Background:  Exenatide (exendin‐4) can reduce blood glucose levels, increase insulin secretion and improve insulin sensitivity through mechanisms that are not completely understood.

Methods:  In the present study, we examined the effects of exenatide treatment on glucose tolerance (intravenous glucose tolerance test), insulin sensitivity (euglycaemic–hyperinsulinaemic clamps), insulin signalling (insulin receptor substrate 1 tyrosine phosphorylation) and adipocytokine levels (visfatin and adiponectin) in high fat–fed rats.

Results:  Administration of exenatide (0.5 or 2.0 μg/kg twice daily × 6 weeks) prevented high‐fat diet (HFD)–induced increases in body weight, plasma free fatty acids, triglycerides and total cholesterol. Exenatide also prevented HFD‐induced deterioration in peripheral and hepatic insulin sensitivity, insulin clearance, glucose tolerance and decreased tyrosine phosphorylation of insulin receptor substrate‐1 (IRS‐1) in fat and skeletal muscles. Interestingly, plasma visfatin levels decreased in exenatide‐treated rats, whereas expression and plasma levels of adiponectin increased.

Conclusions:  These results indicate that chronic exenatide treatment enhances insulin sensitivity and protects against high fat–induced insulin resistance.