TABLE 2.
| First author and year | Study type and n | Method for quantification | Endpoint assessment | Population and country | Statistical methods and models | Main finding | Effect measure and size |
|---|---|---|---|---|---|---|---|
| Studies on retinol and retinoic acid | |||||||
| Tavridou et al., 1997 (36) | Case-control study, 32 cases, 148 controls | HPLC | Impaired glucose tolerance, ascertained by an oral glucose tolerance test | 32 cases with impaired glucose tolerance, 148 healthy controls, UK | t-test | Subjects with impaired glucose tolerance had higher serum retinol than healthy controls (2.5 vs. 2.1 µmol/L) | Only P values and no effect sizes given |
| Abahusain et al., 1999 (37) | Case-control study, 107 cases, 143 controls | HPLC | Impaired glucose tolerance based on morning fasting glucose or an oral glucose tolerance test | 107 subjects with type 2 diabetes mellitus and 143 controls, Saudi Arabia | t-test | Serum retinol was similar between cases and controls, whereas serum and urine RBP4 were higher among cases | Only P values and no effect sizes given |
| Higuchi et al., 2015 (38) | Cross-sectional study, n = 951 | UPLC | Insulin resistance based on the HOMA-IR and the Matsuda Index | General population, Japan | Logistic regression adjusted for sex, age, physical activity, BMI, alcohol intake, and smoking | Subjects in the upper retinol quartile (3.1–5.2 µmol/L) were not more insulin resistant compared with lower quartiles | OR for insulin resistance in the upper retinol quartile: 0.86 (0.53, 1.40). OR for low insulin sensitivity in the upper retinol quartile: 0.89 (0.56, 1.43) |
| Kim et al., 2017 (39) | Prospective case-control study, 55 cases and 220 controls | UPLC | Incident T2DM was ascertained by fasting glucose or history of diabetes treatment | 55 cases with impaired fasting glucose at baseline and 220 healthy controls, South Korea | Logistic regression adjusted for age, fasting glucose and γ-glutamyl transpeptidase | Metabolomics analysis revealed that reinaldehyde, retinoic acid, and retinyl esters at baseline predicted incident type 2 diabetes | OR for incident T2DM associated with high (>2.76) vs. low (<2.76) retinoic acid/retinaldehyde ratio: 2.21 (1.13, 4.32) |
| Studies on RBP4 | |||||||
| Cho et al., 2006 (40) | Case-control study with 57 controls, 48 subjects with impaired glucose tolerance and 49 subjects with T2DM | ELISA | Impaired glucose tolerance, assessed by an oral glucose tolerance test | Individuals with normal or impaired glucose tolerance, or T2DM, South Korea | ANOVA and univariate Pearson's correlation | Log-transformed RBP4 was slightly higher among subjects with impaired glucose tolerance and type 2 diabetes compared with subjects with normal glucose tolerance. In subjects with normal glucose tolerance, fasting plasma glucose was moderately associated with RBP4 | Only P values and no effect sizes reported. Correlation between fasting plasma glucose and RBP4: Pearson's r = 0.37 |
| Graham et al., 2006 (41) | Case-control study in 3 subpopulations: group 1: 5 healthy controls, 7 obese without diabetes, and 9 obese with diabetes. Group 2: 20 controls with normal glucose tolerance, 20 subjects with impaired glucose tolerance, and 20 subjects with T2DM. Group 3: 26 nonobese relatives of subjects with T2DM | ELISA and Western blotting | Impaired glucose tolerance and T2DM was assessed by oral glucose tolerance tests | Lean, overweight, and obese subjects with and without T2DM, USA, Germany, and Sweden | Univariate Spearman rank correlations | In group 1, obese patients with and without diabetes had higher concentrations of RBP4. In group 2, serum RBP4 was higher among subjects with impaired glucose tolerance and T2DM compared with subjects with normal glucose concentrations. In group 3, serum RBP4 was positively correlated to fasting insulin | Correlation of RBP4 with fasting insulin in group 1: Spearman's r = 0.72. Correlation of RBP4 with glucose disposal rate in group 2: Spearman's r = –0.78. Correlation of RBP4 with fasting insulin in group 3: Spearman's r = 0.71 |
| Broch et al., 2007 (42) | Cross-sectional study, n = 107 | Nephelometry | Insulin response, ascertained by the insulin AUC the first 10 min after an intravenous glucose tolerance test | Nondiabetic men with a BMI ranging from 19 to 40, Spain | Univariate Pearson's correlation and multivariable linear regression model adjusted for BMI, age, and insulin sensitivity | RBP4 was inversely correlated to acute insulin response in the total population, and after a glucose load in obese subjects | Univariate correlation of RBP4 with insulin response: Pearson's r = –0.27. In a multivariable regression model, the standardized coefficient was –0.41 among obese subjects |
