Non-Alcoholic Fatty Liver Disease with Sarcopenia and Carotid Plaque Progression Risk in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: We aimed to evaluate whether non-alcoholic fatty liver disease (NAFLD) with or without sarcopenia is associated with progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). METHODS: We investigated 852 T2DM patients who underwent abdominal ultrasonography, bioelectrical impedance analysis, and carotid artery ultrasonography at baseline and repeated carotid ultrasonography after 6 to 8 years. NAFLD was confirmed by abdominal ultrasonography, and sarcopenia was defined as a sex-specific skeletal muscle mass index (SMI) value <2 standard deviations below the mean for healthy young adults. SMI was calculated by dividing the sum of appendicular skeletal mass by body weight. We investigated the association between NAFLD with or without sarcopenia and the progression of carotid atherosclerosis. RESULTS: Of the 852 patients, 333 (39.1%) were classified as NAFLD without sarcopenia, 66 (7.7%) were classified as sarcopenia without NAFLD, and 123 (14.4%) had NAFLD with sarcopenia at baseline. After 6 to 8 years, patients with both NAFLD and sarcopenia had a higher risk of atherosclerosis progression (adjusted odds ratio, 2.20; P<0.009) than controls without NAFLD and sarcopenia. When a subgroup analysis was performed on only patients with NAFLD, female sex, absence of central obesity, and non-obesity were significant factors related to increased risk of plaque progression risk in sarcopenic patients. CONCLUSION: NAFLD with sarcopenia was significantly associated with the progression of carotid atherosclerosis in T2DM patients.

Prevalence and risk of diabetic complications in young-onset versus late-onset type 2 diabetes mellitus.

AIMS: To compare the prevalence and risk of diabetic complications between people with young-onset and late-onset type 2 diabetes mellitus (T2DM). METHODS: In this observational study, 10,447 people with T2DM had at least one study of diabetic complications: retinopathy, neuropathy, chronic kidney disease (CKD), carotid artery plaque. We use odds ratios to compare complications between young-onset T2DM (YOD) and late-onset T2DM (LOD). RESULTS: We compare 1,791 people with YOD (diagnosed < 40 years) and 8,656 with LOD (diagnosed ≥ 40 years). The YOD had a higher prevalence of these complications than the LOD (p < 0.011) after adjustment for confounding factors. Further adjustment for diabetes duration greatly attenuated the odds ratios however, neuropathy remained significantly more frequent in people with YOD (adjusted odds ratio: 1.39, 95% confidence interval: 1.13-1.71, p = 002). In cluster analysis on the 2,126 study participants who were diagnosed with T2DM within the previous two years, 47% of the YOD group were in the severe insulin-deficient diabetes cluster in comparison to 23% LOD; 28% and 44% respectively were in the mild age-related diabetes. CONCLUSION: People with YOD had a higher prevalence of complications than those with LOD, but this was mostly attributed to a longer duration of diabetes. However, the prevalence of neuropathy remained significantly higher even after adjusting for factors including the duration of diabetes.

Differences in complication patterns in subgroups of type 2 diabetes according to insulin resistance and beta-cell function.

This study aimed to determine whether the patterns of diabetic complications differed when patients with type 2 diabetes mellitus (T2DM) were simply classified according to insulin sensitivity and beta-cell function. This observational study included 8861 patients with T2DM who underwent concurrent testing for fasting glucose, fasting insulin, and one or more diabetic complications. We categorized the patients into four groups according to insulin sensitivity and beta-cell function. Compared with the reference group (mild insulin resistance and beta-cell dysfunction), the "severe beta-cell dysfunction" group had lower odds of chronic kidney disease [adjusted odds ratios (aOR) 0.611]. The "severe insulin resistance" group had higher odds of carotid artery plaque presence (aOR 1.238). The "severe insulin resistance and beta-cell dysfunction" group had significantly higher odds of large fiber neuropathy (aOR 1.397, all p < 0.05). After a median of five years of follow-up, this group distinction did not lead to a difference in risk of new diabetic retinopathy or chronic kidney disease. In addition, there was no significant difference among the groups in plaque progression risk over 8-10 years in the longitudinal follow-up analysis. The patterns of complications differ when patients with T2DM are classified according to insulin resistance and beta-cell dysfunction. However, there were no differences in the risk of developing new complications.

