Ji Hee Yu

Evening Chronotype Is Associated With Metabolic Disorders and Body Composition in Middle-Aged Adults

CONTEXT Chronotype is a trait determining individual circadian preference in behavioral and biological rhythm relative to external light-dark cycle. However, little is known about the relationship between chronotype and metabolic disorders. OBJECTIVE The aim of this study was to examine whether late chronotype is related to metabolic abnormalities and body composition in middle-aged adults, independent of sleep duration and lifestyle. DESIGN AND PARTICIPANTS A total of 1620 participants aged 47-59 years were recruited from the Korean Genome and Epidemiology Study. MAIN OUTCOME MEASURES Chronotype was assessed by the Morningness-Eveningness Questionnaire. Associations of chronotype with diabetes, metabolic syndrome, sarcopenia, and visceral obesity were analyzed. All participants underwent the oral glucose tolerance test, and body composition was measured with dual energy x-ray absorptiometry. Visceral obesity was designated as visceral fat area, measured by abdominal computed tomography, of >100 cm(2). RESULTS Chronotype was classified as morning in 29.6% of subjects, evening in 5.9%, neither morning nor evening in 64.5%. Evening type, when compared with morning type, was significantly associated with diabetes (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.01-2.95), metabolic syndrome (OR, 1.74; 95% CI, 1.05-2.87), and sarcopenia (OR, 3.16; 95% CI, 1.36-7.33) after adjusting for confounding factors. Gender differences in the associations were evident. In men, evening type was associated with diabetes (OR, 2.98; 95% CI, 1.39-6.39) and sarcopenia (OR, 3.89; 95% CI, 1.33-11.33). Only metabolic syndrome was associated with evening type in women (OR, 2.22; 95% CI, 1.11-4.43). CONCLUSIONS At the population level, evening chronotype was independently associated with diabetes, metabolic syndrome, and sarcopenia. These results support the importance of circadian rhythms in metabolic regulation.

Prevalence and Determinants of Diabetic Nephropathy in Korea: Korea National Health and Nutrition Examination Survey

Background Diabetic nephropathy is a leading cause of end stage renal disease and is associated with an increased risk of cardiovascular mortality. It manifests as albuminuria or impaired glomerular filtration rate (GFR), and the prevalence of diabetic nephropathy varies with ethnicity. The prevalence of diabetic nephropathy and its determinants in Korean adults have not previously been studied at the national level. This cross-sectional study was undertaken to ascertain the prevalence and determinants of albuminuria and chronic kidney disease (CKD) in Korean patients with diabetes. Methods The Korea National Health and Nutrition Examination Survey (KNHANES) V, conducted in 2011, was used to define albuminuria (n=4,652), and the dataset of KNHANES IV-V (2008-2011) was used to define CKD (n=21,521). Selected samples were weighted to represent the entire civilian population in Korea. Albuminuria was defined as a spot urine albumin/creatinine ratio >30 mg/g. CKD was defined as a GFR <60 mL/min/1.73 m2. Results Among subjects with diabetes, 26.7% had albuminuria, and 8.6% had CKD. Diabetes was associated with an approximate 2.5-fold increased risk of albuminuria, with virtually no difference between new-onset and previously diagnosed diabetes. Only systolic blood pressure was significantly associated with albuminuria, and old age, high serum triglyceride levels, and previous cardiovascular disease (CVD) were related with CKD in subjects with diabetes. Conclusion Korean subjects with diabetes had a higher prevalence of albuminuria and CKD than those without diabetes. Blood pressure was associated with albuminuria, and age, triglyceride level, and previous CVD were independent determinants of CKD in subjects with diabetes.

Risk of the Development of Diabetes and Cardiovascular Disease in Metabolically Healthy Obese People: The Korean Genome and Epidemiology Study

AbstractThe reported effects of a metabolically healthy obese (MHO) phenotype on diabetes and cardiovascular disease (CVD) risk are contradictory. Within the context of a population-based cohort study, we aimed to investigate the long-term risk of an MHO status for the development of diabetes and CVD, and whether consistency of this phenotype or age affected cardiometabolic outcomes.We recruited 7588 subjects without diabetes or CVD, aged 40 to 69 years at baseline examination, from the Korean Genome and Epidemiology Study, and followed-up these subjects for 10 years biennially. Participants were divided into 4 groups based on the body mass index and the presence of metabolic syndrome: metabolically healthy normal weight (MHNW), MHO, metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obese (MUO). We defined persistent phenotypes if subjects maintained the same phenotype at every visit from baseline to their last visit. Incident diabetes and CVD morbidity or mortality were identified during 10 years of follow-up.Compared to MHNW controls, MUNW and MUO groups had increased risk for development of diabetes (hazard ratio [HR] 3.0 [95% CI: 2.5–3.6], and 4.0 [3.4–4.7], respectively) and CVD (HR 1.6 [1.3–2.0], and 1.9 [1.5–2.4], respectively). However, the MHO group showed only a marginal increase in risk for diabetes and CVD (HR 1.2 [0.99–1.6], 1.4 [0.99–1.8], respectively). The impact of MHO on the development of diabetes was more prominent in younger individuals (HR 1.9 [1.2–3.1] vs 1.1 [0.8–1.4], <45 years vs ≥45 years at baseline). Only 15.8% of MHO subjects maintained the MHO phenotype at every visit from baseline to the 5th biennial examination (persistent MHO). In subjects with persistent MHO, the risk for diabetes and CVD was significantly higher than those with persistent MHNW (1.9 [1.2–3.1], 2.1 [1.2–3.7], respectively).MHO phenotype, even if maintained for a long time, was associated with a significantly higher risk for the development of diabetes and CVD in Korean subjects.

