Intracellular lipid accumulation and insulin resistance in skeletal muscle and liver

Abstract

Insulin resistance is one of the hallmarks of type 2 diabetes. Recent data, using 1H-magnetic resonance spectroscopy (MRS), suggests that insulin resistance is associated with increased intracellular lipid content in muscle and liver, independently of obesity. However, the roles of intracellular fat accumulation in insulin target organs are not fully understood. Thus, to clarify the role of intracellular fat in muscle and liver, we performed 3 intervention studies with 1H-MRS. First, we examined three days low, normal and high fat diet on intramyocellular lipid (IMCL) in sprinters and endurance runners (n=7, respectively). This study showed that IMCL in tibialis anterior (TA) was increased by 200% and decreased by 50% after high and low fat diet, respectively, compared with normal fat diet in endurance runners. However, these changes were not observed in sprinters. Interestingly, the IMCL level of endurance runner was three times higher than that of sprinter, and was similar to that of type 2 diabetes, although their insulin sensitivity is supernormal. This paradox may be explained by the difference of muscle fiber type among those subjects. In addition, our preliminary data suggested that IMCL level was decreased by ∼30% after 60 minutes running (∼60% VO2max) in endurance runners. From these results, we hypothesized that diet and/or exercise therapy may decrease IMCL level in type 2 diabetes and obese subjects, thus improving insulin resistance. To test this hypothesis, we treated type 2 diabetic patients by diet therapy alone (D-group, n=7) or diet plus exercise (D+E group. n=7) for 2-week (1). We performed a hyperinsulinemic-euglycemic clamp study with oral glucose load before and after treatment to measure insulin sensitivity in muscle and liver, respectively. IMCL in TA muscle and intrahepatic lipid (IHL) were evaluated by 1H-MRS. After ∼2-week intervention, body weight was decreased by ∼2 %. IMCL was decreased by 19% and the glucose infusion rate (GIR), mainly reflecting muscle insulin sensitivity, was increased by 57% in the D+E group. whereas both IMCL and GIR were not altered in the D group. On the other hand, IHL showed significant decrease (∼25%) in both groups, which was associated with improved hepatic insulin sensitivity. Finally, to further investigate the role of diet therapy, we examined the effect of long-term (3 months) diet therapy in 13 non-diabetic obese men. After 3 months diet therapy, body weight decreased by 6 % (from 99.9 to 93.8 kg). IHL significantly reduced from 13.4 to 8.4 %, which was associated with improved hepatic insulin sensitivity. However, neither IMCL nor GIR was altered. Taken together, it is suggested that intracellular fat accumulation is an important therapeutic target in insulin resistant subjects. Exercise and diet therapy may be required to improve fat accumulation and insulin resistance in muscle and liver, respectively. Endurance training may induce paradoxical increase in IMCL.