Effect of Paxlovid in COVID-19 treatment during the periods of SARS-CoV-2 Omicron BA.5 and BN.1 subvariant dominance in the Republic of Korea: a retrospective cohort study.

BACKGROUND: This study was conducted to assess the efficacy of nirmatrelvir/ritonavir treatment in patients with coronavirus disease 2019 (COVID-19), particularly those aged 60 years and older. Using real-world data, the period during which the BN.1 Omicron variant was dominant was compared to the period dominated by the BA.5 variant. METHODS: In this retrospective cohort study, data were collected regarding 2,665,281 patients infected with severe acute respiratory syndrome coronavirus 2 between July 24, 2022, and March 31, 2023. Propensity score matching was utilized to match patients who received nirmatrelvir/ ritonavir in a 1:4 ratio between BN.1 and BA.5 variant groups. Multivariable logistic regression analysis was employed to assess the effects of nirmatrelvir/ritonavir within these groups. RESULTS: Compared to the prior period, the efficacy of nirmatrelvir/ritonavir did not significantly differ during the interval of Omicron BN.1 variant dominance in the Republic of Korea. Among patients treated with nirmatrelvir/ritonavir, a significantly lower risk of mortality was observed in the BN.1 group (odds ratio [OR], 0.698; 95% confidence interval [CI], 0.557-0.875) compared to the BA.5 group. However, this treatment did not significantly reduce the risk of severe or critical illness, including death, for those in the BN.1 group (OR, 0.856; 95% CI, 0.728-1.007). CONCLUSION: Nirmatrelvir/ritonavir has maintained its effectiveness against COVID-19, even with the emergence of the BN.1 Omicron subvariant. Consequently, we strongly recommend the administration of nirmatrelvir/ritonavir to patients exhibiting COVID-19-related symptoms, irrespective of the dominant Omicron variant or their vaccination status, to mitigate disease severity and decrease the risk of mortality.

Effectiveness of Molnupiravir Treatment in Patients with COVID-19 in Korea: A Propensity Score Matched Study.

BACKGROUND: The MOVe-OUT (efficacy and safety of molnupiravir [MK-4482] in non-hospitalized adult participants with COVID-19 [MK-4482-002]) trial reported that the administration of molnupiravir in unvaccinated patients with coronavirus disease 2019 (COVID-19) before the Omicron epidemic showed a preventive effect of 31% against hospitalization and death. However, studies on the preventive effect of molnupiravir against progression to severe disease and death in patients with COVID-19 during the Omicron epidemic are limited. This study aimed to evaluate the preventive effect of molnupiravir against severe/critical illness or death and death in Korean patients with COVID-19 who were vaccinated mostly during the Omicron epidemic. MATERIALS AND METHODS: This study used large-scale retrospective cohort data to select patients with COVID-19 who were either treated or not treated with molnupiravir, between August 2022 and March 2023, at a ratio of 1 : 4 using the propensity score matching method. In total, 762,768 patients comprised the non- administered group, and 190,692 patients comprised the molnupiravir-administered group. The preventive effect of molnupiravir against severe/critical illness or death and death was analyzed using logistic regression analysis. RESULTS: The preventive effect of molnupiravir against severe/critical illness or death and death, represented by the odds ratio (OR) and 95% confidence interval (CI), in the molnupiravir-administered and non-administered group was (OR: 0.714; CI: 0.667 - 0.764) and (OR: 0.749; CI: 0.682 - 0.823), respectively. As age increased, the preventive effect against severe/critical illness or death and death increased. The preventive effect against severe/critical illness or death at ≥60 years was (OR: 0.669; CI: 0.624 - 0.717), at ≥70 years was (OR: 0.614; CI: 0.570 - 0.661), and at ≥80 years was (OR: 0.563; CI: 0.515 - 0.615). The preventive effect against death at ≥60 years was (OR: 0.729; CI: 0.663 - 0.802), at ≥70 years was (OR: 0.676; CI: 0.612 - 0.747), and at ≥80 years was (OR: 0.622; CI: 0.554 - 0.698). CONCLUSION: Although molnupiravir showed a relatively weak preventive effect against severe/critical illness or death (29%) and death (25%) among patients with COVID-19, it exhibited a stronger protective effect in older patients than in younger patients. In particular, the preventive effect against severe/critical illness or death (44%) and death (38%) in those aged ≥80 years was pronounced. This study strongly suggests that molnupiravir administration can alleviate the burden on the medical system, and treat patients with COVID-19 effectively by reducing its progression to severe disease and death.