HIF‐1α Expression as a Protective Strategy of HepG2 Cells Against Fatty Acid‐Induced Toxicity

Free fatty acid‐induced lipotoxicity via increased endoplasmic reticulum (ER) stress and hepatocyte apoptosis is a key pathological mechanism of non‐alcoholic steatohepatitis. A role of hypoxia‐inducible factor 1α (HIF‐1α) in this process has been suggested, but direct evidence is lacking. Here, we used HepG2 cells as a model to study whether HIF‐1α can reduce palmitic acid‐induced lipotoxicity and ER stress. In HepG2 cells treated with 500 µM palmitic acid, HIF‐1α expression increased transiently, the decline was associated with increased cleaved caspase‐3 expression. Overexpression and knockdown of HIF‐1α decreased and exacerbated, respectively, palmitic acid‐induced lipoapoptosis. The overexpression also blunted upregulation of the ER stress markers, C/EBP homologous protein (CHOP) and chaperone immunoglobulin heavy chain binding protein (Bip), while the knockdown increased the level of CHOP. In line with this, CHOP promoter activity decreased following HIF‐1α binding to the CHOP promoter hypoxia response element. These results indicate that hepatocyte lipotoxicity is associated with decreased HIF‐1α expression. It also suggests that upregulation of HIF‐1α can be a possible strategy to reduce lipotoxicity in non‐alcoholic fatty liver disease. J. Cell. Biochem. 115: 1147–1158, 2014.

Chronotype Differences in Health Behaviors and Health-Related Quality of Life: A Population-Based Study Among Aged and Older Adults

This study investigates health behaviors, health-related quality of life (HRQOL) and sleep among chronotypes in a community-based sample (n = 2,976). Analysis of covariance indicated evening types (E-types) had a significantly higher percentage of current smokers and more sleep-interfering behaviors compared to intermediate and morning types (M-type), and also lower physical activity and more sleep disturbance compared to M-types. E-types also had worse mental HRQOL compared to both chronotypes, and worse physical HRQOL compared to M-types. Exploratory analyses indicated E-types consumed more caffeinated beverages at night, smoked or ate heavy meals before bedtime, kept irregular sleep-wake schedules, and took more naps. Mediational analyses indicated that sleep-interfering behavior partially mediated the relationship between chronotype and sleep disturbance, and physical activity partially mediated the relationship between chronotype and mental HRQOL. E-types had more unhealthy behaviors, which may subsequently place them at higher risk for health problems.

Obstructive sleep apnea with excessive daytime sleepiness is associated with non-alcoholic fatty liver disease regardless of visceral fat

Background/Aims: Obstructive sleep apnea (OSA) is associated with an increased risk of obesity and non-alcoholic fatty liver disease (NAFLD), but it remains unclear whether the risk of NAFLD is independently related to OSA regardless of visceral obesity. Thus, the aim of the present study was to examine whether OSA alone or in combination with excessive daytime sleepiness (EDS) or short sleep duration was associated with NAFLD independent of visceral fat in Korean adults. Methods: A total of 621 participants were selected from the Korean Genome and Epidemiology Study (KoGES). The abdominal visceral fat area (VFA) and hepatic fat components of the participants were assessed using computed tomography scans and they were then categorized into four groups depending on the presence of OSA and EDS. Results: The proportions of NAFLD were 21.1%, 18.5%, 32.4%, and 46.7% in participants without OSA/EDS, with only EDS, with only OSA, and with both OSA and EDS, respectively. A combination of OSA and EDS increased the odds ratio (OR) for developing NAFLD (OR, 2.75; 95% confidence interval [CI], 1.21 to 6.28) compared to those without OSA/EDS, and this association remained significant (OR, 2.38; 95% CI, 1.01 to 5.59) even after adjusting for VFA. In short sleepers (< 5 hours) with OSA, the adjusted OR for NAFLD was 2.50 (95% CI, 1.08 to 5.75) compared to those sleeping longer than 5 hours without OSA. Conclusions: In the present study, OSA was closely associated with NAFLD in Korean adults. This association was particularly strong in those with EDS or short sleep duration regardless of VFA.

