Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes

TLDR

Endoplasmic reticulum stress links obesity, insulin resistance, and type 2 diabetes. The study investigates whether orally active chemical chaperones can exploit this ER stress–insulin resistance connection for therapeutic benefit. Treatment with 4‑phenyl butyric acid and taurine‑conjugated ursodeoxycholic acid alleviated ER stress, normalized hyperglycemia, restored insulin sensitivity, resolved fatty liver, and enhanced insulin action in liver, muscle, and adipose tissues, demonstrating potent antidiabetic effects.

Abstract

Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.