Table 1

Principal observational (retrospective or prospective) cohort studies of the association between NAFLD (detected by imaging techniques) and the risk of incident type 2 diabetes (ordered by publication year)

Authors, year (ref.)Study design; sample size and population; follow-up; and NAFLD diagnostic toolDiagnosis of incident diabetesNumber incident cases of diabetes; % in non-NAFLD vs. NAFLD cases (when available)Adjustments consideredMain findingsNOS
Okamoto et al., 2003 (17)Retrospective cohort study; n = 840 (14.3% with NAFLD) Japanese subjects without diabetes; 10 years; liver ultrasonographyFasting glucose >6.1 mmol/L or HbA1c ≥6.5%n = 82 incident cases; 7.6% vs. 22.5%Age, sex, BMI, family history of diabetes, fasting glucose, HbA1c, alcohol intake, frequency of check-ups, changes of BMI during follow-upNAFLD was associated with incident diabetes in univariate analysis (OR 2.62, 95% CI 1.6–4.3). This association disappeared after adjusting for potential confounding factors (aOR 1.83, 95% CI 0.9–3.5)6
Shibata et al., 2007 (18)Retrospective cohort study with a nested case-control analysis; n = 3,189 (33.6% with NAFLD) male Japanese workers with normal glucose tolerance without known chronic liver diseases; 4 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L or 2-h glucose ≥11.1 mmol/L on 75-g OGTTn = 109 incident cases; 1.8% vs. 8.1%Age and BMI (in the whole-cohort analysis), age, BMI, smoking history, blood pressure, physical activity, follow-up duration, metabolic syndrome (in the nested case-control analysis)NAFLD was independently associated with incident diabetes both in the whole cohort (aHR 5.50, 95% CI 3.6–8.5) and in the nested case-control analysis (aHR 4.60, 95% CI 3.0–6.9)4
Kim et al., 2008 (19)Retrospective cohort study; n = 5,372 (33.3% with NAFLD) South Korean subjects without diabetes without known chronic liver diseases; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 234 incident cases; 2.3% vs. 8.5%Age, sex, BMI, family history of diabetes, smoking, fasting glucose, HDL cholesterol, triglycerides, serum ALTNAFLD was independently associated with incident diabetes (aHR 1.51, 95% CI 1.04–2.2). Moderate/severe NAFLD had higher HRs vs. mild NAFLD. Exclusion of drinkers did not attenuate this association8
Bae et al., 2011 (20)Retrospective cohort study; n = 7,849 (29.2% with NAFLD) South Korean subjects without diabetes; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, clinical history, or drug treatmentn = 435 incident cases; 3.7% vs. 9.9%Age, sex, BMI, triglycerides, HDL cholesterol, systolic blood pressure, smoking, physical activity, alcohol intake, IFG statusNAFLD was independently associated with incident diabetes (aHR 1.33, 95% CI 1.1–1.7). This association was much stronger in pre-existing IFG8
Sung et al., 2012 (22)Retrospective cohort study; n = 12,853 (27.6% with NAFLD) South Korean subjects without diabetes; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 223 incident cases; 0.8% vs. 4.3%Age, sex, BMI, educational status, smoking, physical activity, alcohol intake, HOMA-IR, serum triglycerides, serum ALTThe clustering of increased HOMA-IR, overweight/obesity, and NAFLD markedly increases the odds of developing diabetes, with effects independent of each other and of confounding factors. NAFLD was associated with incident diabetes (aOR 2.42, 95% CI 1.7–3.4)7
Park et al., 2013 (21)Prospective cohort study (health check-up); n = 25,232 (35% with NAFLD) South Korean men without diabetes without known chronic liver diseases; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, clinical historyn = 2,108 incident cases; 7% in no-steatosis vs. 9.8% in mild steatosis vs. 17.8% in moderate-severe steatosisAge, waist circumference, HDL cholesterol, triglycerides, systolic blood pressure, C-reactive protein, HOMA-IR, serum creatinine, family history of diabetes, physical activity, metabolic syndromeNAFLD was independently associated with incident diabetes; the HRs were increased in mild steatosis (1.09, 95% CI 0.8–1.5) and in moderate/severe steatosis (1.73, 95% CI 1.0–3.0) vs. no-steatosis8
