The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice.

Interleukin (IL)-1ß plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE−/−) mice. ApoE−/− mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE−/− mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE−/− mice and suppressed inflammatory genes (IL-1ß and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk.

Comparison of pancreatic volume and fat amount linked with glucose homeostasis between healthy Caucasians and Koreans.

AIM: To compare pancreatic volume and fat amount, and their associations with glucose homeostasis, in a Korean and a white population. MATERIALS AND METHODS: In 43 healthy Korean and 43 healthy white people, matched for age (±3 years) and body mass index (BMI; ±1 kg/m2 ), we measured pancreatic volume and fat amount in the pancreas and abdomen using computed tomography. Pancreatic ß-cell function and insulin resistance were estimated according to biochemical characteristics and a 75-g oral glucose tolerance test. Body composition and resting energy expenditure (REE) were examined using bioimpedance and indirect calorimetry, respectively. RESULTS: The mean ±SD age of the participants was 29.9 ± 5.9 years and 30.0 ± 5.2 years, and BMI was 24.0 ±3.7 and 24.1 ±3.2 kg/m2 in the white participants and the Korean participants, respectively. Pancreatic volume in the white participants was greater than that in Korean participants (77.8 ±11.6 vs 68.2 ±12.1 cm3 ; P < .001). Pancreatic fat content in Korean participants was 22.8% higher than in white participants (P = .051). Insulinogenic index, disposition index, muscle mass and REE were significantly lower in Korean participants. Pancreatic volume was positively associated with indices linked to ß-cell function; fat content in the pancreas was negatively associated with such indices, and positively with insulin resistance after adjusting for relevant variables including REE. CONCLUSIONS: A smaller pancreas and higher fat deposition might be crucial determinants of vulnerability to diabetes in Korean people compared with white people with similar BMI and body fat levels.

A genome-wide association study on thyroid function and anti-thyroid peroxidase antibodies in Koreans.

Genetic factors are thought to be an important determinant of thyroid function and autoimmunity. However, there are limited data on genetic variants in Asians. In this study, we performed a genome-wide association study on plasma thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentration and anti-thyroid peroxidase (anti-TPO) antibody positivity in 4238 Korean subjects. In the Stage 1 genome scan, 3396 participants from the Ansung cohort were investigated using 1.42 million genotyped or imputed markers. In the Stage 2 follow-up, 10 markers were genotyped in 842 participants from the Korean Longitudinal Study on Health and Aging cohort. An intronic variant in VAV3, rs12126655, which has been reported in Europeans, was significantly associated with plasma TSH concentration in the joint Stages 1 and 2 analyses (P = 2.2 × 10(-8)). We observed that a novel variant, rs2071403, located 75 bp proximal to the translational start site of TPO was significantly associated with plasma anti-TPO antibody positivity in the joint Stages 1 and 2 analyses (P = 1.3 × 10(-10)). This variant had a marginal sex-specific effect, and its association was more significant in females. Subjects possessing the rs2071403A allele, associated with an absence of the anti-TPO antibody, had decreased TPO mRNA expression in their thyroid tissue. Another intronic variant of HLA-DPB2, rs733208, had a suggestive association with anti-TPO antibody positivity (P = 4.2 × 10(-7)). In conclusion, we have identified genetic variants that are strongly associated with TSH level and anti-TPO antibody positivity in Koreans. Further replications and meta-analysis are required to confirm these findings.

Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is an emerging metabolic regulator associated with glucose and lipid metabolism. However, previous studies of FGF21 have been largely confounded by obesity, and data are limited for advanced outcomes such as coronary artery disease (CAD) and ectopic fat accumulation. We investigated the associations between serum FGF21 concentrations and glucose/lipid metabolism, CAD, and pericardial fat deposition in subjects strictly matched for obesity parameters. DESIGN, PATIENTS AND MEASUREMENTS: We enrolled 189 patients who had undergone cardiac multidetector coronary computed tomography. We measured cardiometabolic parameters and serum FGF21 levels within body mass index (BMI)-matched groups. Correlations and linear regressions were analysed among serum FGF21 levels, pericardial fat volumes and cardiometabolic parameters. Serum FGF21 concentrations were compared in patients with and without diabetes, metabolic syndrome (MS) or CAD. RESULTS: Serum FGF21 concentrations were significantly higher in BMI-matched patients with MS (107·2 ± 83·6 vs 82·1 ± 67·4 ng/l without MS, P < 0·05), but not among those with diabetes (84·3 ± 56·4 vs 96·3 ± 98·9 ng/l without diabetes, P = 0·300) or CAD (89·6 ± 65·8 vs 84·2 ± 83·1 ng/l without CAD, P = 0·633). Serum FGF21 concentrations correlated positively with triglycerides, low-density lipoprotein-cholesterol, insulin, HOMA-IR and pericardial fat volume. They showed an independent association with pericardial fat volume (ß = 0·111 ± 0·053, P < 0·05). CONCLUSIONS: Serum FGF21 concentrations were significantly associated with lipid profiles, insulin resistance, pericardial fat volume and MS, independently of obesity, but not with overt CAD or diabetes.

