[Show abstract][Hide abstract] ABSTRACT: Background:
Elevated serum gamma-glutamyltransferase (GGT) has been demonstrated to be associated with coronary artery calcification (CAC). CAC progression is an important marker of atherosclerosis and correlates with future cardiovascular risk. However, there is a lack of research that directly examines the association between serum GGT and CAC progression. The aim of this study was to elucidate the association between serum GGT activity and CAC progression.
We enrolled 1246 asymptomatic participants who underwent repeated CAC score measurement during routine health examinations. To eliminate the dependence of the inter scan variability on the baseline CAC scores, square root-transformed CAC scores were used to analyze CAC progression. In addition, the annualized rate of change in CAC scores was computed.
Serum GGT activities were significantly higher in "progressors" than "nonprogressors". The prevalence of progression increased with the GGT tertile (11.9%, 20.1% and 27.9% in the 1st, 2nd, and 3rd GGT tertiles, respectively; p < 0.001). In the multivariate logistic regression analysis, the odds ratio (95% confidence interval) for CAC score progression was 1.85 (1.14-3.00) in the highest GGT tertile group. By multivariate linear regression analysis, baseline serum GGT activity demonstrated a positive association with the annualized change in CAC score (β = 0.002; p = 0.006) after adjusting for cardiovascular risk factors.
Elevated serum GGT levels are independently associated with CAC progression. Serum GGT levels may be a potential biomarker of future coronary atherosclerosis and prognosis.
[Show abstract][Hide abstract] ABSTRACT: Aims:
To compare the association between cardiovascular diseases (CVD) and prediabetes defined by fasting plasma glucose (FPG)-only, HbA1c-only, or combined criteria in a Korean population.
In total, 76,434 South Korean individuals who voluntarily underwent a general health examination in the Health Screening and Promotion Center at Asan Medical Center were analyzed after excluding patients with previous history of CVD. CVD events and death during a median follow-up of 3.1 (interquartile range, 1.9-4.3) years were recognized from the nationwide health insurance claims database and death certificates by using ICD-10 codes.
Age- and sex-adjusted hazard ratios (HRs) for overall CVD events were significantly increased for participants with prediabetes by FPG-only criteria (1.19 [1.08-1.31]), HbA1c-only criteria (1.28 [1.16-1.42]), and combined criteria (1.20 [1.09-1.32]). After adjusting for multiple conventional risk factors such as hypertension, LDL and HDL cholesterol levels, smoking status, and family history of CVD and BMI, the HRs for overall CVD were significantly increased only for participants with prediabetes by HbA1c-only criteria. Age- and sex-adjusted HRs for major ischemic heart disease (IHD) events were significantly increased for participants with prediabetes by HbA1c-only and combined criteria. For percutaneous coronary intervention, age- and sex-adjusted HRs were significantly higher for participants with prediabetes only by HbA1c-only criteria. For diabetes, multivariate-adjusted HRs for all outcomes were significantly increased by all three criteria.
Adding the HbA1c criterion in defining prediabetes can be helpful in identifying individuals with an increased risk of CVD in Koreans. This article is protected by copyright. All rights reserved.
No preview · Article · Sep 2015 · Journal of Diabetes
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study sought to investigate whether the metabolically healthy obese (MHO) phenotype is associated with an increased risk of incident type 2 diabetes in a Korean population and, if so, whether systemic inflammation affects this risk in MHO individuals.
Design and methods:
The study population comprised 36 135 Koreans without type 2 diabetes. Participants were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). High-sensitive C-reactive protein (hsCRP) was used as a surrogate marker of systemic inflammation. Subjects were classified into low (ie, hsCRP < 0.5 mg/L) and high (ie, hsCRP ≥ 0.5 mg/L) systemic inflammation groups.
