# The pancreatic β-cell incretin response is modulated by mitochondrial transaminase GPT2

## TL;DR

This study shows that reducing GPT2 improves β-cell function and incretin response in type 2 diabetes, suggesting it as a potential therapeutic target.

## Contribution

The study identifies GPT2 as a novel modulator of β-cell incretin sensitivity and function in type 2 diabetes.

## Key findings

- Gpt2βKO mice showed improved oral glucose tolerance and insulin secretion.
- GPT2 was increased in human islets from T2D donors and under glucolipotoxic conditions.
- Silencing GPT2 reversed incretin unresponsiveness in T2D islets and improved β-cell survival.

## Abstract

The effect of the incretin hormones GLP-1 and GIP to promote pancreatic β-cell function is exploited by an expansive menu of incretin mimetics for the treatment of type 2 diabetes (T2D); however, the incretin effect is well known to diminish as T2D progresses. Here, we show that silencing of stress-inducible mitochondrial protein glutamic pyruvate transaminase 2 (GPT2) enhances the β-cell incretin response. Mice with β-cell specific Gpt2 deficiency (Gpt2βKO) have improved oral glucose tolerance and insulin secretion due to enhanced β-cell incretin sensitivity. In the diet induced obesity (DIO) model of T2D, Gpt2βKO mice maintained lower non-fasting glucose and improved oral glucose tolerance and insulin secretion. The effect of GLP-1 receptor (GLP-1R) agonism on β-cell survival was also enhanced in Gpt2βKO islets. GPT2 was markedly induced in human islets from donors with type 2 diabetes and in non-diabetic donor islets exposed to glucolipotoxicity. Silencing GPT2 in human β-cells enhanced β-cell incretin sensitivity and survival, and it reversed incretin unresponsiveness in T2D islets. These findings raise GPT2 as a therapeutic target to mitigate β-cell dysfunction in T2D.