Mechanism of Fatty Acid-induced Impairment of Glucose-simulated Insulin Secretion - Effect of Buphenyl

Summary

An increase of plasma free fatty acids impairs insulin secretion and insulin sensitivity, thereby playing an important role in causing type 2 diabetes. Lipotoxicity plays an important role in the progression from normal glucose tolerance to fasting hyperglycemia and coversion to frank type 2 diabetes. A recent publication in the journal Science showed that buphenyl, when given to obese diabetic mice, resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease and inhancement of insulin action in liver, muscle and adipose tissue. the mechanism of action is believed to be due to reduction of endoplasmic reticulum (ER) stress. Buphenyl is currently approved for the treatment of rare inherited disorders of the urea cycle. We plan to administer Buphenyl orally to humans at a dose far lower than that used for the treatment of urea cycle disorders for 2 weeks prior to the testing of pancreatic function. One potential mechanism whereby chromically elevated plasma FFAs and glucose impairment beta cell function and insuln sensitivity is by ER stress and this can be prevented by administeration of buphenyl.

Timeline

Start

2007-09

Primary completion

2009-12

Completion

2010-03

Drugs

Indications