| Gavi et al., 2007 (43) | Cross-sectional study, n = 92 | ELISA | Insulin sensitivity, ascertained by a euglycemic insulin clamp | Subjects free of diabetes, USA | Univariate Pearson's correlation | Serum concentrations of RBP4 was inversely correlated to insulin sensitivity | Correlation between log-transformed RBP4 and insulin sensitivity: Pearson's r = 0.32 |
| Hahn et al., 2007 (44) | Case-control study in 200 cases and 64 controls | ELISA | Insulin resistance assessed by fasting glucose and the HOMA-IR | Women with PCOS, Germany | Univariate Spearman's correlation | No differences in RBP4 between cases and controls. Among women with PCOS. RBP4 was correlated to fasting glucose but not insulin sensitivity | Correlation for RBP4 with fasting glucose: Spearman's r = 0.14. Correlation for RBP4 with HOMA-IR: r = 0.09 |
| Promintzer et al., 2007 (45) | Cross-sectional study, n = 40 | Nephelometry validated against Western blotting | Insulin sensitivity and resistance ascertained by an oral glucose tolerance test and euglycemic insulin clamp | 20 subjects who were classified as insulin resistant and 20 subjects who were insulin sensitive, Austria | t-test | No associations between insulin sensitivity and RBP4. Plasma concentrations did not respond markedly to a clamp test or an oral glucose tolerance test | No effect sizes given |
| Qi et al., 2007 (46) | Cross-sectional study, n = 3289 | ELISA validated against Western blotting | Insulin resistance assessed by HOMA-IR | Participants residing in urban and rural areas of China | Partial Spearman's correlation analyses adjusted for age, sex, region, and residence | Weak partial correlation between RBP4 and fasting insulin and HOMA-IR | Correlation for RBP4 and fasting insulin and HOMA-IR: Spearman's r = 0.12 and 0.11, respectively |
| Stefan et al., 2007 (47) | Cross-sectional study, n = 75 | ELISA | Insulin sensitivity assessed by euglycemic insulin clamp and an oral glucose tolerance test | Subjects free of diabetes, Germany | Univariate Pearson's correlation analyses and multivariable regression analyses adjusted for sex, age, height, body fat, visceral fat, and intramyocellular lipid content | A moderate inverse correlation was observed for RBP4 and insulin sensitivity as measured by clamp and an oral glucose tolerance test. This was also seen in a multivariable regression model | Correlation between RBP4 and insulin sensitivity as measured by clamp: Pearson's r = –0.26 and as measured by an oral glucose tolerance test: Pearson's r: –0.25. In multivariable regression plasma RBP4 was inversely associated with insulin sensitivity as measured by an oral glucose tolerance test (β: -0.007, SE: 0.003) |
| Takebayashi et al., 2007 (48) | Case-control and single-arm intervention, 22 controls and 101 diabetic patients in the case-control study. 22 in the single-arm intervention | EIA | Insulin resistance, as assessed by HOMA-IR. Diabetic retinopathy ascertained by the Davis’ classification. RBP4 ascertained by EIA kit | Men and women hospitalized for diabetes and healthy controls, Japan | Simple linear regression for RBP4 and HOMA-IR. t-test for comparison of means | RBP4 not associated with insulin resistance but was higher in patients with diabetic retinopathy compared with patients without retinopathy. No changes in RBP4 were observed after 3 mo of pioglitazone treatment | R value for RBP4 and HOMA-IR (–0.16, SE not given).Only P values and no effect sizes given for differences according to diabetic retinopathy classification. Only P value and no effect sizes given for single-arm intervention |
| von Eynatten et al., 2007 (49) | Cross-sectional study, n = 365 | ELISA validated against Western blotting | Insulin resistance, as assessed by HOMA-IR | 126 subjects with T2DM, 143 subjects with coronary artery disease and 96 controls, Germany | Multivariable linear regression model adjusted for BMI, LDL, VLDL, history of hypertension, and HbA1c | No associations were observed for RBP4 and HOMA-IR | β for RBP4 and HOMA-IR in subjects with T2DM: –0.007; and with coronary artery disease: 0.09. SEs were not given |