During a median followup of 36.5 months (range, 4.8-81.7 mo), 635 of the 36 135 individuals (1.8%) developed type 2 diabetes. The MHO group had a significantly higher risk of incident type 2 diabetes (multivariate-adjusted hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16-2.11) than the metabolically healthy nonobese (MHNO) group. However, the risk of the MHO group varied according to the degree of systemic inflammation. Compared with the MHNO/low systemic inflammation group, the risk of type 2 diabetes in the MHO/low systemic inflammation group was not significantly elevated (multivariate-adjusted HR, 1.61; 95% CI, 0.77-3.34). However, the MHO/high systemic inflammation group had an elevated risk of incident type 2 diabetes (multivariate-adjusted HR, 3.73; 95% CI 2.36-5.88).
MHO subjects show a substantially higher risk of incident type 2 diabetes than MHNO subjects. The level of systemic inflammation partially explains this increased risk.
No preview · Article · Dec 2014 · Journal of Clinical Endocrinology & Metabolism
[Show abstract][Hide abstract] ABSTRACT: Objective
The degree of subclinical coronary atherosclerosis detected by coronary multidetector computed tomography (MDCT) in four groups defined by the state of metabolic health and obesity in an asymptomatic Korean population was compared.Methods
The data of 4009 asymptomatic subjects who participated in a routine health screening examination were collected. Significant coronary artery stenosis defined as >50% stenosis, plaque, and coronary artery calcium scores (CACS) were assessed by MDCT. Participants were stratified by BMI (cut-off value, 25 kg/m2) and metabolically healthy state, which was defined by Wildman criteria.ResultsMHO subjects had a significantly higher prevalence of significant subclinical coronary atherosclerotic burden compared with metabolically healthy nonobese (MHNO) subjects. The adjusted odds ratios of the MHO group for various coronary MDCT findings (MHNO group as the reference), such as coronary artery stenosis, any plaque, calcified plaque, mixed plaque, CACS > 0, and CACS > 100, were 1.87 (95% CI 1.15-3.03), 1.31 (1.01-1.71), 1.40 (1.05-1.86), 1.57 (1.01-2.48), 1.38 (1.04-1.82), and 1.69 (1.03-2.78), respectively.Conclusions
Our data illustrate that MHO subjects have substantial subclinical coronary atherosclerotic burden. Thus, it is important to consider the metabolic health state and obesity in evaluating cardiovascular risk.
[Show abstract][Hide abstract] ABSTRACT: Bilirubin, a natural product of heme catabolism by heme oxygenase, one of key antioxidant enzymes, has been recognized as a substance with potent antioxidant and cytoprotective properties. Several studies have shown a significant negative relationship between serum bilirubin levels and the risk of metabolic disorders, including type 2 diabetes. However, longitudinal studies investigating the association of elevated serum bilirubin levels and type 2 diabetes are lacking. In the present study, we aimed to investigate the longitudinal effects of baseline serum bilirubin concentrations on the development of type 2 diabetes in healthy Korean men.
This 4year retrospective longitudinal observational study was conducted at the Asan Medical Center, Seoul, Republic of Korea. The study population consisted of 5960 men without type 2 diabetes who underwent routine health examinations in 2007 (baseline) and 2011 (follow-up). Baseline serum bilirubin concentrations were determined by the vanadate oxidation method.
During a 4year period, 409 incident cases of diabetes (6.9 %) were identified. Incident type 2 diabetes decreased across the baseline bilirubin quartile categories (P for trend <0.001). In multivariable-adjusted model, the relative risk (RR) for the development of type 2 diabetes was significantly lower in the highest (i.e., 1.30-2.00mg/dl) than in the lowest bilirubin quartile category (i.e., ≤0.90mg/dl), even after adjustment for confounding variables (RR=0.69, 95% confidence interval 0.48-0.99, P for trend=0.041).
The results indicate that serum total bilirubin level may provide additional information for predicting future development of type 2 diabetes in healthy subjects.