Effectiveness of Paxlovid, an Oral Antiviral Drug, Against the Omicron BA.5 Variant in Korea: Severe Progression and Death Between July and November 2022.

BACKGROUND: Paxlovid is an oral antiviral drug that received emergency use authorization in South Korea for the treatment of patients with mild-to-moderate coronavirus disease 2019 (COVID-19) on January 14, 2022. Since the onset of the severe acute respiratory syndrome coronavirus 2 pandemic, the virus has continued to evolve. The emergence of new variants has raised concerns about possible reductions in the effectiveness of vaccines and drugs. The effectiveness of Paxlovid in patients infected with the omicron variant and subvariants has not yet been determined. This study assessed the effectiveness of Paxlovid at reducing the risk of severe/critical illness or death and death in patients with mild-to-moderate COVID-19 caused by omicron subvariant BA.5. METHODS: In this nationwide retrospective cohort study, data on 8,902,726 patients were collected from four sources (the Drug Utilization Review database, COVID-19 Patient Information Management System, confirmed patient information, and basic epidemiological investigation data) between July 1 and November 30, 2022. Multivariable logistic regression analysis was conducted, with adjustment for age, sex, severe acute respiratory syndrome coronavirus 2 immunity (vaccination), and comorbidities. RESULTS: A total of 1,936,925 patients with COVID-19 were included in the analysis, including 420,996 patients treated with Paxlovid, and 1,515,959 patients not treated with Paxlovid. Paxlovid treatment in patients aged ≥ 60 years of age was associated with significantly reduced risk of severe/critical illness or death (46.0%), and death rate (32.5%), and its effectiveness was high, regardless of vaccination status. CONCLUSION: Paxlovid is effective at reducing the risk of death due to COVID-19 in patients with omicron BA.5 infection, especially in older patients, regardless of vaccination status. This suggests that older patients with COVID-19-related symptoms should be administered Paxlovid, regardless of their vaccination status, to reduce severity and risk of death.

Increased glutamate in type 2 diabetes in the Korean population is associated with increased plasminogen levels.

BACKGROUND: Glutamate is a major neurotransmitter, although it causes cytotoxicity and inflammation in nonneuronal organs. This study aimed to investigate the metabolic disorders in which glutamate, associated with type 2 diabetes onset, is induced in the liver. METHODS: An analysis of Korean community-based Ansan-Ansung cohort study data as well as functional research using in vitro and mouse models were performed. RESULTS: Groups with high plasma glutamate levels (T2, T3) had a significantly increased risk of diabetes incidence after 8 years, compared to the group with relatively low glutamate levels (T1). Analysis of the effect of glutamate on diabetes onset in vitro showed that glutamate induces insulin resistance by increasing glucose-related protein 78 (GRP78) and phosphoenolpyruvate carboxykinase (PEPCK) expression in SK-Hep-1 human liver cells. In addition, three different genes, FRMB4B, PLG, and PARD3, were significantly associated with glutamate and were identified via genome-wide association studies. Among glutamate-related genes, plasminogen (PLG) levels were most significantly increased in several environments in which insulin resistance was induced, and was also upregulated by glutamate. Glutamate-induced increase in PLG in liver cells was caused by metabotropic glutamate receptor 5 activation, and PLG levels were also upregulated after extracellular secretion. Moreover, glutamate increased the expression of plasminogen activator inhibitor-1 (PAI-1). Thus, extracellular secreted PLG cannot be converted to plasmin (fibrinolytic enzyme) by increased PAI-1. CONCLUSIONS: Increased glutamate is closely associated with the development of diabetes, and it may cause metabolic disorders by inhibiting the fibrinolytic system, which plays an important role in determining blood clots, a hallmark of diabetes.