Kasturiratne et al., 2013 (23)Retrospective cohort study; n = 2,276 (40.7% with NAFLD) Sri Lankan individuals without diabetes without known chronic liver diseases; 3 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 242 incident cases; 10.5% vs. 19.7%Age, sex, family history of diabetes, BMI, waist circumference, hypertension, serum ALT, dyslipidemia, IFG statusNAFLD was independently associated with incident diabetes (aHR 1.64, 95% CI 1.2–2.2). NAFLD was the only independent predictor of incident diabetes among those with IFG at baseline5
Chang et al., 2013 (24)Retrospective cohort study; n = 38,291 (30.4% with NAFLD) South Korean subjects without diabetes without known chronic liver diseases; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, or drug treatmentn = 2,025 incident cases; 3.5% in no-NAFLD vs. 7.4% in NAFLD with low NFS vs. 15.3% in NAFLD with intermediate or high NFSAge, sex, smoking, alcohol intake, physical activity, family history of diabetes, total cholesterol, triglycerides, HDL cholesterol, HOMA-IR, C-reactive proteinThe aHRs for incident diabetes in NAFLD with low NFS and NAFLD with intermediate or high NFS vs. no NAFLD were 2.01, 95% CI 1.8–2.2, and 4.74, 95% CI 3.7–6.1, respectively. This association remained significant in subjects with fasting glucose levels <100 mg/dL or with HbA1c <5.8%8
Choi et al., 2013 (25)Retrospective cohort study; n = 7,849 (29% with NAFLD) South Korean without diabetes subjects without known chronic liver diseases; 4 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥ 6.5%, or drug treatmentn = 435 incident cases; 3.5% in controls vs. 4.6% in the increased ALT vs. 7.3% in the steatosis vs. 11.8% in the combined abnormality groupAge, sex, BMI, systolic blood pressure, triglycerides, HDL cholesterol, IFG status, physical activity, smoking, alcohol intakeThe HRs and 95% CI of incident diabetes progressively increased across the elevated ALT, the hepatic steatosis, and the combined abnormality groups. Subjects in the combined abnormality group had the highest risk of incident diabetes (aHR 1.64, 95% CI 1.3–2.1)8
Yamazaki et al., 2015 (26)Retrospective cohort study; n = 3,074 (23.7% with NAFLD) Japanese subjects without diabetes without known chronic liver diseases; 11.3 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, clinical history, or drug treatmentn = 189 incident cases; 3.1% vs. 16.1%Age, sex, family history of diabetes, BMI, IFG status, dyslipidemia, hypertension, physical activityNAFLD was independently associated with incident diabetes (aOR 2.37, 95% CI 1.6–3.5). NAFLD improvement was associated with a reduction of incident diabetes (aOR 0.27, 95% CI 0.1–0.6)8
Ming et al., 2015 (27)Retrospective cohort study; n = 508 (19.1% with NAFLD) Chinese subjects without diabetes without known chronic liver diseases; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, 2-h glucose ≥11.1 mmol/L on 75-g OGTT, or drug treatmentn = 20 incident cases; 2.4% vs. 10.3%Age, sex, educational level, smoking, alcohol intake, physical activity, family history of diabetes, BMI, blood pressure, fasting glucose, 2-h glucose, triglycerides, HDL cholesterolNAFLD was independently associated with incident diabetes (aHR 4.46, 95% CI 1.9–10.7) but not with incident prediabetes (aHR 1.64, 95% CI 0.97–2.8)6
Li et al., 2015 (28)Retrospective cohort study; n = 4,736 (29.8% with NAFLD) Chinese subjects without diabetes without known chronic liver diseases; 4 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 380 incident cases; 4.1% vs. 17.4%Age, sex, blood pressure, lipids, serum ALT, uric acid, creatinineNAFLD was independently associated with incident diabetes (aHR 3.37, 95% CI 2.4–4.3)7
