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 tool | Diagnosis of incident diabetes | Number incident cases of diabetes; % in non-NAFLD vs. NAFLD cases (when available) | Adjustments considered | Main findings | NOS |
|---|---|---|---|---|---|---|
| Okamoto et al., 2003 (17) | Retrospective cohort study; n = 840 (14.3% with NAFLD) Japanese subjects without diabetes; 10 years; liver ultrasonography | Fasting 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-up | NAFLD 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 ultrasonography | Fasting glucose ≥7.0 mmol/L or 2-h glucose ≥11.1 mmol/L on 75-g OGTT | n = 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 234 incident cases; 2.3% vs. 8.5% | Age, sex, BMI, family history of diabetes, smoking, fasting glucose, HDL cholesterol, triglycerides, serum ALT | NAFLD 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 association | 8 |
| Bae et al., 2011 (20) | Retrospective cohort study; n = 7,849 (29.2% with NAFLD) South Korean subjects without diabetes; 5 years; liver ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, clinical history, or drug treatment | n = 435 incident cases; 3.7% vs. 9.9% | Age, sex, BMI, triglycerides, HDL cholesterol, systolic blood pressure, smoking, physical activity, alcohol intake, IFG status | NAFLD was independently associated with incident diabetes (aHR 1.33, 95% CI 1.1–1.7). This association was much stronger in pre-existing IFG | 8 |
| Sung et al., 2012 (22) | Retrospective cohort study; n = 12,853 (27.6% with NAFLD) South Korean subjects without diabetes; 5 years; liver ultrasonography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 223 incident cases; 0.8% vs. 4.3% | Age, sex, BMI, educational status, smoking, physical activity, alcohol intake, HOMA-IR, serum triglycerides, serum ALT | The 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, clinical history | n = 2,108 incident cases; 7% in no-steatosis vs. 9.8% in mild steatosis vs. 17.8% in moderate-severe steatosis | Age, waist circumference, HDL cholesterol, triglycerides, systolic blood pressure, C-reactive protein, HOMA-IR, serum creatinine, family history of diabetes, physical activity, metabolic syndrome | NAFLD 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-steatosis | 8 |
| 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 242 incident cases; 10.5% vs. 19.7% | Age, sex, family history of diabetes, BMI, waist circumference, hypertension, serum ALT, dyslipidemia, IFG status | NAFLD 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 baseline | 5 |
| 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, or drug treatment | n = 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 NFS | Age, sex, smoking, alcohol intake, physical activity, family history of diabetes, total cholesterol, triglycerides, HDL cholesterol, HOMA-IR, C-reactive protein | The 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥ 6.5%, or drug treatment | n = 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 group | Age, sex, BMI, systolic blood pressure, triglycerides, HDL cholesterol, IFG status, physical activity, smoking, alcohol intake | The 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, clinical history, or drug treatment | n = 189 incident cases; 3.1% vs. 16.1% | Age, sex, family history of diabetes, BMI, IFG status, dyslipidemia, hypertension, physical activity | NAFLD 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, 2-h glucose ≥11.1 mmol/L on 75-g OGTT, or drug treatment | n = 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 cholesterol | NAFLD 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 380 incident cases; 4.1% vs. 17.4% | Age, sex, blood pressure, lipids, serum ALT, uric acid, creatinine | NAFLD 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 tomography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 216 incident cases | Age, sex, race, family history of diabetes, BMI, waist circumference, systolic blood pressure, triglycerides, HDL cholesterol, fasting glucose, C-reactive protein, exercise, statin use | NAFLD (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 ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, or drug treatment | n = 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, NAFLD | Age, sex, family history of diabetes, alcohol intake, smoking, regular exercise, HbA1c | aHRs 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, respectively | 7 |
| 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, HbA1c ≥6.5%, or drug treatment | n = 368 incident cases | Age, BMI, triglycerides, fasting glucose, IFG status | NAFLD 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 1,262 incident cases; 4.6% in no-NAFLD vs. 10.6% in mild NAFLD vs. 18.1% in moderate-severe NAFLD | Age, sex, BMI, waist circumference, alcohol intake, smoking, exercise, family history of diabetes, fasting glucose, triglycerides, total cholesterol | aHRs 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, respectively | 8 |
| 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 tomography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 64 incident cases | Age, 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-up | NAFLD 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, clinical history, or drug treatment | n = 6,555 incident cases | Age, sex, BMI, hypertension, family history of diabetes, smoking, alcohol intake, exercise, triglycerides, HDL cholesterol, total cholesterol, serum AST, ALT, GGT, and ALP levels | NAFLD 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 ultrasonography | Fasting glucose ≥7.0 mmol/L, 2-h glucose ≥11.1 mmol/L on 75-g OGTT, clinical history, or drug treatment | n = 453 incident cases; 2.1% vs. 3.7% | Age, BMI, smoking, marital status, alcohol intake, hypertension, dyslipidemia | NAFLD 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.