Prediction of type 2 diabetes in women with a history of gestational diabetes using a genetic risk score.

AIMS/HYPOTHESIS: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of future development of type 2 diabetes. Recently, over 65 genetic variants have been confirmed to be associated with diabetes. We investigated whether this genetic information could improve the prediction of future diabetes in women with GDM. METHODS: This was a prospective cohort study consisting of 395 women with GDM who were followed annually with an OGTT. A weighted genetic risk score (wGRS), consisting of 48 variants, was assessed for improving discrimination (C statistic) and risk reclassification (continuous net reclassification improvement [NRI] index) when added to clinical risk factors. RESULTS: Among the 395 women with GDM, 116 (29.4%) developed diabetes during a median follow-up period of 45 months. Women with GDM who went on to develop diabetes had a significantly higher wGRS than those who did not (9.36 ± 0.92 vs 8.78 ± 1.07; p < 1.56 × 10(-7)). In a complex clinical model adjusted for age, prepregnancy BMI, family history of diabetes, blood pressure, fasting glucose and fasting insulin concentration, the C statistic marginally improved from 0.741 without the wGRS to 0.775 with the wGRS (p = 0.015). The addition of the wGRS to the clinical model resulted in a modest improvement in reclassification (continuous NRI 0.430 [95% CI 0.218, 0.642]; p = 7.0 × 10(-5)). CONCLUSIONS/INTERPRETATION: In women with GDM, who are at high risk of diabetes, the wGRS was significantly associated with the future development of diabetes. Furthermore, it improved prediction over clinical risk factors.

Plasma FGF21 levels are increased in patients with hypothyroidism independently of lipid profile.

Thyroid hormone is a potent regulator of metabolic and energy homeostasis implicated in various metabolic diseases. Fibroblast growth factor 21(FGF21) is a systemic metabolic regulator known to modulate various biological functions similar to the actions of thyroid hormone. We investigated the differences in plasma FGF21 concentrations in patients with varying thyroid function. Ninety drug-naïve subjects who underwent thyroid evaluation at Seoul National University Bundang Hospital were enrolled and classified into euthyroid, subclinical hypothyroid, and overtly hypothyroid groups. Biochemical markers and plasma FGF21 levels were measured and analyzed. The mean age of the subjects was 42.6 ± 9.1 years. The mean body mass index (BMI), waist circumference, and fasting glucose concentrations were similar between groups. Overtly hypothyroid subjects exhibited significantly higher concentrations of total cholesterol, triglyceride, and LDL-cholesterol than the other groups (p<0.01). Mean plasma FGF21 concentrations in euthyroid, subclinical hypothyroid and overtly hypothyroid groups were 43.2 ± 39.2 pg/mL, 63.6 ± 73.6 pg/mL, and 101.5 ± 74.9 pg/mL, respectively (p<0.01 between groups). Plasma FGF21 concentrations remained significantly higher in overtly hypothyroid subjects after adjusting for serum triglyceride concentrations (p<0.005). Multivariate analysis revealed a significant positive linear relationship between serum TSH concentrations and plasma FGF21 concentrations (ß = 0.192, p = 0.002) and a significant negative linear relationship between free T4 and plasma FGF21 concentrations (ß = -0.382, p = 0.037) after adjusting for gender, BMI and serum concentrations of triglycerides and glucose. Plasma FGF21 levels were significantly increased in patients with hypothyroidism independently of BMI, or lipid or glucose metabolism.

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition.