Full-text · Article · Oct 2013 · Metabolism: clinical and experimental
[Show abstract][Hide abstract] ABSTRACT: Elevated ferritin concentration has been implicated in the etiology of type 2 diabetes. Accumulating evidence, mostly from studies conducted on western populations, has demonstrated a strong association between the elevated ferritin concentrations and incident type 2 diabetes. In Asian populations, however, the longitudinal studies investigating the association of elevated serum ferritin levels and type 2 diabetes are lacking. In present study, we aimed to determine whether elevated serum ferritin levels are related to the incident type 2 diabetes in healthy Korean men.
This 4 year longitudinal observational study was conducted at the Asan Medical Center, Seoul, Republic of Korea. The study population consisted of 2,029 men without type 2 diabetes who underwent routine health examination in 2007 (baseline) and 2011 (follow-up). Baseline serum ferritin concentrations were measured by chemiluminescent two-site sandwich immunoassay. In multiple-adjusted model, the relative risk (RR) for incident type 2 diabetes was significantly higher in highest compared with the lowest ferritin quartile category, even after adjusting for confounding variables including homeostasis model assessment of insulin resistance (RR = 2.17, 95% confidence interval 1.27-3.72, P for trend = 0.013).
These results demonstrated that elevated level of serum ferritin at baseline was associated with incident type 2 diabetes in an Asian population.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:: Successful treatment of acromegaly is known to normalize serum insulin-like growth factor-1 (IGF-1) levels within days after surgery. However, our clinical observations indicate that many cases of acromegaly show delayed normalization of serum IGF-1 levels following complete tumor resection. OBJECTIVE:: To study long-term changes of the serum IGF-1 levels in acromegalic patients for whom surgical treatment was thought to be successful. METHODS:: A retrospective observational study was performed with 46 acromegalic patients with no residual tumor on sellar magnetic resonance imaging, and a nadir GH of < 0.4 µg/L on postoperative oral glucose tolerance test. RESULTS:: In all patients, serum IGF-1 levels returned to the normal reference values for age and sex during the observational period (12-132 months). The mean duration from the time of surgery until IGF-1 normalization was 10 months (range, 3 days-57 months). 27 patients (59%) reached normal IGF-1 ranges within three months of surgery, whereas 19 patients (41%) achieved delayed (> 3 months) IGF-1 normalization. 11 patients (24%) recovered normal IGF-1 levels during the 12-57 month period post-operation. The possibility of delayed IGF-1 cure was increased 8.8 fold with an immediate postoperative IGF-1 level increase of 100 µg/L. CONCLUSION:: Satisfactory remission of acromegaly by IGF-1 criteria was delayed in a large proportion of acromegalic patients, especially those with high postoperative IGF-1 levels. Hence, additional treatment can be delayed in clinically stable acromegalic patients who show no evidence of residual tumors on postoperative MRI and a normal GH suppressive response to a glucose load.
[Show abstract][Hide abstract] ABSTRACT: Despite the noninvasiveness and accuracy of multidetector computed tomography (MDCT), its use as a routine screening tool for occult coronary atherosclerosis is unclear. We investigated whether the ratio of apolipoprotein B (apoB) to apolipoprotein A1 (apoA1), an indicator of the balance between atherogenic and atheroprotective cholesterol transport could predict occult coronary atherosclerosis detected by MDCT. We collected the data of 1,401 subjects (877 men and 524 women) who participated in a routine health screening examination of Asan Medical Center. Significant coronary artery stenosis defined as > 50% stenosis was detected in 114 subjects (8.1%). An increase in apoB/A1 quartiles was associated with increased percentages of subjects with significant coronary stenosis and noncalcified plaques (NCAP). After adjustment for confounding variables, each 0.1 increase in serum apoB/A1 was significantly associated with increased odds ratios (ORs) for coronary stenosis and NCAP of 1.23 and 1.18, respectively. The optimal apoB/A1 ratio cut off value for MDCT detection of significant coronary stenosis was 0.58, which had a sensitivity of 70.2% and a specificity of 48.2% (area under the curve, 0.61; 95% CI, 0.58-0.63, P < 0.001). Our results indicate that apoB/A1 ratio is a good indicator of occult coronary atherosclerosis detected by coronary MDCT.
