Diabetes Metab J.  2021 May;45(3):417-429. 10.4093/dmj.2020.0039.

Distinct Dose-Dependent Association of Free Fatty Acids with Diabetes Development in Nonalcoholic Fatty Liver Disease Patients

• Li F
• Ye J
• Sun Y
• Lin Y
• Wu T
• Shao C
• Ma Q
• Liao X
• Feng S
• Zhong B

• KMID: 2516343
• DOI: http://doi.org/10.4093/dmj.2020.0039

Abstract

Background
Excessive delivery of free fatty acids (FFAs) to the liver promotes steatosis and insulin resistance (IR), with IR defined as reduced glucose uptake, glycogen synthesis and anti-lipolysis stimulated by normal insulin levels. Whether the associations between FFAs and diabetes development differ between patients with and without nonalcoholic fatty liver disease (NAFLD) remains unclear.
Methods
Consecutive subjects (2,220 NAFLD subjects and 1,790 non-NAFLD subjects according to ultrasound imaging) were enrolled from the First Affiliated Hospital of Sun Yat-sen University between 2009 and 2019. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated.
Results
There was an approximate J-shaped relationship between FFA levels and HOMA-IR in the NAFLD group. Higher FFA concentration quartiles were associated with higher risks of IR (odds ratio [OR], 9.24; 95% confidence interval [CI], 6.43 to 13.36), prediabetes (OR, 10.48; 95% CI, 5.66 to 19.39), and type 2 diabetes mellitus (T2DM; OR, 19.43; 95% CI, 12.75 to 29.81) in the NAFLD group but not in the non-NAFLD group. The cut-off points for the FFA levels increased in a stepwise manner in discriminating IR, prediabetes and T2DM (573, 697, and 715 μmol/L) in the NAFLD group but not in non-NAFLD individuals.
Conclusion
A distinct dose-dependent relationship of FFA levels was found with IR, prediabetes and T2DM in NAFLD patients. Screening serum FFA levels in NAFLD patients would be valuable in preventing diabetes development.

Keyword

Diabetes mellitus, type 2; Fatty acids, nonesterifie; Non-alcoholic fatty liver disease

Figure

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  Fig. 1. Nonlinear relationships of lipid profiles, homeostasis model assessment of insulin resistance (HOMA-IR), and fasting plasma glucose levels with free fatty acids (FFAs) in non-nonalcoholic fatty liver disease (NAFLD), NAFLD and subgroup NAFLD defined by magnetic resonance imaging proton density fat fraction (MRI-PDFF) groups adjusted for age, sex, and body mass index. (A) Triglycerides (TG), (B) cholesterol (CHOL), (C) low-density lipoprotein cholesterol (LDL-C), (D) high-density lipoprotein cholesterol (HDL-C), (E) HOMA-IR, and (F) fasting plasma glucose (FPG).

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  Fig. 2. Comparison of free fatty acid levels among subgroups with different body fat distribution and diabetes development. Subgroups were divided by (A) obesity, (B) abdominal obesity, (C) liver steatosis, (D) pancreatic fat infiltration, and (E) diabetes development. Obesity was defined as a body mass index (BMI) ≥25 kg/m2; abdominal obesity was defined as a waist circumference >90 cm for men and >80 cm for women; subjects was classified as absent, mild, moderate and severe steatosis based on the average liver fat content assessed using the magnetic resonance imaging proton density fat fraction (MRI-PDFF); pancreatic fat infiltration was defined as an average pancreatic fat content ≥5%, as assessed by MRI-PDFF. NAFLD, nonalcoholic fatty liver disease; FFA, free fatty acid; NS, not significant; SD, standard deviation. aP<0.05, bP<0.01, cP<0.001, dP<0.0001.

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  Fig. 3. Receiver operator characteristic (ROC) curve of factors for predicting insulin resistance (IR), prediabetes and type 2 diabetes mellitus (T2DM) in non-nonalcoholic fatty liver disease (NAFLD), NAFLD and subgroup NAFLD defined by magnetic resonance imaging proton density fat fraction (MRI-PDFF) groups. (A, B, C) ROC curve for predicting IR, prediabetes and T2DM in patients with non-NAFLD, (D, E, F) ROC curve for predicting IR, prediabetes and T2DM in NAFLD individuals, (G, H, I) ROC curve for predicting IR, prediabetes and T2DM in the subgroup of NAFLD defined by MRI-PDFF. FFA, free fatty acid; AUC, area under curve; BMI, body mass index; WC, waist circumference; UA, uric acid; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; LFC, liver fat content.

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