Urine Metabolite of Mice with Orientia tsutsugamushi Infection.

Scrub typhus is an acute febrile, mite-borne disease endemic to the Asia-Pacific region. In South Korea, it is a seasonal disease that occurs frequently in the autumn, and its incidence has increased steadily. In this study, we used a liquid chromatography and flow injection analysis-tandem mass spectrometry-based targeted urine metabolomics approach to evaluate the host response to Orientia tsutsugamushi infection. Balb/c mice were infected with O. tsutsugamushi Boryong, and their urine metabolite profile was examined. Metabolites that differed significantly between the experimental groups were identified using the Kruskal-Wallis test. Sixty-five differential metabolites were identified. The principal metabolite classes were acylcarnitines, glycerophospholipids, biogenic amines, and amino acids. An ingenuity pathway analysis revealed that several toxic (cardiotoxic, hepatotoxic, and nephrotoxic) metabolites are induced by scrub typhus infection. This is the first report of urinary metabolite biomarkers of scrub typhus infection and it enhances our understanding of the metabolic pathways involved.

The effect of the association between CETP variant type and alcohol consumption on cholesterol level differs according to the ALDH2 variant type.

Alcohol consumption is associated with a high increased lipid profile and this association may depend on genetic risk factors. In this study, we aimed to assess the effects of genetic variation associated with alcohol consumption on lipid profiles using data from two Korean population studies. We performed a genotype association study using the HEXA (n = 51,349) and KNHANES (n = 9158) data. Genotype analyses of the two sets of Korean population data showed associations of increased total cholesterol and high-density lipoprotein (HDL)-cholesterol with CETP rs708272. The HEXA and KNHANES populations revealed differences in HDL cholesterol according to the presence of CETP rs708272, independent of ALDH2 rs671 and alcohol consumption. In contrast, total cholesterol levels were associated with alcohol consumption and ALDH2 rs671 in men with CETP rs708272 (CT and TT genotypes). Furthermore, in drinkers with ALDH2 rs671 (GA and AA genotypes), higher total cholesterol was associated with the CETP rs708272 TT minor homozygous genotype based on both HEXA and KNHANES data. Our findings demonstrated that alcohol consumption and genetic variation in either CETP or ALDH2 may be associated with cholesterol levels. We hope these findings will provide a better understanding of the relationship between alcohol consumption and cholesterol according to each individual's genetic background.

The potential effects of HECTD4 variants on fasting glucose and triglyceride levels in relation to prevalence of type 2 diabetes based on alcohol intake.

Excessive alcohol intake is an important cause of major public health problem in East Asian countries. Growing evidence suggests that genetic factors are associated with alcohol consumption and the risk for alcohol-associated disease, and these factors contribute to the risk of developing chronic diseases, including diabetes. This study aims to investigate the association of type 2 diabetes with genetic polymorphisms within HECTD4 based on alcohol exposure. We performed a genome-wide association study involving the cohorts of the KoGES-HEXA study (n = 50,028) and Ansan and Ansung study (n = 7,980), both of which are prospective cohort studies in Korea. The top three single-nucleotide polymorphisms (SNPs) of the HECTD4 gene, specifically rs77768175, rs2074356 and rs11066280, were found to be significantly associated with alcohol consumption. We found that individuals carrying the variant allele in these SNPs had lower fasting blood glucose, triglyceride, and GGT levels than those with the wild-type allele. Multiple logistic regression showed that statistically significant associations of HECTD4 gene polymorphisms with an increased risk of type 2 diabetes were found in drinkers. Namely, these SNPs were associated with decreased odds of diabetes in the presence of alcohol consumption. As a result of examining the effect of alcohol on the expression of the HECTD4 gene, ethanol increased the expression of HECTD4 in cells, but the level was decreased by NAC treatment. Similar results were obtained from liver samples of mice treated with alcohol. Moreover, a loss of HECTD4 resulted in reduced levels of CYP2E1 and lipogenic gene expression in ethanol-treated cells, while the level of ALDH2 expression increased, indicating a reduction in ethanol-induced hepatotoxicity.

