Ki-Chul Sung

Combined Influence of Insulin Resistance, Overweight/Obesity, and Fatty Liver as Risk Factors for Type 2 Diabetes

OBJECTIVE There is dissociation between insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes, suggesting that different mechanisms are involved. Our aim was to 1) quantify risk of incident diabetes at follow-up with different combinations of these risk factors at baseline and 2) determine whether each is an independent risk factor for diabetes. RESEARCH DESIGN AND METHODS We examined 12,853 subjects without diabetes from a South Korean occupational cohort, and insulin resistance (IR) (homeostasis model assessment-IR ≥75th centile, ≥2.0), fatty liver (defined by standard ultrasound criteria), and overweight/obesity (BMI ≥25 kg/m2) identified at baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes at 5-year follow-up were estimated using logistic regression. RESULTS We identified 223 incident cases of diabetes from which 26 subjects had none of the three risk factors, 37 had one, 56 had two, and 104 had three. In the fully adjusted model, the OR and CI for diabetes were 3.92 (2.86–5.37) for IR, 1.62 (1.17–2.24) for overweight/obesity, and 2.42 (1.74–3.36) for fatty liver. The OR for the presence of all three factors in a fully adjusted model was 14.13 (8.99–22.21). CONCLUSIONS The clustering of IR, overweight/obesity, and fatty liver is common and markedly increases the odds of developing type 2 diabetes, but these factors also have effects independently of each other and of confounding factors. The data suggest that treatment for each factor is needed to decrease risk of type 2 diabetes.

Interrelationship between Fatty Liver and Insulin Resistance in the Development of Type 2 Diabetes

CONTEXT Although fatty liver and insulin resistance are known to be associated, the relationship between the two in the development of type 2 diabetes mellitus (T2DM) is unclear. OBJECTIVE We investigated the 5-yr risk of developing T2DM in individuals diagnosed with fatty liver using ultrasound and stratified by insulin sensitivity using quartiles of fasting insulin concentration. DESIGN AND METHODS We examined the clinical and laboratory data of 11,091 Koreans who had a medical evaluation including fasting insulin concentration and abdominal ultrasound at baseline and had a follow-up after 5 yr. RESULTS At baseline, 27% of the population had fatty liver. Almost half (47%) of the individuals with fatty liver had baseline insulin concentration in the highest quartile compared with 17% in those without fatty liver (P < 0.001). Regardless of baseline insulin concentration, individuals with fatty liver had significantly (P < 0.001) more baseline clinical and metabolic abnormalities, including higher glucose and triglyceride concentration and lower high-density lipoprotein cholesterol concentration. In addition, regardless of baseline insulin concentration, individuals with fatty liver had a significantly increased risk for incident T2DM compared with those without fatty liver [crude odds ratio, 5.05 (95% confidence interval, 2.08-12.29) in the lowest insulin quartile and 6.34 (3.58-11.21) in the highest quartile]. In individuals in the highest insulin quartile, the odds ratio for developing T2DM remained significant even after multivariate adjustment including baseline glucose concentration [2.42 (1.23-4.75)]. CONCLUSION Although associated with insulin resistance, fatty liver diagnosed by ultrasound appears to independently increase the risk of T2DM.

Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people.

OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) ≥75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression. RESULTS There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score ≤0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01–1.45]; P = 0.04) and HOMA-IR (1.10 [1.02–1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20–1.95]; P = 0.001). CONCLUSIONS Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD.

Relationship of serum osteoprotegerin levels with coronary artery disease severity, left ventricular hypertrophy and C-reactive protein.

OPG (osteoprotegerin) is an inhibitor of osteoclastogenesis and recent work suggests it has a role in atherosclerosis. Therefore we measured serum OPG levels in patients with coronary artery disease, compared the serum OPG levels among the different groups according to the number of stenotic vessels and determined whether there was any correlation with aortic calcification, LV (left ventricular) mass index and serum CRP (C-reactive protein) levels. Subjects (n=100; mean age, 57 years) who underwent coronary angiograms were enrolled. Blood pressure, body mass index, fasting blood glucose, lipid profiles and CRP levels were measured and the LV mass indices were calculated using ECGs. Serum OPG levels were measured by ELISA. The presence of calcification in the aortic notch was checked by a chest X-ray. The subjects were divided into four groups according to the number of stenotic vessels. The mean serum OPG levels increased significantly as the number of stenotic vessels increased, and the mean serum OPG levels were higher in the group with three-vessel disease compared with the groups with no- or one-vessel disease. The mean serum CRP level was significantly higher in the group with three-vessel disease compared with the groups with no-, one- and two-vessel disease. Age and LV mass index showed significant positive correlations with serum OPG levels, although significance was lost after an adjustment for age. Serum CRP levels were positively correlated with serum OPG levels even after an adjustment for age. There were no differences in serum OPG levels according to the presence of fasting hyperglycaemia or aortic calcification. In conclusion, serum OPG level was related to the severity of stenotic coronary arteries and serum CRP levels. LV mass indices showed no significant correlation with OPG levels. The precise mechanism for the role of OPG in atherosclerosis needs to be investigated further.

