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

Mol Metab. 2019 Nov:29:1-11. doi: 10.1016/j.molmet.2019.08.009. Epub 2019 Aug 15.

Abstract

Objective: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Diabetes; FXR; Insulin secretion; RYGB; TRPA1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Diabetes Mellitus, Type 2 / surgery
  • Diabetes Mellitus, Type 2 / veterinary
  • Evoked Potentials
  • 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
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Wistar
  • Rats, Zucker
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • TRPA1 Cation Channel / genetics
  • TRPA1 Cation Channel / metabolism*

Substances

  • Histones
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • TRPA1 Cation Channel
  • farnesoid X-activated receptor
  • Nuclear Receptor Coactivator 1