Shah et al., 2015 (29)Prospective cohort study; n = 3,153 (24.9% with NAFLD) U.S. individuals without diabetes from the Multi-Ethnic Study of Atherosclerosis without known chronic liver diseases; 9.1 years; liver computed tomographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 216 incident casesAge, sex, race, family history of diabetes, BMI, waist circumference, systolic blood pressure, triglycerides, HDL cholesterol, fasting glucose, C-reactive protein, exercise, statin useNAFLD (defined as first quartile of hepatic attenuation on computed tomography) was independently associated with incident diabetes (aHR 2.06, 95% CI 1.5–2.8; P < 0.001)8
Fukuda et al., 2016 (30)Retrospective cohort study; n = 4,629 (38.4% with NAFLD) Japanese subjects without diabetes without known chronic liver diseases; 12.8 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, or drug treatmentn = 351 incident cases; 3.2% in nonoverweight, no-NAFLD vs. 14.4% in nonoverweight, NAFLD vs. 8.0% in overweight, no-NAFLD vs. 26.4% in overweight, NAFLDAge, sex, family history of diabetes, alcohol intake, smoking, regular exercise, HbA1caHRs for incident diabetes vs. nonoverweight without NAFLD group were 3.59, 95% CI 2.1–5.8, in the nonoverweight with NAFLD group, 1.99, 95% CI 1.5–2.7, in the overweight without NAFLD group, and 6.77, 95% CI 5.2–8.9, in the overweight with NAFLD group, respectively7
Chen et al., 2016 (31)Prospective cohort study; n = 6,542 (3.2% with NAFLD) Chinese subjects without diabetes without known chronic liver diseases; 6 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, or drug treatmentn = 368 incident casesAge, BMI, triglycerides, fasting glucose, IFG statusNAFLD was independently associated with incident diabetes (aHR 2.17, 95% CI 1.6–3.0)7
Li et al., 2017 (32)Prospective cohort study; n = 18,111 (31.8% with NAFLD) Chinese subjects without diabetes without known chronic liver diseases; 4.6 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 1,262 incident cases; 4.6% in no-NAFLD vs. 10.6% in mild NAFLD vs. 18.1% in moderate-severe NAFLDAge, sex, BMI, waist circumference, alcohol intake, smoking, exercise, family history of diabetes, fasting glucose, triglycerides, total cholesterolaHRs for incident diabetes vs. those without NAFLD group were 1.88, 95% CI 1.6–2.2, in the mild NAFLD group and 2.34, 95% CI 1.9–3.0, in the moderate-severe NAFLD group, respectively8
Ma et al., 2017 (33)Retrospective cohort study; n = 1,051 (17.8% with NAFLD) U.S. individuals without diabetes without known chronic liver diseases; 6.2 years; liver computed tomographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 64 incident casesAge, sex, smoking, exercise, alcohol intake, fasting glucose, systolic blood pressure, BMI, visceral adipose tissue, and changes in BMI, visceral adipose tissue, and liver fat during follow-upNAFLD was independently associated with incident diabetes (aOR 2.66, 95% CI 1.2–5.7)8
Chen et al., 2017 (34)Prospective cohort study; n = 132,377 (32% with NAFLD) Taiwanese subjects without diabetes without known chronic liver diseases; 18 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, clinical history, or drug treatmentn = 6,555 incident casesAge, sex, BMI, hypertension, family history of diabetes, smoking, alcohol intake, exercise, triglycerides, HDL cholesterol, total cholesterol, serum AST, ALT, GGT, and ALP levelsNAFLD was independently associated with incident diabetes (aHR 2.38, 95% CI 1.6–2.5, for the whole sample; aHR 2.08, 95% CI 1.9–2.2, for men and aHR 2.65, 95% CI 1.4–2.9, for women)8
Liu et al., 2017 (35)Retrospective cohort study; n = 18,507 (18.8% with NAFLD) Chinese elderly men without diabetes without known chronic liver diseases; 5 years; liver ultrasonographyFasting glucose ≥7.0 mmol/L, 2-h glucose ≥11.1 mmol/L on 75-g OGTT, clinical history, or drug treatmentn = 453 incident cases; 2.1% vs. 3.7%Age, BMI, smoking, marital status, alcohol intake, hypertension, dyslipidemiaNAFLD was independently associated with incident diabetes (aHR 1.67, 95% CI 1.4–2.1)7
  • ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; aHR, adjusted HR; aOR, adjusted OR; GGT, γ-glutamyl transferase; HOMA-IR, HOMA of insulin resistance; IFG, impaired fasting glycemia; OGTT, oral glucose tolerance test.