To investigate the role of genetic predisposition in the pathogenesis of polycystic ovary syndrome (PCOS) in relation to obesity, we performed a genome-wide association study of PCOS in Koreans (n=1741). PCOS is a heterogeneous endocrinal disorder of uncertain etiology. Obesity is one of the well-known risk factors for PCOS. Genome-wide association study. Women with or without PCOS. A total of 1881 samples were genotyped using Illumina HumanOmni1 Quad v1 and processed by R packages. The PCOS patients were divided into two subgroups according to PCOS diagnostic criteria (Rotterdam and National Institutes of Health (NIH)). For PCOS-associated loci in the two definitions, we successfully confirmed significant associations of GYS2 for body mass index in the discovery stage. We further replicated pleiotropic associations of GYS2 in a childhood obesity study (n=482) and in a gestational diabetes study (n=1710), respectively. Our study provides a preliminary framework upon diverse genetic effects underlying PCOS in Korean women. A newly identified GYS2 gene as a predisposing factor of PCOS might expand understanding of the biological pathways in metabolic and endocrine regulation.

Bisphenol A impairs mitochondrial function in the liver at doses below the no observed adverse effect level.

Bisphenol A (BPA) has been reported to possess hepatic toxicity. We investigated the hypothesis that BPA, below the no observed adverse effect level (NOAEL), can induce hepatic damage and mitochondrial dysfunction by increasing oxidative stress in the liver. Two doses of BPA, 0.05 and 1.2 mg/kg body weight/day, were administered intraperitoneally for 5 days to mice. Both treatments impaired the structure of the hepatic mitochondria, although oxygen consumption rate and expression of the respiratory complex decreased only at the higher dose. The hepatic levels of malondialdehyde (MDA), a naturally occurring product of lipid peroxidation, increased, while the expression of glutathione peroxidase 3 (GPx3) decreased, after BPA treatment. The expression levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) also increased. In HepG2 cells, 10 or 100 nM of BPA also decreased the oxygen consumption rate, ATP production, and the mitochondrial membrane potential. In conclusion, doses of BPA below the NOAEL induce mitochondrial dysfunction in the liver, and this is associated with an increase in oxidative stress and inflammation.

Plasma vaspin concentrations are elevated in metabolic syndrome in men and are correlated with coronary atherosclerosis in women.

OBJECTIVE: Vaspin is visceral adipose-tissue-derived adipokine, which has an insulin-sensitizing effect in obese type 2 diabetic rodent models. As adipokines may serve as a link between visceral adiposity and atherosclerosis, we investigated whether plasma vaspin concentrations were associated with the metabolic syndrome and coronary atherosclerosis. DESIGN AND METHODS: We measured fasting plasma vaspin levels in 81 subjects with the metabolic syndrome and 241 age- and sex-matched control subjects without the metabolic syndrome using the enzyme-linked immunosorbent assay. Multi-detector row cardiac computed tomography was performed to evaluate coronary atherosclerosis. We analysed sex-specific plasma vaspin concentrations according to the presence of the metabolic syndrome and the severity of coronary atherosclerosis. RESULTS: Plasma vaspin concentrations were significantly higher in men with the metabolic syndrome compared with those without the metabolic syndrome [median 0·60 (inter-quartile range 0·40-0·99) ng/ml vs 0·40 (0·26-0·66) ng/ml, P = 0·002]. There was a positive correlation between plasma vaspin concentrations and body mass index, waist circumference, and per cent body fat in men. However, these relationships were not found in women. Plasma vaspin concentrations were associated with the presence and severity of coronary artery stenosis such as higher Agatstone calcium score, number of diseased vessels and characteristics of coronary artery plaque only in women. CONCLUSIONS: Higher plasma vaspin concentrations are significantly associated with metabolic syndrome in men. In women, vaspin concentrations are associated with coronary atherosclerosis. Further studies regarding the role of vaspin in the pathogenesis of obesity and atherosclerosis are required.

Retinol-binding protein-4 was associated with sensitization to inhalant allergens in the elderly population.