Full-text · Article · May 2013 · Journal of Korean medical science
[Show abstract][Hide abstract] ABSTRACT: Objective:
Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells.
Materials and methods:
We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative free fatty acid. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway.
Pretreatment of ucOC (30 ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, wortmannin. Treatment of ucOC (ranged from 0.3 to 30 ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner.
Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Plasma homocysteine (Hcy) is considered to be a marker of endothelial dysfunction and a predictor of cardiovascular disease (CVD). Arterial stiffness measured by brachial-ankle pulse wave velocity (baPWV) is not only a marker of vascular damage but a significant predictor of CVD. Previous studies about the effect of high plasma Hcy levels on arterial stiffness have yielded inconsistent results. We therefore assessed the association between Hcy and baPWV in a relatively large number of subjects with type 2 diabetes mellitus (DM).
[Show abstract][Hide abstract] ABSTRACT: DDAH-II mediates the vaspin-induced changes in the levels of NO, ADMA and the eNOS activity in HAECs. A-B. Effect of DDAH II siRNA on vaspin-induced changes in the levels of NO (A) and ADMA (B) in conditioned media of HAECs. HAECs were treated with control siRNA ± vaspin 100 ng/ml or DDAH II siRNA ± vaspin 100 ng/ml. Relative concentrations of NO and ADMA were measured at 24 hr after vaspin treatment. C. Effect of DDAH II siRNA on vaspin induced eNOS phosphorylation in HAECs. HAECs were treated with control siRNA ± vaspin 100 ng/ml or DDAH II siRNA ± vaspin 100 ng/ml. Relative expression of eNOS was measured at 16 hr after vaspin treatment. The blocked expression of DDAH II by DDAH II siRNA was confirmed by using the real time PCR for DDAH II mRNA in every experiment. Data are shown as means ± SEM of at least three independent experiments.*p<0.05 vs. control siRNA alone; #p<0.05 vs. control siRNA+vaspin. DDAH II, dimethylarginine dimethylaminohydrolase II; NO, nitric oxide; ADMA, asymmetric dimethylarginine; eNOS, endothelial nitric oxide synthase.
[Show abstract][Hide abstract] ABSTRACT: The antioxidant effect of vaspin against hydrogen peroxide (H2O2)-induced oxidative stress in HAECs. Intracellular ROS generation was measured by a flow cytometry (FACSCaliber, Becton Dickinson, NJ, USA) using DCHF2-DA (Molecular Probes). A. The representative microphotographs of DCFH2-DA (green fluorescence) staining. The green fluorescence was visualized using a confocal microscopy (LSM710, ZEISS, Germany). Magnification, x 40. B. Quantification of fluorescence density was done using a flow cytometry. Data are shown as means ± SEM of at least three independent experiments. HAECs were treated with 100 ng/ml of vaspin 1 hr before the incubation of H2O2 for 15 min, which was followed by the incubation of 2.5 µmol/ml DCFH2-DA for 15 min. Fluorescence was measured at 30 min after the incubation of DCHF2-DA.
[Show abstract][Hide abstract] ABSTRACT: STAT3 mediates the vaspin-induced changes in the levels of NO, ADMA and the expression of DDAH II in HAECs. A-B. Effect of STAT3 siRNA on vaspin-induced changes in the levels of NO (A) and ADMA (B) in conditioned media of HAECs. HAECs were treated with control siRNA ± vaspin 100 ng/ml or STAT3 siRNA ± vaspin 100 ng/ml. Relative concentrations of NO and ADMA were measured at 24 hr after vaspin treatment. C. Effect of STAT3 siRNA on vaspin induced DDAH II mRNA expression in HAECs. HAECs were treated with control siRNA ± vaspin 100 ng/ml or STAT3 siRNA ± vaspin 100 ng/ml. Relative expressions of STAT3 and DDAH II mRNA was measured at 16 hr after vaspin treatment. Data are shown as means ± SEM of at least three independent experiments.*p<0.05 vs. control siRNA alone; #p<0.05 vs. control siRNA+vaspin. STAT3, signal transducer and activator of transcription 3; NO, nitric oxide; ADMA, asymmetric dimethylarginine; DDAH II, dimethylarginine dimethylaminohydrolase II.
