Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via FXR-mediated TRPA1 expression

• Published in: Molecular metabolism (Germany) 2019-11, Vol.29, p.1-11
• Main Authors: Kong, Xiangchen, Tu, Yifan, Li, Bingfeng, Zhang, Longmei, Feng, Linxian, Wang, Lixiang, Zhang, Lin, Zhou, Huarong, Hua, Xianxin, Ma, Xiaosong
• Format: Article
• Language: English
• Subjects: Animals; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - surgery; Diabetes Mellitus, Type 2 - veterinary; Evoked Potentials; FXR; Gastric Bypass; Histones - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Coactivator 1 - antagonists & inhibitors; Nuclear Receptor Coactivator 1 - genetics; Nuclear Receptor Coactivator 1 - metabolism; Original; Promoter Regions, Genetic; Rats; Rats, Wistar; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA Interference; RNA, Small Interfering - metabolism; RYGB; TRPA1; TRPA1 Cation Channel - genetics; TRPA1 Cation Channel - metabolism
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2019.08.009

Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic β-cells and involved in insulin secretion. We aimed to explore the role of BAs/FXR and TRPA1 in improved GSIS in diabetic rats after RYGB. RYGB or sham surgery was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 transgenic mice. Gene and protein expression of islets were assessed by qPCR and western blotting. Electrophysiological properties of single β-cells were studied using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured using enzyme-linked immunosorbent assays or intravenous glucose tolerance test (IVGTT). RYGB increases GSIS, particularly the first-phase of GSIS in both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. Importantly, the effects of RYGB were attenuated in TRPA1-deficient mice. Moreover, GK β-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1−/− β-cells displayed a marked hyperpolarization and decreased glucose-evoked action potential firing, which was associated with impaired GSIS. RYGB restored TRPA1 expression and current in GK β-cells. This was accompanied by improved glucose-evoked electrical activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of TRPA1. The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 expression plays a critical role in the enhanced GSIS and remission of diabetes in GK rats after RYGB. •RYGB-restored TRPA1 expression in diabetic β-cells.•RYGB-induced TRPA1 is mediated by FXR-SRC1-increased ACH3 at TRPA1 promoter.•TRPA1 is required for β-cell stimulus-secretion coupling.•Modulation of TRPA1 expression in β-cells may constitute a novel therapeutic strategy to improve β-cell function in T2D.