European Journal of Clinical Nutrition (2019) 73:770–775
Carbohydrates, glycemic index and diabetes mellitus
Reappraisal of attenuated insulin sensitivity in the evolution of
non-alcoholic fatty liver disease
Takahiro Miyakoshi1●Hiroyuki Sagesaka1●Yuka Sato1●Kazuko Hirbayashi2●Hideo Koike2●Koh Yamashita1●
Seiichi Usuda3●Kendo Kiyosawa3●Masanori Shimodaira4●Toru Aizawa1
Received: 21 January 2018 / Revised: 16 April 2018 / Accepted: 8 May 2018 / Published online: 17 July 2018
© Macmillan Publishers Limited, part of Springer Nature 2018
Background/objectives It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease
(NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution.
Subjects/methods We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single
point insulin sensitivity estimator (SPISE =[600 × HDL-c0.185]/[TG0.2 ×BMI
1.338]), correlating with 1/HOMA-IR in an
independent cohort (n=1537, Spearman rho =0.519, P< 0.01). Fatty liver (FL) was diagnosed by ultrasonography and
diabetes by fasting plasma glucose (FPG) ≥7 mmol/L and/or glycohemoglobin A1c ≥6.5%. Multinominal comparison was
performed with incident FL (FLw/oDM,n=486), diabetes (DMw/oFL,n=171), and FL plus diabetes (FL/diabetes, n=58) as
targets; none of the above (n=4,138) was the control. SPISE was taken as a predictor with adjustment for covariates.
Trajectory of SPISE during the 5 years before development of each condition was also assessed.
Results With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FLw/oDM and FL/diabetes with
OR (95% CI) 3.47 (2.60–4.63) and 1.78 (1.10–2.87), respectively, and tertile 2 (8.07–10.06) related to FLw/oDM with OR
(95% CI) 1.38 (1.03–1.85). Low SPISE was not signiﬁcantly related to incident diabetes. At −5 years, SPISE was 12% (P<
0.05) and 13% (P< 0.01) lower in those developed FLw/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE
in the two groups was 18% and 21% lower than the control, respectively (P< 0.01).
Conclusions Attenuation of Si indexed by SPISE was a risk factor for NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is a globally
prevalent disease; further, non-alcoholic steatohepatitis, a
severe, advanced form of NAFLD, can progress to liver
cirrhosis and hepatocellular carcinoma [1,2]. Metabolic
abnormality in NAFLD resembles that of diabetes, with
attenuated insulin sensitivity (Si) playing a central role [1–
5]. However, it is unclear if attenuated Si is a cause or
consequence of NAFLD. With the increasing access to a
large number of adult health records, we critically examined
the signiﬁcance of attenuated Si in NAFLD evolution.
Moreover, special attention was paid for understanding the
aggregate interrelationship between NAFLD and diabetes.
As a quantitative index of Si, the single point insulin sen-
sitivity estimator (SPISE)  was used. SPISE validation
was performed by the authors in an independent Japanese
population. SPISE can be calculated using body mass index
(BMI), high-density lipoprotein cholesterol (HDL-c), and
triglycerides (TG) ; therefore, it can be easily used for the
general health examination.
1Diabetes Center, Aizawa Hospital, Matsumoto, Japan
2Health Center, Aizawa Hospital, Matsumoto, Japan
3Department of Gastroenterology, Aizawa Hospital,
4Takara Clinic, Nagokuma Kanae 2511, Iida, Japan
Electronic supplementary material The online version of this article
(https://doi.org/10.1038/s41430-018-0246-3) contains supplementary
material, which is available to authorized users.