Hepatic insulin resistance (H-IR) is a major pathogenesis of type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD). Due to pandemic obesity, in addition to reducing toxic lipids in the liver, searching for other factors that may regulate hepatic insulin sensitivity (H-IS) is inevitable in humans with NAFLD. To find such factors, we performed comprehensive assessment in the patients with NAFLD (n=36) aged 47.4±12.3, BMI 29.4±4.7 kg/m2, DM/non-DM 23/13, HbA1c 6.7±1.0% (mean±SD). We assessed putative biomarkers in blood and urine, body composition, tissue lipid content by 1H-MRS, tissue IS by hyperinsulinemic euglycemic clamp, hepatic histological scores and gene expressions using biopsies, and life styles. Furthermore, we developed a new magnetic resonance imaging analytic method that can exactly evaluate the whole liver volume, whole hepatic lipid volume, and whole hepatic lean volume. We performed single regression analysis between H-IS assessed by clamped % suppression of endogenous glucose production and all evaluated indices. As results, existence of diabetes, fasting plasma glucose, and HbA1c showed significant negative correlation with H-IS, while plasma adiponectin, muscle IS and adipose tissue IS showed significant positive correlation with H-IS. Interestingly, whole liver volume (cm3/m2) and lean hepatic volume (cm3/m2) corrected by body surface area showed negative correlation with H-IS (β=-0.02, -0.03 and p<0.05, <0.01, respectively), specifically in patients with T2DM. Finally, multiple regression analysis confirmed that lean hepatic volume is a negative factor for the H-IS (β=-0.02, p<0.05).

Conclusion: Through comprehensive assessment including our new whole hepatic volume evaluation, we first demonstrated that lean hepatic volume strongly associates with H-IR specifically in patients with T2DM. Not only hepatic volume control but quality control supported by adiponectin or other insulin-targeted organs is necessary for H-IS in humans with NAFLD.


H. Igarashi: None. F. Shigiyama: None. S. Hiruma: None. T. Hirose: None. N. Kumashiro: Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.


Japan Society for the Promotion of Science (26702032, JP17H02180)

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