Synergistic effect between the KCNQ1 haplotype and alcohol consumption on the development of type 2 diabetes mellitus in Korean cohorts.

Potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM). Association studies between KCNQ1 genetic variants and T2DM have been reported. The multifactorial disease T2DM is caused by interactions between genetic susceptibility and environmental factors. In this study, we examined the associations between the KCNQ1 haplotype, which consists of the major alleles rs3852528, rs11024175, and rs2237892 (ht: ACC), and environmental factors such as alcohol consumption, which are related to the risk of T2DM, in two independent Korean populations. Data from health examination studies, i.e., HEXA (n = 50,357 subjects) and the Ansung-Ansan community-based Korean cohort study (n = 7603), were analyzed. In both cohorts, fasting blood glucose levels were significantly increased in moderate-to-heavy drinkers and carriers of the homozygous ACC haplotype. A significant association between the KCNQ1 haplotype and alcohol consumption in the risk of diabetes was observed in the HEXA (OR 1.587; 95% CI 1.128-2.234) and Ansung-Ansan (OR 2.165; 95% CI 1.175-3.989) cohorts compared with abstainers not carrying the KCNQ1 haplotype. Associations of the KCNQ1 haplotype with alcohol consumption and ß-cell function were observed in the Ansung-Ansan cohort. Moderate-to-heavy drinkers with the ACC haplotype had lower fasting insulin levels and mean 60 min insulinogenic index (IGI60) compared with light drinkers and abstainers not carrying the ACC haplotype. These findings indicate that KCNQ1 variants play a synergistic role with alcohol consumption in the development of T2DM and impaired ß-cell function.

Association between KCNJ11 rs5219 variant and alcohol consumption on the effect of insulin secretion in a community-based Korean cohort: a 12-year follow-up study.

Chronic alcohol consumption is known to be associated with type 2 diabetes (T2D), which is developed by two underlying mechanisms, ß-cell dysfunction and insulin resistance. Identification of genetic variants in association with the development of T2D may help explain the genetic risk factors of T2D. In this study, we tried to find out some genetic variations, which interact with alcohol consumption and also are associated with ß-cell function through 12 year's follow-up study in Korean population. We performed a genotype association study using the community-based Ansung-Ansan Cohort data (baseline n = 3120; follow-up n = 433). Genotype association analyses of the baseline data showed that alcohol consumption is associated with the decreases of blood insulin levels and insulin secretion in participants with the KCNJ11 rs5219 risk allele. Moreover, multivariate logistic regression analyses revealed that the risk allele group is vulnerable to impairment of ß-cell function in response to alcohol consumption (OR 1.450; 95% CI 1.061-1.982). Furthermore, 12-year' follow-up results showed that alcohol consumption synergistically decreases insulin secretion in participants with KCNJ11 rs5219 risk alleles. Our findings demonstrate that the KCNJ11 rs5219 risk allele in combination with alcohol consumption could be a potential risk factor of ß-cell dysfunction. We hope that this new findings could be helpful to further understand the development of T2D depending on individual genetic background in association with alcohol consumption.

Factors Associated With Viral Load Kinetics of Middle East Respiratory Syndrome Coronavirus During the 2015 Outbreak in South Korea.

We conducted a retrospective study of Middle East respiratory syndrome coronavirus (MERS-CoV) viral load kinetics using data from patients hospitalized with MERS-CoV infection between 19 May and 20 August 2015. Viral load trajectories were considered over the hospitalization period using 1714 viral load results measured in serial respiratory specimens of 185 patients. The viral load levels were significantly higher among nonsurvivors than among survivors (P = .003). Healthcare workers (P = .001) and nonspreaders (P < .001) had significantly lower viral loads. Viral RNA was present on the day of symptom onset and peaked 4-10 days after symptom onset.