Association Between Serum Bilirubin and the Progression of Carotid Atherosclerosis in Type 2 Diabetes.

OBJECTIVE: This study investigated whether serum bilirubin levels can predict the progression of carotid atherosclerosis in individuals with type 2 diabetes mellitus (T2DM). METHODS: This observational study included 1,381 subjects with T2DM in whom serial measurements of carotid intima-media thickness (CIMT) were made at 1- to 2-year intervals for 6-8 years. The progression of carotid atherosclerosis was defined as newly detected plaque lesions on repeat ultrasonography. After dividing total serum bilirubin levels into tertiles, the association between total serum bilirubin at baseline and plaque progression status was analyzed. RESULTS: Among 1,381 T2DM patients, 599 (43.4%) were categorized as having plaque progression in their carotid arteries. Those with plaque progression were significantly older; showed a higher prevalence of hypertension, abdominal obesity, and chronic kidney disease; and had a longer duration of T2DM, higher levels of total cholesterol (TC), triglycerides, and insulin resistance, and lower total bilirubin concentrations than those with no plaque progression. When total serum bilirubin levels were divided into tertiles, the highest tertile group was younger than the lowest tertile group, with higher levels of TC and high-density lipoprotein cholesterol. Multiple logistic regression analysis demonstrated that higher serum bilirubin levels were associated with a significantly lower risk of CIMT progression (odds ratio, 0.584; 95% confidence interval, 0.392-0.870; p=0.008). Age (p<0.001), body mass index (p=0.023), and TC (p=0.019) were also associated with the progression of carotid atherosclerosis in T2DM patients. CONCLUSION: Total serum bilirubin is independently associated with progression of atherosclerosis in the carotid arteries in T2DM patients.

Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.

BACKGROUND: There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes. METHODS: From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1-2 years. Ultrasonographic findings at baseline and after 6-8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression. RESULTS: Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6-8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025-1.832; p < 0.05). Among patients with hepatic steatosis, only individuals with fibrosis showed significant association with atherosclerosis progression (AOR: 1.615, 95% CI 1.005-2.598; p < 0.05). The association between hepatic fibrosis and atherosclerosis progression was significant in all metabolic subgroups regardless of age, body mass index, presence of metabolic syndrome, or insulin sensitivity (all p < 0.05). Furthermore, subjects with hepatic steatosis & fibrosis and ≥ 4 components of metabolic syndrome criteria showed markedly increased risk of atherosclerosis progression (AOR: 2.430, 95% CI 1.087-5.458; p < 0.05). CONCLUSIONS: Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Association between Non-Alcoholic Steatohepatitis and Left Ventricular Diastolic Dysfunction in Type 2 Diabetes Mellitus.

BACKGROUND: Impaired diastolic heart function has been observed in persons with non-alcoholic fatty liver disease (NAFLD) and/or with type 2 diabetes mellitus (T2DM). However, it is unclear whether NAFLD fibrotic progression, i.e., non-alcoholic steatohepatitis, poses an independent risk for diastolic dysfunction in T2DM. We investigated the association between liver fibrosis and left ventricular (LV) diastolic dysfunction in T2DM. METHODS: We analyzed 606 patients with T2DM, aged ≥50 years, who had undergone liver ultrasonography and pulsed-wave Doppler echocardiography. Insulin sensitivity was measured by short insulin tolerance test. Presence of NAFLD and/or advanced liver fibrosis was determined by abdominal ultrasonography and NAFLD fibrosis score (NFS). LV diastolic dysfunction was defined according to transmitral peak early to late ventricular filling (E/A) ratio and deceleration time, using echocardiography. RESULTS: LV diastolic dysfunction was significantly more prevalent in the NAFLD versus non-NAFLD group (59.7% vs. 49.0%, P=0.011). When NAFLD was stratified by NFS, subjects with advanced liver fibrosis exhibited a higher prevalence of diastolic dysfunction (49.0%, 50.7%, 61.8%; none, simple steatosis, advanced fibrosis, respectively; P for trend=0.003). In multivariable logistic regression, liver fibrosis was independently associated with diastolic dysfunction (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.07 to 2.34; P=0.022) after adjusting for insulin resistance and cardiometabolic risk factors. This association remained significant in patients without insulin resistance (OR, 4.32; 95% CI, 1.73 to 11.51; P=0.002). CONCLUSIONS: Liver fibrosis was associated with LV diastolic dysfunction in patients with T2DM and may be an independent risk factor for diastolic dysfunction, especially in patients without systemic insulin resistance.