[Show abstract][Hide abstract] ABSTRACT: Vaspin is an adipocytokine recently identified in the visceral adipose tissue of diabetic rats and having anti-diabetic effects. We have recently shown that vaspin has anti-atherogenic effect through Akt-mediated inhibition of endothelial cell apoptosis. Decreased activity of endothelial nitric oxide synthase (eNOS) plays an important role in the pathogenesis of atherosclerosis. Asymmetric dimethylarginine (ADMA) is a well-known endogenous competitive inhibitor of eNOS and risk factor of cardiovascular diseases. The aim of this study was to examine whether vaspin might protect against atherosclerosis through its beneficial effects on the ADMA-eNOS system. Treatment of vaspin significantly increased NO secretion from endothelial cells and isolated aorta from Sprague-Dawley (SD) rats. Furthermore, treatment of vaspin prevented fatty acid-induced decrease in endothelium-dependent vasorelaxation in isolated aorta of SD rat. For the mechanism of vaspin-induced NO biosynthesis, vaspin activated the STAT3 signaling pathway and stimulated eNOS phosphorylation (Ser 1177), a marker of eNOS activation, through STAT3-dependent mechanism. Furthermore, vaspin treatment increased the expression of dimethylarginine dimethylaminohydrolase (DDAH) II, the responsible enzyme for the degradation of ADMA, leading to a reduction in ADMA levels. Vaspin-induced increase in DDAH II gene expression was through STAT3-mediated stimulation of DDAH II promoter activity. These results suggest that vaspin increases eNOS activity by reducing ADMA level through STAT3-mediated regulation of DDAH II expression. Our findings provide a novel molecular mechanism of antiatherogenic actions of vaspin.
[Show abstract][Hide abstract] ABSTRACT: Background:
Increased oxidative stress contributes to the development of arterial stiffness. Arterial stiffness, as measured by brachial-ankle pulse wave velocity (baPWV), has been known to be correlated with oxidative stress. Serum ceruloplasmin (CP), a copper-carrying protein, may indicate the overall level of oxidative stress in the body. The present study investigated whether serum CP levels are associated with baPWV in Korean men with type 2 diabetes mellitus (DM).
Subjects and methods:
Serum CP levels and conventional risk factors were measured in 760 Korean men with type 2 DM. Arterial stiffness was assessed by baPWV obtained with an automatic device (model VP-1000; Colin, Komaki, Japan).
Correlation analysis indicated a significant positive association between serum CP and baPWV (r = 0.109, P = 0.003). Age-adjusted baPWV increased gradually according to serum CP quartiles (Q1, 1,500.3 ± 18.4 cm/s; Q2, 1,511.6 ± 17.8 cm/s; Q3, 1,551.8 ± 17.9 cm/s; Q4, 1,622.1 ± 17.8 cm/s; P for trend < 0.001). Multivariate linear regression analysis showed that serum CP was independently associated with baPWV in various models.
A positive relationship was identified between CP and baPWV in adult male subjects with type 2 DM, which was independent of conventional cardiovascular risk factors. Further studies are needed to confirm whether CP contributes to the pathogenesis of increased arterial stiffness in subjects with type 2 DM.
No preview · Article · Oct 2012 · Diabetes Technology & Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Background:
This study investigated the incidence of β-cell dysfunction and the clinical and biochemical factors affecting that in patients with type 2 diabetes having more than 3 years of follow-up.
Subjects and methods:
β-Cell dysfunction was assessed by measuring changes in the fasting serum C-peptide concentrations. Patients were classified into two groups: cases showing a decreased (Group D) or an unchanged or increased (Group I) C-peptide concentration from the baseline.