Amino Acid Metabolites Associated with Chronic Kidney Disease: An Eight-Year Follow-Up Korean Epidemiology Study.

The discovery of metabolomics-based biomarkers has been a focus of recent kidney dysfunction research. In the present study, we aimed to identify metabolites associated with chronic kidney disease (CKD) in the general population using a cross-sectional study design. At baseline, 6.5% of subjects had CKD. Pearson correlation analysis showed that 28 metabolites were significantly associated with estimated glomerular filtration rate (eGFR) after Bonferroni correction. Among these metabolites, 4 acylcarnitines, 12 amino acids, 4 biogenic amines, 1 phosphatidylcholine, and 1 sphingolipid were associated with CKD (p < 0.05). After eight years, 13.5% of subjects had CKD. Three amino acid metabolites were positively associated with new-onset CKD: citrulline [odds ratio (OR): 2.41, 95% confidence interval (CI): 1.26-4.59], kynurenine (OR: 1.98, 95% CI: 1.05-3.73), and phenylalanine (OR: 2.68, 95% CI: 1.00-7.16). The kynurenine:tryptophan ratio was also associated with CKD (OR: 3.20; 95% CI: 1.57-6.51). The addition of multiple metabolites significantly improved the CKD prediction by C statistics (0.756-0.85, p < 0.0001), and the net reclassification improvement was 0.84 (95% CI: 0.72-0.96). Elevated hs-C reactive protein (CRP) was associated with new-onset CKD (OR: 1.045, 95% CI: 1.005-1.086); however, this association disappeared following adjustment with the kynurenine:tryptophan ratio. The levels of citrulline and kynurenine and their ratio to tryptophan in CKD patients with proteinuria were worse than those with one or neither characteristic. Together, the results of this study demonstrate that amino acid metabolites are associated with CKD eight years after initial metabolite assessment. These results could improve the identification of subjects at high risk of CKD who have modified amino acid metabolism.

Association between the incidence of hypertension and alcohol consumption pattern and the alcohol flushing response: A 12-year follow-up study.

BACKGROUND: Alcohol consumption is associated with hypertension, and this association depends on the alcohol consumption pattern and alcohol flushing response. In this 12-year follow-up study, we investigated the relationship between the alcohol consumption pattern and incidence of hypertension in the Korean population. METHODS: We analyzed 1,366 Korean participants in the Ansung-Ansan cohort study without hypertension at baseline. The subjects were classified into four alcohol consumption patterns: never-drinking, light alcohol consumption, moderate alcohol consumption, and heavy alcohol consumption, and as flushers or non-flushers in response to alcohol. RESULTS: In flushers, moderate and heavy alcohol consumption patterns increased the risk of incident hypertension compared with never-drinkers [moderate: HR 1.811 (95% CI 1.084-3.028); heavy: HR 2.494 (95% CI 1.185-5.247)], but non-flushers were not associated with increased risk of incident hypertension according to the alcohol consumption pattern. In addition, a heavy alcohol consumption pattern increased the risk of hypertension among flushers compared with non-flushers [HR 2.232 (95% CI 1.054-4.728)]. CONCLUSION: In this 12-year follow-up study, we observed that moderate and heavy alcohol consumption was associated with an increased risk of hypertension in flushers. Especially, a heavy alcohol consumption pattern in flushers markedly increased the risk of hypertension.

Protective Effects of Dietary MUFAs Mediating Metabolites against Hypertension Risk in the Korean Genome and Epidemiology Study.

