Evidence of Hepatic Glucagon Resistance Associated with Hepatic Steatosis: Reversal Effect of Training

Abstract The present study was undertaken to test the hypothesis that a high-fat diet-induced hepatic steatosis is associated with a reduction in hepatic glucose output (HGO) in response to a hyperglucagonemic infusion, and that this postulated state of hepatic glucagon resistance in high-fat fed rats is attenuated by concurrent exercise training. In four groups of anesthetized rats, glucagon (2 ug/kg/min iv) was infused over a period of 60 min to measure HGO. Two groups of rats were either fed a standard (SD) or a high-fat (HF; 42 % kcal) diet for eight weeks and were assigned either to a Sedentary (Sed) or a treadmill-trained (TR) group. Training was initiated two weeks after the beginning of the diet protocol and was progressively increased over a period of 6 weeks reaching 60 min at 26 m/min, 10 % grade, for the last 3 weeks. The HF compared to the SD diet resulted in ∼ 28 % higher (p < 0.01) liver triglyceride levels in Sed rats. This increase was completely prevented by the exercise training program in the HF-TR group. Plasma glucagon (∼ 90000 pg/ml) and insulin (∼ 500 pmol/l) levels were increased to a similar extent in all four groups, with the exception of higher (p < 0.05) insulin levels in SD-Sed group. Glucagon induced-hyperglycemia (∼ 300 mg/dl) was higher (p < 0.05) in the SD-Sed than in HF-Sed and SD-TR groups. Glucagon infusion resulted in a significantly (p < 0.05) lower increase (∼ 35 %) in HGO in HF-Sed compared to SD-Sed group. The lower level of HGO in HF-Sed compared to SD-Sed rats was observed whether HGO was measured after 25, 40, or 60 min of glucagon infusion. Exercise training in HF fed rats resulted in a significant (p < 0.05) attenuation (50 %) of the state of HF-induced glucagon resistance. Comparisons of all individual liver triglyceride and 60-min HGO values revealed that liver triglyceride values were highly (p < 0.001) predictive of the decreased glucagon action on HGO (R = - 0.849). The present results indicate that the feeding of a high-fat diet induces a state of hepatic glucagon resistance, which is partially attenuated by concurrent exercise training. It is suggested that liver lipid infiltration may interfere with the action of glucagon, thus inducing glucagon resistance in liver.