| Diamanti-Kandarakis et al., 2008 (50) | Case-control study, 35 cases, 45 controls | ELISA | Insulin resistance as assessed by HOMA-IR | 35 women with PCOS and 45 health controls, Greece | Univariate Pearson's correlation | No correlation between RBP4 and insulin resistance | Correlation for RBP4 with insulin and HOMA-IR: Pearson's r = –0.09 and 0.026, respectively |
| Gomez-Ambrosi, et al., 2008 (51) | Cross-sectional, n = 42 | ELISA validated against Western blotting | Impaired glucose tolerance, ascertained by an oral glucose tolerance test | 11 lean, 10 obese with normal glucose tolerance, 11 obese with impaired glucose tolerance, and 10 obese with T2DM, Spain | t-test | No associations were observed for RBP4 and insulin resistance | No effect sizes given |
| Hutchison et al., 2008 (52) | Case-control 38 cases, 17 controls. Subsequent intervention with either metformin or oral contraceptive pill in PCOS subjects for 6 mo | Western blotting | Impaired glucose tolerance, ascertained by an oral glucose tolerance test | 38 overweight women with PCOS, 17 healthy controls, Australia. 19 were randomly assigned to metformin treatment and 19 to oral contraceptives in the intervention | ANOVA and bivariate Pearson's correlations | No associations between insulin resistance and RBP4. Insulin resistance improved and no changes were detected in RBP4 after treatment with metformin | No effect sizes given |
| Lewis et al., 2008 (53) | Prospective cohort study, n = 206 | ELISA | Insulin resistance assessed by HOMA-IR | Overweight subjects recruited from the general public and lipid outpatient clinic | Bivariate Spearman's correlation | No correlation between 36-mo change in insulin resistance and RBP4 | Correlation between change in plasma RBP4 and HOMA-IR: Spearman's r = 0.06 |
| Mohlig et al., 2008 (54) | Cross-sectional study, n = 110 | ELISA | Insulin sensitivity as assessed by HOMA-S% | Women with PCOS | Bivariate Spearman's correlation | RBP4 was inversely correlated to insulin sensitivity | Correlation for RBP4 and insulin sensitivity: Spearman's r = –0.29 |
| Bahr et al., 2009 (55) | Case-control, 19 cases, 20 controls | ELISA validated against Western blotting | Insulin resistance assessed by HOMA-IR | 19 with liver cirrhosis and 20 healthy controls, the Netherlands | Bivariate Spearman's correlation | No correlations were observed for RBP4 and insulin resistance in patients with liver cirrhosis | Correlation for RBP4 and HOMA-IR: Spearman's r = –0.05 |
| Chavez et al., 2009 (56) | Cross-sectional, n = 72 | ELISA | Whole-body and hepatic insulin sensitivity, assessed by an oral glucose tolerance test and euglycemic insulin clamp | 16 lean subjects with normal glucose tolerance, 17 obese subjects with normal glucose tolerance, and 39 subjects with impaired glucose tolerance or T2DM, USA | Bivariate Pearson's or Spearman's correlation | No correlations were observed for glucose disposal or hepatic insulin resistance | Correlation of plasma RBP4 with whole-body and hepatic insulin resistance: r (method not given) = 0.06 and 0.07, respectively |
| Erikstrup et al., 2009 (35) | Cross-sectional study, n = 233 | HPLC-MS (retinol), ELISA (RBP4) | Impaired glucose tolerance and T2DM, ascertained by an oral glucose tolerance test | Subjects with normal and impaired glucose tolerance as well as persons with T2DM, Denmark | 3-factor ANOVA | Plasma concentration of RBP4 was lower among T2DM subjects compared with subjects with normal glucose tolerance. Plasma concentrations of retinol were lower among T2DM subjects compared with subjects with both normal and impaired glucose tolerance. The ratio of RBP4 to retinol was higher among subjects with T2DM compared with subjects with normal glucose tolerance | Mean difference in RBP4 normal glucose tolerance vs. T2DM: 0.16 µmol/L (0.02, 0.30).Mean difference in retinol normal glucose tolerance vs. T2DM: 0.34 µmol/L (0.18, 0.49); impaired glucose tolerance vs. T2DM: 0.24 µmol/L (0.02, 0.45). Mean difference in RBP4/retinol ratio, T2DM vs. normal glucose tolerance: 0.09 (0.05, 0.13) |
| Lee et al., 2009 (57) | Cross-sectional study, n = 111 | ELISA | Insulin resistance assessed by HOMA-IR | Men and women from the general population aged >70 y, South Korea | Bivariate Pearson's correlation | RBP4 was positively correlated to insulin resistance. Particularly strong associations were found among the obese | Correlation for RBP4 and insulin resistance: Spearman's r = 0.31 in the total population, r = 0.47 among obese, and r = 0.16 among nonobese |