Of the 504 patients included in this study, 259 (51%) showed decreased C-peptide concentrations, of whom 20% showed a decrease of ≥50%. Most patients, however, had a final C-peptide concentration of ≥1 ng/mL, with only 18 (4%) individuals having a level <0.6 ng/mL. Patients in Group D had a longer duration of diabetes, higher initial hemoglobin A1c concentration, and longer treatment durations with sulfonylurea and insulin compared with Group I. After adjusting for diabetes duration and C-peptide follow-up period, the duration of sulfonylurea treatment was found to be the only factor independently associated with decreases in the C-peptide concentration.
Although β-cell function deteriorates over time in patients with type 2 diabetes, these cases mainly have fasting serum C-peptide concentrations of ≥1 ng/mL. A longer treatment duration with sulfonylurea is associated with a more rapid decline in the C-peptide concentration.
[Show abstract][Hide abstract] ABSTRACT: Fibroblast growth factor 21 (FGF21) was originally identified as a paroxysm proliferator activated receptor-α target gene product and is a hormone involved in metabolic regulation. The purpose of this study was to investigate the diurnal variation of serum FGF21 concentration in obese and non-obese healthy volunteers.
Blood samples were collected from five non-obese (body mass index [BMI] ≤23 kg/m(2)) and five obese (BMI ≥25 kg/m(2)) healthy young men every 30 to 60 minutes over 24 hours. Serum FGF21 concentrations were determined by radioimmunoassay. Anthropometric parameters, glucose, free fatty acid, insulin, leptin, and cortisol concentrations were also measured.
The serum FGF21 concentrations displayed various individual oscillation patterns. The oscillation frequency ranged between 6 and 12 times per day. The average duration of oscillation was 2.52 hours (range, 1.9 to 3.0 hours). The peaks and troughs of FGF21 oscillation showed no circadian rhythm. However, the oscillation frequency had a diurnal variation and was lower during the light-off period than during the light-on period (2.4 vs. 7.3 times, P<0.001). There was no difference in the total frequency or duration of oscillations between non-obese and obese subjects, but obese individuals had increased numbers of larger oscillations (amplitude ≥0.19 ng/mL).
Various oscillation patterns in serum FGF21 concentration were observed, and reduced oscillation frequencies were seen during sleep. The oscillation patterns of serum FGF21 concentration suggest that FGF21 may be secreted into systemic circulation in a pulsatile manner. Obesity appeared to affect the amplitude of oscillations of serum FGF21.
[Show abstract][Hide abstract] ABSTRACT: Objective The ratio of apolipoprotein B (apoB) to apolipoprotein A1 (apoA1) has been reported to be associated with the metabolic syndrome (MetS). However, the optimal cut-off value of apoB/A1 ratio for detecting subjects with MetS has remained undetermined. In the present study, we aimed to investigate whether apoB/A1 ratio can be an indicator of MetS and to determine the optimal cut-off value of apoB/A1 ratio in detecting subjects with MetS in a Korean population.
Design This cross-sectional study was conducted at the Asan Medical Center, Seoul, Republic of Korea.
Subjects and measurements We collected the data of 10 940 subjects who participated in a routine health screening examination regarding conventional risk factors and serum levels of apoB and apoA1.
Results The odds for MetS were significantly higher in the highest compared with the lowest apoB/A1 ratio quartiles, after adjustment for confounding variables, in both men [odds ratio (OR) = 4·07, 95% CI = 3·42–4·84] and women (OR = 8·41, 95% CI = 5·85–12·08). The optimal apoB/A1 ratio cut-off value for the detection of MetS was 0·65, which had a sensitivity of 63·5% and a specificity of 61·3% (area under the curve = 0·67, 95% CI = 0·66–0·68, P < 0·001) in men and 0·62, which had a sensitivity of 67·9% and a specificity of 61·9% (area under the curve = 0·70, 95% CI = 0·69–0·71, P < 0·001) in women.
Conclusions These results suggest that apoB/A1 ratio is independently associated with MetS and that an apoB/A1 ratio >0·65 in men and 0·62 in women is a marker of MetS independent from conventional risk factors.
No preview · Article · Jan 2012 · Clinical Endocrinology