The influence of diabetes and antidiabetic medications on the risk of pancreatic cancer: a nationwide population-based study in Korea

This study investigated the effects of diabetes and antidiabetic medications on the risk of pancreatic cancer(PaC). We extracted data on Koreans with newly diagnosed diabetes and selected age- and sex-matched controls provided by the National Health Insurance Corporation. Incident PaC was defined as a new registration in the Korea Central Cancer Registry under ICD-10 C25 with admission history until 2015. During 19,429,617.1 person-years, 8,589 PaCs were identified in 1,005,409 subjects for diabetes group and 4,021,636 subjects for control group. The diabetes group showed more than a two-fold risk for PaC compared with the control group. Among antidiabetic medications, metformin, thiazolidinedione, and dipeptidyl peptidase-4 inhibitor exposure was associated with decreased risk for future PaC(hazard ratio[95% confidence interval] = 0.86[0.77–0.96], 0.82[0.68–0.98], 0.57[0.51–0.64], respectively), whereas sulfonylurea and insulin exposure was related to increased risk(hazard ratio[95% CI] = 1.73[1.57–1.91], 2.86[1.43–5.74], respectively) compared to subjects with no drug exposure. Moreover, subjects with dual exposure history to metformin plus thiazolidinedione or metformin plus dipeptidyl peptidase-4 inhibitor had a lower risk of PaC compared to metformin-only treated subjects. In conclusion, Korean adults with diabetes are at higher risk of PaC compared with nondiabetic individuals, and this risk may be modified by antidiabetic medications.

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha-2-HS-glycoprotein

Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The α2‐HS‐glycoprotein gene (AHSG) and its protein, fetuin‐A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA‐dependent manner. In HepG2 cells treated with 300 μmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 μmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA‐overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid‐induced ER stress markers, CHOP, Bip, ATF‐6, XBP‐1, ATF‐4, and PERK. In addition, in the high‐fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one‐third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p‐AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression.

The FTO rs9939609 polymorphism is associated with short leukocyte telomere length in nonobese individuals

Abstract The fat mass and obesity-associated (FTO) rs9939609 polymorphism have been associated with the increased metabolic risk and mortality, irrespective of obesity. The mechanism underlying this association is not known. We aimed to evaluate whether the FTO rs9939609 risk variant is independently associated with metabolic risk factors and/or leukocyte telomere length (LTL). We further aimed to investigate whether this relationship is modified by obesity status. A total of 2133 participants were recruited from the Korean Genome and Epidemiology Study. LTL was measured using the real-time quantitative polymerase chain reaction methodology. The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline. The proportions of the TT, TA, and AA genotypes were 76.7%, 21.5%, and 1.8%, respectively, and obese subjects comprised 44.5% of the total subjects. Among the 1184 nonobese subjects, body mass index, waist circumference, and visceral fat area were higher in subjects with the FTO risk allele than in noncarriers. In contrast, only high-sensitive C-reactive protein level was associated with the FTO risk allele in the obese subjects. LTL was significantly shorter in carriers of the FTO risk allele compared with noncarriers after controlling for several confounding factors (P < .01). Of particular note, this significant association between the FTO risk allele and LTL appeared only in nonobese subjects (P = .03). Multivariate linear regression analyses identified older age, low high-density lipoprotein cholesterol level, and the presence of the FTO risk allele as independent risk factors affecting LTL. This finding was evident only in nonobese subjects. The FTO rs9939609 polymorphism is an independent risk factor for obesity and also for biological aging in the nonobese population.

U-shaped association between sleep duration and urinary albumin excretion in Korean adults: 2011-2014 Korea National Health and Nutrition Examination Survey

Although sleep duration has been extensively studied in metabolic diseases, few studies have investigated the impact of sleep duration on chronic kidney disease. The aim of this study was to examine the relationship between sleep duration and albuminuria in the general population. Among 24,948 adults who participated in the 2011–2014 KNHANES, a total of 19,994 subjects were included in this analysis. Subjects were categorized into the following five groups according to self-reported sleep duration: less than 5 h, 6 h, 7 h, 8 h, and more than 9 h. The association between sleep duration and urinary albumin-creatinine ratio (UACR) was examined cross-sectionally. Subjects with both short and long sleep durations were significantly associated with higher UACR levels and higher proportions of patients with microalbuminuria (30–299 mg/g) and macroalbuminuria (≥300 mg/g) compared to those with a sleep duration of 7 hours. The U-shaped association between sleep duration and UACR remained significant even after adjustment for potential confounders, including age, sex, body mass index, smoking, alcohol, education, income, exercise, estimated glomerular filtration rate, diabetes mellitus, hypertension and hypercholesterolemia. The U-shaped association is more evident in the subgroup aged 65 or older, or in female subjects. Our findings suggest that both short and long sleep durations have a U-shaped association with UACR levels in the general population, independent of potential confounders.