Dataset Information

Mechanism of Roux-en-Y gastric bypass treatment for type 2 diabetes in rats.

ABSTRACT:

Objectives

Roux-en-Y gastric bypass (RYGB) is a novel therapy for diabetes. We aimed to explore the therapeutic mechanism of RYGB.

Methods

After RYGB, animal models were established, and gene expression profile of islets was assessed. Additionally, gastrointestinal hormones were measured using enzyme-linked immunosorbent assays. Ca(2+) was studied using confocal microscopy and patch-clamp technique. The morphology of islets and beta cells was observed using optical microscopy and electron microscopy.

Results

RYGB was an effective treatment in diabetic rats. Expression profiling data showed that RYGB produced a new metabolic environment and that gene expression changed to adapt to the new environment. The differential expression of genes associated with hormones, Ca(2+) and cellular proliferation was closely related to RYGB and diabetes metabolism. Furthermore, the data verified that RYGB led to changes in hormone level and enhanced Ca(2+) concentration changes and Ca(2+) channel activity. Morphological data showed that RYGB induced the proliferation of islets and improved the function of beta cells.

Conclusions

RYGB promoted a new metabolic environment while triggering changes to adapt to the new environment. These changes promoted the cellular proliferation of islets and improved the function of beta cells. The quantity of beta cells increased, and their quality improved, ultimately leading to insulin secretion enhancement.

SUBMITTER: Yu H

PROVIDER: S-EPMC3653054 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 ?-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 ?-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 ?-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1-/- ?-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 ?-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.