Ectopic Fat Accumulation and Distant Organ-Specific Insulin Resistance in Japanese People with Nonalcoholic Fatty Liver Disease

Ken-Ichiro Kato,Hirofumi Misu,Kumpei Tokuyama,Yasuji Ryu,Osamu Matsui,Tsuguhito Ota,Shuichi Kaneko,Toshinari Takamura,Shoichiro Nagasaka,Yumie Takeshita,Munehide Matsuhisa

doi:10.1371/journal.pone.0092170

Ken-Ichiro Kato, Hirofumi Misu + Show 9 more

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https://doi.org/10.1371/journal.pone.0092170

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Abstract

ObjectiveThe 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).MethodsOrgan-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.ResultsHGP×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).ConclusionUnexpectedly, 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.

Highlights

Insulin resistance (IR) is a core pathology of type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular diseases [1,2,3]
Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organspecific IR
Liver fat was associated with hepatic IR and with skeletal muscle IR, suggesting a central role of fatty liver in systemic IR and that a network exists between liver and skeletal muscle

Summary

Introduction

Insulin resistance (IR) is a core pathology of type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular diseases [1,2,3]. The severity of IR may differ among the major insulin-target organs, the liver, skeletal muscle, and adipose tissue [4]. Accumulating evidence suggests that ectopic fat accumulation in insulin-target organs leads to development of IR in each organ by altering oxidative stress [5,6,7] and gene expression profiles [8,9]. To understand organ networks that sense excess energy and regulate insulin action, elucidating the association between fat accumulation and organ-specific IR among the liver, skeletal muscle, and adipose tissue is important, especially in humans. Liver biopsy remains gold standard for diagnosis of NAFLD because it more accurately measures liver fat than proton magnetic resonance spectroscopy (1H-MRS) under some conditions [16]

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Conclusion