Resolution of Fatty Liver and Risk of Incident Diabetes

CONTEXT Fatty liver is associated with an increased risk of type 2 diabetes, but whether an increased risk remains in people in whom fatty liver resolves over time is not known. OBJECTIVE The objective of the study was to assess the risk of incident diabetes at a 5-year follow-up in people in whom: 1) new fatty liver developed; 2) existing fatty liver resolved, and 3) fatty liver severity worsened over 5 years. DESIGN AND METHODS A total of 13,218 people without diabetes at baseline from a Korean occupational cohort were examined at baseline and after 5 years, using a retrospective study design. Fatty liver status was assessed at baseline and follow-up as absent, mild, or moderate/severe using standard ultrasound criteria. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for incident diabetes at follow-up were estimated after controlling for multiple potential confounders. RESULTS Two hundred thirty-four people developed incident diabetes. Over 5 years, fatty liver resolved in 828, developed in 1640, and progressed from mild to moderate/severe in 324 people. Resolution of fatty liver was not associated with a risk of incident diabetes [aOR 0.95 (95% CIs 0.46, 1.96), P = .89]. Development of new fatty liver was associated with incident diabetes [aOR 2.49 (95% CI 1.49, 4.14), P < .001]. In individuals in whom severity of fatty liver worsened over 5 years (from mild to moderate/severe), there was a marked increase in the risk of incident diabetes [aOR 6.13 (2.56, 95% CI 14.68) P < .001 (compared with the risk in people with resolution of fatty liver)]. CONCLUSION Change in fatty liver status over time is associated with markedly variable risks of incident diabetes.

Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension

BACKGROUND & AIMS Approximately 50% of hypertensive patients have non-alcoholic fatty liver disease (NAFLD), but whether change in fatty liver status over time modifies risk of developing hypertension is uncertain. Our aim was to determine whether a change in fatty liver status (either development of new fatty liver, or resolution of existing fatty liver) over five years modified risk of incident hypertension at five year follow-up. METHODS 11,448 patients without hypertension were examined at baseline and at five year follow-up, using a retrospective cohort study design. Fatty liver status (absent or present) was assessed at baseline and follow-up using standard ultrasound criteria. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for incident hypertension at follow-up were estimated controlling for potential confounders, compared to the reference group (patients who did not have fatty liver at either baseline or follow-up). RESULTS 911 patients developed incident hypertension. Incident fatty liver developed during follow-up in 1418 patients and fatty liver at baseline resolved during follow-up in 684 patients. Developing incident fatty liver was associated with incident hypertension, even after adjustment for multiple confounders (aOR=1.60 (95% CI 1.30, 1.96; p<0.001). Further adjustment for change in body mass index between baseline and follow-up only slightly attenuated this association (aOR=1.36 (95% CI 1.10, 1.67; p=0.004). With resolution of fatty liver at follow-up, risk of incident hypertension was not different from the reference group (aOR=1.21 (95% CI 0.90, 1.63; p=0.21). CONCLUSIONS Development of incident fatty liver is associated with increased risk of hypertension.

Plasma omentin-1 levels are reduced in non-obese women with normal glucose tolerance and polycystic ovary syndrome

OBJECTIVE Omentin-1 is a novel adipokine that increases insulin sensitivity and is expressed in visceral adipose tissue. The aim of this study was to determine the metabolic parameters that influence plasma omentin-1 levels in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS A cross-sectional study was performed in 87 women with PCOS and 53 body mass index (BMI)-matched healthy controls including 39 non-obese, normal-weight (NW) PCOS women with normal glucose tolerance (NGT) and 44 BMI- and homeostasis model assessment (HOMA)-matched controls. Indices of insulin sensitivity, metabolic variables, circulating androgen levels, serum adiponectin, and omentin-1 levels were measured. A 75 g oral glucose tolerance test was performed in all participants. RESULTS Plasma omentin-1 levels were significantly lower in women with PCOS compared with those in BMI-matched controls (P<0.001). A significantly lower level of plasma omentin-1 was observed in non-obese women with PCOS and NGT compared with that in BMI- and HOMA-matched controls (P<0.001). Omentin-1 level was negatively correlated with BMI, indices of insulin sensitivity, and circulating androgens and was associated with greater 2 h postprandial glucose, C-peptide, and insulin levels compared with fasting values. Within the NW and NGT groups, omentin-1 levels remained negatively correlated with BMI, 2 h postprandial C-peptide, and circulating androgens and demonstrated a negative linear trend according to quartile of free testosterone (P=0.028). CONCLUSIONS Plasma levels of omentin-1 were reduced in non-obese women with PCOS and NGT. Postprandial hyperinsulinemia and hyperglycemia contributed more to lower omentin-1 levels than did fasting values in the setting of PCOS. Increased androgen levels contributed to decreased omentin-1 levels in women with PCOS.