BACKGROUND AND AIMS: Metabolites related to dietary factors can be used to identify biological markers to prevent metabolic disease. However, most studies have been conducted in the United States and Europe, and those in the Asian region are limited. We investigated the effects of dietary monounsaturated fatty acids (MUFAs) and metabolites on new-onset hypertension in the Korean Genome and Epidemiology Study. METHOD AND RESULTS: A total of 1529 subjects without hypertension were divided into tertiles of dietary MUFAs intake. After a 4-year follow-up, 135 serum metabolites were measured using the AbsoluteIDQ p180 kit. During the 4-year follow-up period, 193 new-onset hypertension incidences were observed. The highest MUFAs intake group was inversely associated with the risk of hypertension compared with the lowest MUFAs intake group (odds ratio (OR) = 0.49, (95% confidence interval (CI) = 0.29-0.82)). Of the 135 metabolites, eight were significantly associated with MUFAs intake. Phosphatidylcholine-diacyl (PC aa) C 38:1 and hydroxysphingomyelin (SM OH) C 16:1 were associated with a decrease in hypertension risk (PC aa C 38:1, OR = 0.60 (95% CI = 0.37-0.96); SM OH C 16:1, OR = 0.42 (95% CI = 0.20-0.90)). The highest MUFAs intake group had a significantly decreased risk of hypertension, even considering PC aa C 38:1 and SM (OH) C 16:1 as a mediator. CONCLUSION: We confirmed that dietary MUFAs intake, and PC aa C 38:1 and SM (OH) C 16:1 had protective effects against hypertension. Furthermore, high MUFAs intake combined with PC aa C 38:1 and SM (OH) C 16:1 has the most significant effect on reducing the risk hypertension.

The association between alcohol metabolism and genetic variants of ADH1A, SRPRB, and PGM1 in Korea.

BACKGROUND: Excessive alcohol consumption is a major public health problem in East Asian countries. Alcohol use leads to a cascade of problems including increased chances of risky behavior and a wide range of negative health consequences, from alcoholic liver disease to upper gastric and liver cancer. These alcohol effects are known to be influenced by ethnic variability and genetics. METHODS: In this study, subjects were administered a single dose of alcohol (0.6 g/kg for men or 0.4 g/kg for women), and blood alcohol and acetaldehyde concentrations were measured eight times over 5 hours. To investigate genetically susceptible factors to alcohol metabolism, we selected single-nucleotide polymorphisms (SNP) of genes identified by prior genetic association studies for alcohol metabolism, alcohol consumption, alcohol dependence, and related traits, and performed genotyping on all subjects (n = 104). RESULTS: We identified variations in the ADH1A, SRPRB, and PGM1 genes, which are directly associated with blood alcohol or acetaldehyde concentrations. Namely, the T allele of SRPRB rs17376019 and the C allele of PGM1 rs4643 were associated with lower blood alcohol levels, while the ADH1 rs1229976 C allele group exhibited markedly higher blood acetaldehyde levels than those of the ADH1 rs1229976 T allele group. CONCLUSION: This study demonstrates that genetic variations in ADH1A, SRPRB, and PGM1 are associated with variations in blood alcohol and acetaldehyde concentration after alcohol intake.

Association between alcohol intake and incident hypertension in the Korean population.

BACKGROUND AND AIMS: Alcohol consumption is generally associated with increased risk of hypertension. However, the effect of alcohol intake on the incidence of hypertension remains controversial due to inconsistent results across studies. We investigated the association between alcohol intake and hypertension in a Korean population. METHODS AND RESULTS: The two studies that we evaluated herein, the CAVAS study (N = 6259) and the Ansan-Ansung study (N = 2461), were part of the Korean Genome and Epidemiology study on participants aged between 40 and 69 years who underwent community-based health checkups (2 years for the CAVAS study follow-up and 12 years for the Ansan-Ansung study follow-up). We categorized the participants into four groups based on baseline and follow-up period measurements. We found that baseline alcohol consumption increased the risk of incident hypertension in the CAVAS study [HR (95% CI), low: 1.094 (0.848-1.411); intermediate: 1.661 (1.227-2.141); high: 1.723 (1.274-2.330)]. Intermediate and high alcohol consumption were associated with increased risk of incident hypertension in men [2.086 (1.438-3.027) for intermediate, and 1.952 (1.294-2.944) for high], but only women had increased risk of incident hypertension with high consumption [1.950 (1.100-3.455)]. In addition, we found a positive association between the alcohol consumption pattern (over 10 years) and the risk of incident hypertension in the Ansan-Ansung study [HR (95% CI), light: 1.316 (1.126-1.539); moderate: 1.445 (1.193-1.750); heavy: 1.897 (1.488-2.419)]. Moderate and heavy consumption patterns carried higher risks of incident hypertension compared with never-drinking in men [moderate: 1.292 (1.033-1.617); heavy: 1.703 (1.293-2.242)], but women with light consumption patterns were at increased risk of incident hypertension [1.572 (1.302-1.899)]. CONCLUSIONS: This large prospective cohort study revealed a linear association between baseline alcohol consumption, subsequent alcohol consumption patterns (over more than 10 years), and hypertension risk in the Korean population.