Color Doppler Ultrasonography Is a Useful Tool for Diagnosis of Peripheral Artery Disease in Type 2 Diabetes Mellitus Patients with Ankle-Brachial Index 0.91 to 1.40.

BACKGROUND: The clinical utility of ankle-brachial index (ABI) is not clear in subjects with less severe or calcified vessel. Therefore, we investigated the usefulness of color Doppler ultrasonography for diagnosing peripheral artery disease (PAD) in type 2 diabetes mellitus (T2DM) subjects. METHODS: We analyzed 324 T2DM patients who concurrently underwent ABI and carotid intima-media thickness (CIMT) measurements and color Doppler ultrasonography from 2003 to 2006. The degree of stenosis in patients with PAD was determined according to Jager's criteria, and PAD was defined as grade III (50% to 99% stenosis) or IV stenosis (100% stenosis) by color Doppler ultrasonography. Logistic regression analysis and receiver operating characteristic curve analysis were performed to evaluate the risk factors for PAD in patients with ABI 0.91 to 1.40. RESULTS: Among the 324 patients, 77 (23.8%) had ABI 0.91 to 1.40 but were diagnosed with PAD. Color Doppler ultrasonography demonstrated that suprapopliteal arterial stenosis, bilateral lesions, and multivessel involvement were less common in PAD patients with ABI 0.91 to 1.40 than in those with ABI ≤0.90. A multivariate logistic regression analysis demonstrated that older age, current smoking status, presence of leg symptoms, and high CIMT were significantly associated with the presence of PAD in patients with ABI 0.91 to 1.40 after adjusting for conventional risk factors. CIMT showed significant power in predicting the presence of PAD in patients with ABI 0.91 to 1.40. CONCLUSION: Color Doppler ultrasonography is a useful tool for the detection of PAD in T2DM patients with ABI 0.91 to 1.40 but a high CIMT.

ApoB/ApoA-I ratio is independently associated with carotid atherosclerosis in type 2 diabetes mellitus with well-controlled LDL cholesterol levels.

BACKGROUND/AIMS: This study aimed to investigate whether the apolipoprotein (Apo) B/ApoA-I ratio is associated with carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM) subjects with low density lipoprotein cholesterol (LDL-C) levels less than 100 mg/dL. METHODS: This cross-sectional study included 845 subjects aged with T2DM 40 to 75 years who had visited Huh's Diabetes Center in Seoul, Republic of Korea for CIMT measurement. Traditional fasting lipid profiles, ApoB and ApoA-I levels were examined. CIMT was measured at three points on the far wall of 1 cm long section of the common carotid artery in the proximity of the carotid bulb. The mean value of six measurements from right and left carotid arteries were used as the mean CIMT. In this study, carotid atherosclerosis was defined as having a focal plaque or diffuse thickening of the carotid wall (mean CIMT ≥ 1.0 mm). RESULTS: The prevalence of carotid atherosclerosis increased with ApoB/ApoA-I ratio. The ApoB/ApoA-I ratio, expressed as both quartiles (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.21 to 3.79; p for trend = 0.014) and continuous values (OR, 10.05; 95% CI, 3.26 to 30.97; p < 0.001), was significantly associated with a higher risk for carotid atherosclerosis, regardless of conventional cardiovascular disease risk factors. The optimal ApoB/ApoA-I ratio cutoff value for detecting carotid atherosclerosis was 0.57, based on receiver operating characteristic curve analysis with a sensitivity of 58.0% and a specificity of 55.1%. CONCLUSIONS: A high ApoB/ApoA-I ratio was significantly associated with carotid atherosclerosis in T2DM patients with LDL-C levels less than 100 mg/dL.

Waist-to-calf circumstance ratio is an independent predictor of hepatic steatosis and fibrosis in patients with type 2 diabetes.

