Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic fatty liver disease

Abstract

Objective: The aim of this study was to examine the association between ectopic fat and organ-specific insulin resistance (IR) in insulin-target organs in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: Organ-specific IR in the liver (hepatic glucose production (HGP) × fasting plasma insulin (FPI) and suppression of HGP by insulin [%HGP]), skeletal muscle (insulin-stimulated glucose disposal [Rd]), and adipose tissue (suppression of FFA by insulin [%FFA]) was measured in 69 patients with NAFLD using a euglycemic hyperinsulinemic clamp with tracer infusion ([6,6-2H2]glucose). Liver fat, intramyocellular lipid (IMCL), and body composition were measured by liver biopsy, proton magnetic resonance spectroscopy, and bioelectrical impedance analysis, respectively.

Results: HGP × FPI was significantly correlated with Rd (r = -0.57, P<0.001), %HGP with %FFA (r = 0.38, P<0.01), and Rd with %FFA (r = 0.27, P<0.05). Liver steatosis score was negatively associated with Rd (r = -0.47, P<0.001) as well as with HGP × FPI (r = 0.43, P<0.001). Similarly, intrahepatic lipid was negatively associated with Rd (r = -0.32, P<0.05). IMCL was not associated with Rd (r = -0.16, P = 0.26). Fat mass and its percentage were associated with HGP × FPI (r = 0.50, P<0.001; r = 0.48, P<0.001, respectively) and Rd (r = -0.59, P<0.001; r = -0.52, P<0.001, respectively), but not with %FFA (r = -0.21, P = 0.10; r = -0.001, P = 0.99, respectively).

Conclusion: Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organ-specific IR. Instead, liver fat was associated not only with hepatic IR but also with skeletal muscle IR, suggesting a central role of fatty liver in systemic IR and that a network exists between liver and skeletal muscle.

Figure 1. Correlation between liver fat and organ-specific insulin resistance (IR).

(A) univariate correlation between IR in the liver (HGP×FPI) and liver fat (IHL) (r = 0.25, P = 0.09). (B) univariate correlation between skeletal muscle IR index (Rd) and liver fat (IHL) (r = −0.32, P<0.05). (C) IR in the liver (HGP×FPI) stratified by steatosis score. (D) skeletal muscle IR index (Rd) stratified by steatosis score. *P<0.05 vs. score 0 steatosis group. **P<0.01 vs. score 0 steatosis group.

Figure 2. Correlation between ectopic fat and organ-specific insulin resistance (IR).

(A) univariate correlation between skeletal muscle IR index (Rd) and intramyocellular lipid (IMCL) (r = −0.16, P = 0.26). (B) univariate correlation between Rd and fat-free mass (r = 0.22, P = 0.08). (C) univariate correlation between adipose tissue IR index (%FFA) and total fat mass (r = −0.21, P = 0.10). (D) univariate correlation between %FFA and body fat percentage (r = −0.00, P = 0.99).