulation of α-cell TXNIP is associated with reduced glucagon secretion and that this may contribute to the glucose-lowering effects observed in diabetic aTKO mice.

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