| Xu et al., 2009 (58) | Case-control study, 1032 cases and 753 controls | ELISA validated against Western blotting | Impaired glucose tolerance and T2DM assessed/ascertained by fasting blood glucose and/or an oral glucose tolerance test | Of cases, 508 had impaired glucose tolerance and 524 had newly diagnosed diabetes, China | Logistic regression models adjusted for age, sex, current smoking, current alcohol intake, family history of diabetes, BMI, waist/hip ratio, HOMA-IR, estimated glomerular filtration rate, serum concentrations of triglycerides, total cholesterol, HDL, and LDL | RBP4 was associated with an increased risk of impaired glucose regulation and T2DM | OR of impaired glucose regulation and T2DM for 1 µg/mL increase in RBP4: 1.01 (1.0, 1.02) and 1.02 (1.01, 1.04), respectively |
| Suh et al., 2010 (59) | Cross-sectional study, n = 73 | ELISA | Insulin resistance assessed by fasting blood glucose and HOMA-IR | Women free of diabetes, South Korea | Univariate Pearson's correlation. Multivariable models adjusted for age and fasting insulin | RBP4 was positively correlated with fasting glucose and insulin resistance | Correlation of RBP4 with fasting glucose: Pearson's r = 0.52. Correlation of RBP4 with HOMA-IR in women >50 y: r = 0.40. β for RBP4 and HOMA-IR in total population: 0.88, SE: 0.25 |
| Ulgen et al., 2010 (60) | Cross-sectional, n = 70 | ELISA | Insulin resistance assessed by HOMA-IR | 70 nondiabetic obese subjects, Germany | Multivariable linear regression adjusted for age and sex | No associations were observed for RBP4 and insulin sensitivity | β for RBP4 and HOMA-IR: –0.048. SE not given |
| Meisinger et al., 2011 (61) | Cross-sectional study, n = 2614 | Nephelometry | Prediabetes assessed by an oral glucose tolerance test | 2122 participants with normal glucose tolerance, 110 with impaired fasting glucose, 313 with impaired glucose tolerance, and 69 with combined impaired fasting glucose and impaired glucose tolerance, Germany | Multivariable logistic regression adjusted for age, sex, education, hypertension, smoking, physical activity, alcohol intake, BMI, total cholesterol, and HbA1c | Increasing concentrations of RBP4 were positively associated with odds of prediabetes | OR of prediabetes in the upper quartile (concentrations not given for the total population) of RBP4: 1.63 (1.17, 2.27) |
| Luft et al., 2013 (62) | Nested case-control study, 543 cases, 537 controls | ELISA | Incident T2DM was ascertained by physician report, use of antidiabetic medications and/or fasting glucose | 543 cases who developed diabetes, 537 healthy controls, USA | Cox proportional hazards model adjusted for age, race/center indicators, ethanol intake, ethanol intake2, smoking, BMI, BMI2, waist-to-hip ratio, estimated glomerular filtration rate, inflammation score, concentrations of adiponectin, leptin, triglycerides, triglycerides2, HDL, and nonesterified fatty acids, hypertension, family history of diabetes, serum insulin, and plasma glucose | Overall, there were no associations between RBP4 and incident diabetes. However, an interaction by sex was observed and an association was detected among women | Overall HR for T2DM: 3rd vs. 1st tertile of RBP4: 1.31 (0.82, 1.92). HR for T2DM in women: 3rd tertile (30.3–70.0 g/mL) vs. 1st tertile (8.8–23.9 g/mL): 1.74 (1.03, 2.94). HR for T2DM in men: 3rd tertile (35.2–52.9 g/mL) vs. 1st tertile (12.8–28.1 g/mL): 0.94 (0.51, 1.73) |
| Sun et al., 2014 (63) | Prospective cohort study, n = 2091 | ELISA | Incident T2DM ascertained by self-reported doctor-diagnosed T2DM or use of antidiabetic medication or assessment of fasting blood glucose at follow-up visit | The Nutrition and Health of Aging Population in China, general population aged 50–70 y | Sequential logistic regression adjusted for sex, age, region, residence, education, smoking, alcohol intake, physical activity, family history of diabetes, BMI, CRP, concentrations of adiponectin, triglycerides, HDL, γ-glutamyl transpeptidase and creatinine, HOMA-IR, hypertension, ferritin, blood fatty acids, intakes of total energy, fat, heme iron and retinol | Concentrations of RBP4 associated with risk of incident T2DM | RR of T2DM in the 4th (> 46.1 µg/mL) vs. 1st quartile (< 31.3 µg/mL) of RBP4: HR: 1.48 (1.06, 2.03) |
1
All effect measures are given as HR/OR/RR (95% CIs) unless otherwise noted.
2
CRP, C-reactive protein; EIA, enzyme immunoassay; HOMA-S%, homeostatic model assessment of insulin sensitivity; PCOS, polycystic ovary syndrome; RBP4, retinol-binding protein 4; T2DM, type 2 diabetes mellitus; UPLC, ultra-performance liquid chromatography.