Exendin-4 and exercise improve hepatic glucose homeostasis by promoting insulin signaling in diabetic rats.
Recently, it has been reported that a long-acting glucagon-like peptide-1 (exendin-4) and physical exercise improve hepatic insulin action in diabetic rats. However, this phenomenon remains poorly understood. We investigated the long-term effect that exendin-4 and exercise had on hepatic insulin resistance through the modulation of hepatic and/or hypothalamic insulin signaling in 90% pancreatectomized diabetic rats fed 40% energy fat diets. The rats were divided into 4 groups: exendin-4 only, exendin-4 plus exercise training, saline (control), or exercise training only. Rats in the exendin-4 groups were administered with 150 pmol/kg exendin-4 twice a day for 8 weeks, whereas those in the exercise groups ran on an uphill treadmill with a 15 degrees incline at 20 m/min for 30 minutes 5 days a week. Exendin-4 reduced serum glucagon levels in overnight-fasted rats. Exendin-4 treatment by itself decreased hepatic glucose output at hyperinsulinemic states, and exercise without exendin-4 treatment also had the same effect. Exendin-4 promoted hepatic insulin signaling by potentiating tyrosine phosphorylation of the insulin receptor substrate-2 without changing hypothalamic insulin signaling. Exendin-4 also enhanced hypothalamic glucose sensing. However, exercise improved both hepatic and hypothalamic insulin signaling by activating the phosphorylation of cyclic adenosine monophosphate-responding element binding proteins to induce insulin receptor substrate-2 expression. Exendin-4 and exercise decreased the expression of phosphoenolpyruvate carboxykinase, which in turn reduced hepatic glucose output. Exendin-4 in combination with exercise had no additive effects. In conclusion, exendin-4 and exercise improve hepatic glucose homeostasis by promoting hepatic insulin signaling in diabetic rats.
Park
Sunmin
S
Department of Food and Nutrition, College of Natural Science, Institute of Basic Science, Hoseo University, Asan-Si, Chungnam-Do 336-795, South Korea. smpark@hoseo.edu
Hong
Sang Mee
SM
Ahn
Il Sung
IS
D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D002149:Energy Intake; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010805:Physical Conditioning, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D017931:DNA Primers; D007328:Insulin; D005934:Glucagon; D005947:Glucose