BACKGROUND AND AIM: Although a combination of central obesity and decreased skeletal muscle mass has been associated with various cardiometabolic disorders, its influence on the presence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D) is unclear. We investigated whether waist-to-calf circumference ratio (WCR) predicts NAFLD or hepatic fibrosis in T2D. METHODS: Patients with T2D (n = 5507) were enrolled in this study. Hepatic steatosis was diagnosed using abdominal ultrasound and predicting score. NAFLD was defined as 'hepatic steatosis absent other causes of chronic liver disease,' such as virus or alcoholism. Degree of hepatic fibrosis was calculated using non-invasive serum biomarker-based models. Insulin resistance was assessed by short insulin tolerance test. RESULTS: The prevalence of NAFLD and obesity (BMI ≥ 25 kg/m2 , Asian definition) were 46.4% and 38.9%, respectively. NAFLD prevalence was higher with increasing WCR tertiles: lowest tertile (36% in men, 28% in women) versus highest tertile (53.8% in men, 58.2% in women, both P < 0.001 after stratification by insulin resistance status. Increasing WCR tertiles were independently associated with presence of NAFLD: odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.22-1.68 and OR = 1.56, 95% CI = 1.31-1.86, in the middle and highest tertiles, respectively. Furthermore, patients with NAFLD and the highest WCR tertile had significant fibrosis (OR = 8.62, 95% CI = 1.39-53.36, P = 0.021). Also, WCR was correlated with risk of sarcopenia (OR = 3.18, 95% CI = 2.50-4.05, P < 0.001, highest tertile). CONCLUSIONS: Higher WCR is associated with increased risk of NAFLD and hepatic fibrosis independent of insulin resistance. This suggests that WCR may be a useful index to predict high risk of hepatic steatosis in T2D.

Reappraisal of waist circumference cutoff value according to general obesity.

BACKGROUND: Current criterion of waist circumference (WC) for abdominal obesity is not enough to demonstrate characteristics of obese and non-obese populations defined by BMI. The aim of this study was to redefine the cutoff values of WC according to general obesity (BMI ≥ 25 kg/m(2)). METHODS: The receiver operating characteristic curve analysis was performed to determine cutoff values of WC for predicting atherosclerosis according to BMI in 1,063 non-diabetic subjects. To validate this new criterion, diabetic patients (n = 3,690) were divided into three groups based on the current (WC of 90/80 cm for men/women) and new cutoff values of WC: 1) group with WC below the lowest value of two criteria; 2) intermediate group defined as having a WC between them; and 3) group with WC more than the highest value of them. RESULTS: The new cutoff values of WC for predicting atherosclerosis in non-diabetic subjects were 84/76 cm for non-obese men/women, and 93/87 cm for obese men/women, respectively. Of non-obese diabetic patients, the intermediate group (WC 84 ~ 90/76 ~ 80 cm for men/women) was more insulin resistant and showed elevated odds ratio (OR) for having 2 or more metabolic risk factors compared to group with WC below 84/76 cm for men/women [OR 2.48 (95 % CI 1.89-3.25) in men, 2.01 (95% CI 1.45-2.78) in women]. In contrast, among obese diabetic patients, insulin resistance and the likelihood of having 2 or more metabolic risk factors were not different from the intermediate group (WC 90 ~ 93/80 ~ 87 cm for men/women) and group with WC below 90/80 cm for men/women. CONCLUSIONS: The current universal cutoff values of WC may under- or over-estimate the metabolic risks of intermediate groups. Therefore, the WC criteria for abdominal obesity should be applied differently depending on the BMI.

Nonalcoholic Fatty liver disease is associated with increased carotid intima-media thickness only in type 2 diabetic subjects with insulin resistance.