Glycated haemoglobin as a predictor for metabolic syndrome in non-diabetic Korean adults.

Aims  With increasing prevalence of diabetes mellitus and metabolic syndrome (MS), the importance of early detection of insulin resistance is emphasized. However, a simple and practical method of measurement is not readily available. Therefore, we examined the sensitivity and specificity of HbA1c for predicting impaired fasting glucose (IFG) and MS and its association with cardiovascular risk factors, particularly in the normal range of HbA1c levels in non‐diabetic Korean subjects.

Ferritin Is Independently Associated With the Presence of Coronary Artery Calcium in 12 033 Men

Objective—Ferritin concentrations are often increased in patients with metabolic syndrome and type 2 diabetes mellitus, but few reports have examined the associations between ferritin and atherosclerosis. We investigated whether any relationship between ferritin and coronary artery calcium score (CACS) >0 (as a marker of atherosclerosis) was independent of potential confounders, such as iron-binding capacity (transferrin), low-grade inflammation, and cardiovascular risk factors. Methods and Results—Data were analyzed from a South Korean occupational cohort of 12 033 men who underwent a cardiac computed tomography estimation of CACS and measurements of multiple cardiovascular risk factors. One-thousand three- hundred-fifteen of 12 033 (11.2%) subjects had a CACS >0. For people with a CACS >0, median (interquartile range) ferritin concentration was 196.8 (136.3–291.9) compared with 182.2 (128.1–253.6) in people with a CACS=0; P<0.001. In the highest ferritin quartile, 14.7% (442/3008) of subjects had a CACS >0 compared with 9.7% (292/3010) in the lowest quartile (P<0.0001). With increasing ferritin quartiles, there were also higher proportions of people with diabetes mellitus (P<0.0001), hypertension (P<0.0001), coronary heart disease (P=0.003), and a Framingham Risk Score >10% (P<0.0001). In logistic regression modeling with CACS >0 as the outcome, ferritin but not transferrin was independently associated with CACS >0 (odds ratio for highest quartile versus lowest quartile, 1.66 [95% CI, 1.3–1.98]; P=0.0001). Conclusion—Increased ferritin concentrations are associated with the presence of a marker of early coronary artery atherosclerosis, independently of traditional cardiovascular risk factors including Framingham risk score, transferrin, preexisting vascular disease, diabetes mellitus, metabolic syndrome factors, and low-grade inflammation.

Hyperinsulinemia and the Development of Nonalcoholic Fatty Liver Disease in Nondiabetic Adults

BACKGROUND insulin resistance is known to be the most important pathogenic factor in the development of nonalcoholic fatty liver disease. We performed a prospective study to analyze the associations of baseline and changes in fasting insulin levels with future development of nonalcoholic fatty liver disease in nondiabetic adults over a 5-year period. METHODS this study was performed in 4954 subjects who did not have diabetes or nonalcoholic fatty liver disease and who participated in a health checkup program in both 2003 and 2008. The presence of nonalcoholic fatty liver disease was defined by ultrasonographic examination. Subjects were divided into 4 groups according to the baseline quartiles of fasting insulin and dichotomized fasting insulin levels at baseline and after 5 years: low-low, low-high, high-low, high-high. RESULTS after 5 years, 644 subjects (13%) developed nonalcoholic fatty liver disease. The odds ratio (OR) for development of nonalcoholic fatty liver disease increased as the quartiles of the baseline fasting insulin levels increased from the first to the fourth quartile (1.00 vs. 0.99, 1.44, 1.65, respectively). The OR for nonalcoholic fatty liver disease was 2.5-fold higher in the high-high group and 1.6-fold higher in the low-high group compared with that of the low-low group. The OR for nonalcoholic fatty liver disease increased as the quartile of changes in fasting insulin level over the 5-year period increased. CONCLUSION high baseline and continuously increasing fasting insulin levels were the independent determinants for future development of nonalcoholic fatty liver disease during a 5-year follow-up in nondiabetic healthy adults.