Association between alcohol consumption pattern and the incidence risk of type 2 diabetes in Korean men: A 12-years follow-up study.

Moderate alcohol consumption is generally associated with reduced risk of type 2 diabetes. However, this beneficial effects of alcohol intake remains controversial due to inconsistent results across studies. The analysis was performed using data from the Ansung-Ansan cohort study. We categorized the participants into four groups-based on the baseline (one-point measure; non-drinking, <5 g/day, ≥5, <30 g/day, and ≥30 g/day) and follow-up (consumption pattern; never-drinking, light, moderate, and heavy drinking) measurement. At baseline, ≥30 g/day alcohol consumption increased the risk of incident diabetes (HR: 1.42; 95% CI, 1.10-1.85), but ≥5, <30 g/day alcohol consumption had no effects on the incident diabetes. Meanwhile, when using the alcohol consumption pattern, a heavy-drinking pattern increased the risk of incident diabetes (HR = 1.32, 1.01-1.73), but the light and moderate consumption pattern was associated with a reduced risk of type 2 diabetes (HR: 0.66; 0.50-0.87 and HR: 0.74; 0.57-0.95, respectively). At the end point of follow-up, the insulinogenic index (IGI), but not the insulin sensitivity index (ISI), differed among the groups. Alcohol consumption pattern had a J-shaped association with the incident type 2 diabetes in Korean men. The IGI showed an inverted J-shaped association according to alcohol drinking pattern, but the ISI was not a J-shape.

Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with ß-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. METHODS: Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. RESULTS: ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. CONCLUSIONS: Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. LAY SUMMARY: Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.

The Association between Alcohol Consumption and ß-Cell Function and Insulin Sensitivity in Korean Population.

This cross-sectional study was performed to examine the association between alcohol consumption and insulin secretion and sensitivity using the Korean Genome and Epidemiology Study. Alcohol consumption levels were categorized into four groups: (i) abstainers, (ii) low (<5 g/day), (iii) intermediate (<30 g/day), and (iv) high (≥30 g/day) alcohol consumption. ß-cell function and insulin sensitivity were estimated using the insulinogenic index (IGI60), and Matsuda insulin sensitivity index (ISI), respectively. IGI60 and ISI were dichotomized into high and low groups using median cut-off values and four groups were defined (G-I: high IGI60/high ISI; G-II: high IGI60/low ISI; G-III: low IGI60/high ISI; and G-IV: low IGI60/low ISI). Men consumed 26.5 g alcohol per day on average, whereas women only consumed 5.7 g/day, so women were excluded from subsequent analyses due to their low drinking levels. Alcohol consumption was positively associated with high-density lipoprotein (HDL) cholesterol, aspartate aminotransferase (AST), and triglycerides (TG) in men, but was negatively associated with IGI60 (p < 0.05). TG levels were only increased in individuals with decreased insulin sensitivity (G-II) or decreased ß-cell function (G-III) with high alcohol consumption. In addition, alcohol consumption increased HDL cholesterol in the four groups (p < 0.001). In subjects with decreased insulin sensitivity (G-II), intermediate and high alcohol consumption increased the risk of high cholesterol and TG. In individuals with decreased ß-cell function (G-III), alcohol consumption increased the risk of high TG and high AST levels. High alcohol consumption was significantly associated with reduced insulin secretion. In addition, alcohol consumption was related to some metabolic risk factors depending on insulin secretion or sensitivity.