CONTEXT: The association between nonalcoholic fatty liver disease (NAFLD) and subclinical atherosclerosis in type 2 diabetes is controversial. OBJECTIVE: The objective of the study was to investigate the participation of insulin resistance in the association of NAFLD and the carotid atherosclerotic burden in a large cohort of patients with type 2 diabetes. DESIGN, SETTING, AND PATIENTS: This was an observational study performed in 4437 consecutively enrolled patients with type 2 diabetes. MAIN OUTCOMES MEASURES: Hepatic steatosis and mean carotid intima-media thickness (C-IMT) were measured using ultrasonography. Insulin resistance was assessed using the short insulin tolerance test. RESULTS: The prevalence of NAFLD was 72.7% in the whole study population. Among subjects with NAFLD, 23.2% were not insulin resistant. There were significant differences in C-IMT and the frequency of carotid atherosclerosis between groups classified by insulin resistance within the same NAFLD strata. C-IMT was highest in subjects with both NAFLD and insulin resistance [0.844 ± 0.004 (mean ± SE) mm vs 0.786 ± 0.008, 0.821 ± 0.007, and 0.807 ± 0.006 mm, P for trend <.001, respectively, in insulin sensitive subjects without NAFLD, insulin resistant subjects without NAFLD, and insulin sensitive subjects with NAFLD]. These differences remained after adjusting for potential confounders. However, C-IMT in subjects having only NAFLD or insulin resistance was not higher than that in those with neither NAFLD nor insulin resistance. CONCLUSIONS: NAFLD is very common in subjects with type 2 diabetes, but NAFLD not accompanied by insulin resistance is not associated with a carotid atherosclerotic burden. However, having both NAFLD and insulin resistance seemed to be an independent predictor of increased C-IMT.

Ratio of waist-to-calf circumference and carotid atherosclerosis in Korean patients with type 2 diabetes.

OBJECTIVE: To investigate whether waist circumference (WC), calf circumference (CC), and waist-to-calf ratio (WCR) are associated with carotid atherosclerosis in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was an observational study performed in 3,694 Korean patients with type 2 diabetes. Anthropometric measures and carotid ultrasound were performed on each subject. Carotid atherosclerosis was defined as having a clearly isolated focal plaque or mean carotid intima-media thickness (CIMT) ≥1.1 mm. RESULTS: CIMT and the frequency of carotid atherosclerosis were higher with increasing WC quartiles and decreasing CC quartiles. There was an augmentative effect of CC and WC on the frequency of carotid atherosclerosis, which was dramatically higher in both the highest WC quartile and lowest CC quartile. However, except for the relationship between the quartile of CC with the frequency of carotid atherosclerosis in men, those associations disappeared after adjusting for potential confounders. In contrast, WCR was significantly related to CIMT (only in women) and carotid atherosclerosis, even after adjustment (adjusted odds ratio for carotid atherosclerosis for the highest quartile of WCR compared with the lowest quartile being 1.178 [95% CI 1.026-1.353] and 1.276 [1.053-1.545] in men and women, respectively). CONCLUSIONS: A low CC and high WC seems to be associated with a carotid atherosclerotic burden in Korean diabetic patients. In particular, compared with each circumference, WCR is independently associated with carotid atherosclerosis. However, the cross-sectional nature of the study limits conclusions regarding the direction or causality. Further longitudinal study is warranted in this and other ethnic groups.

Insulin resistance and carotid atherosclerosis in patients with type 2 diabetes.

OBJECTIVE: Insulin resistance may provide a crucial link between type 2 diabetes and cardiovascular disease. However, it is still unclear whether insulin resistance itself or hyperinsulinemia is independently associated with subclinical atherosclerosis. We hypothesized that insulin resistance, but not hyperinsulinemia, would be associated with carotid atherosclerosis in patients with type 2 diabetes. METHODS: We examined 2471 patients with type 2 diabetes, consecutively enrolled in Huh Diabetes Center. Insulin sensitivity was directly assessed by a rate constant for plasma glucose disappearance (Kitt) using short insulin tolerance test. Fasting insulin levels were used as a marker of hyperinsulinemia. Both carotid arteries were examined by B-mode ultrasound. Carotid atherosclerosis was defined by having a clearly isolated focal plaque or mean carotid intima-media thickness (IMT) >or=1.1mm. RESULTS: In multiple regression models, insulin sensitivity index (Kitt) but not hyperinsulinemia was significantly associated with carotid IMT adjusting for known risk factors such as age, sex, BMI, smoking, systolic pressure, HDL and LDL cholesterol. One standard deviation decrease in Kitt was associated with 0.046 mm increase in carotid IMT (p=0.015). Furthermore, odds ratio for carotid atherosclerosis was 1.43 (95% CI: 1.10, 1.86) in type 2 diabetic patients with insulin resistance (lowest quartile of insulin sensitivity) adjusting for known risk factors. The results were consistent in all subgroups stratified by sex, age, smoking and hypertension. CONCLUSION: Insulin resistance measured by short insulin tolerance test, but not hyperinsulinemia, is independently associated with carotid atherosclerosis in patients with type 2 diabetes.