BACKGROUND/AIMS: Recent evidence suggests an association between allergic sensitization and metabolic markers. However, this association has rarely been examined in the elderly. Retinol-binding protein-4 (RBP-4) is a recently identified adipokine that acts on the muscle and liver affecting insulin sensitivity. We evaluated the association between metabolic parameters and allergic sensitization in the elderly. METHODS: We analysed the database of the Korean Longitudinal Study on Health and Aging cohort study conducted during 2005 to 2006. Atopy was identified by inhalant allergen skin prick test. Metabolic conditions were assessed using anthropometric indices and serum biomarkers such as fasting glucose, lipid, adiponectin, and RBP-4. RESULTS: Among the 854 elderly subjects, 17.2% had atopy. Plasma RBP-4 levels were significantly higher in the atopic elderly than nonatopic elderly (p = 0.003). When RBP-4 percentiles were categorized as under three groups, the prevalence of atopy and current rhinitis increased significantly with percentiles of RBP-4 levels (p = 0.019 and p = 0.007, respectively). Log RBP-4 was associated with atopy (odds ratio [OR], 4.10; p = 0.009) and current rhinitis (OR, 2.73; p = 0.014), but not with current asthma (OR, 1.17; p = 0.824). Higher RBP-4 level in atopic elderly was also observed in current rhinitis patients. Atopy, but not current rhinitis, showed significant relationships with log RBP-4 levels in multivariate analyses adjusted for other metabolic markers including body mass index. CONCLUSION: RBP-4 positively associated with atopy in the general elderly population irrespective of other metabolic markers.

Sequencing Cell-free Fetal DNA in Pregnant Women With GCK-MODY.

CONTEXT: Individuals with monogenic diabetes due to inactivating glucokinase (GCK) variants typically do not require treatment, except potentially during pregnancy. In pregnancy, fetal GCK genotype determines whether treatment is indicated, but noninvasive methods are not clinically available. OBJECTIVE: This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA. METHODS: This was a proof-of-concept study involving 3 pregnant women with a causal GCK variant that used information from 1) massive parallel sequencing of maternal plasma cell-free DNA, 2) direct haplotype sequences of maternal genomic DNA, and 3) the paternal genotypes to estimate relative haplotype dosage of the pathogenic variant-linked haplotype. Statistical testing of variant inheritance was performed using a sequential probability ratio test (SPRT). RESULTS: In each of the 3 cases, plasma cell-free DNA was extracted once between gestational weeks 24 and 36. The fetal fraction of cell-free DNA ranged from 21.8% to 23.0%. Paternal homozygous alleles that were identical to the maternal GCK variant-linked allele were not overrepresented in the cell-free DNA. Paternal homozygous alleles that were identical to the maternal wild-type-linked allele were significantly overrepresented. Based on the SPRT, we predicted that all 3 cases did not inherit the GCK variant. Postnatal infant genotyping confirmed our prediction in each case. CONCLUSION: We have successfully implemented a noninvasive method to predict fetal GCK genotype using cell-free DNA in 3 pregnant women carrying an inactivating GCK variant. This method could guide tailoring of hyperglycemia treatment in pregnancies of women with GCK monogenic diabetes.

Interaction between cigarette smoking and iodine intake and their impact on thyroid function.

OBJECTIVE: Several population-based studies in iodine-deficient areas have shown an association between smoking and thyroid function. There are no population-based studies about the effects of smoking in iodine-sufficient areas. We examined the effect of smoking on thyroid function and the association with iodine intake in Korea, an area with sufficient iodine intake, much more than recommended by the World Health Organization (WHO). DESIGN: Of 5018 subjects in a population-based cohort, we included 3399 who had no history of thyroid disease were not taking thyroid medication and whose blood samples were available for measurement of thyroid function. MEASUREMENTS: Thyroid function test, questionnaire about smoking status and dietary intake. RESULTS: Of 3399 subjects, 397(11.7%) had subclinical hypothyroidism (SCH). Female sex was an independent risk factor for SCH. Multivariate analysis in female subjects showed the following were independent risk factors for SCH: older age, positive antithyroid peroxidase (anti-TPO) antibody status and iodine intake, whereas current smoking was inversely related with SCH. However, in male subjects, only age showed a weak association with SCH. When the interaction between smoking and other risk factors was analysed, smoking showed no association with anti-TPO antibody status, whereas it showed a significant negative interaction with iodine intake (odds ratio, 0.930; 95% CI, 0.869-0.996; P = 0.037). Furthermore, the risk for SCH was observed only in the never-smoker group; however, it was abolished in current- and ex-smoker groups. CONCLUSION: Cigarette smoking was associated with a lower prevalence of SCH in a negative interaction with iodine intake.

Subclinical hypothyroidism has little influences on muscle mass or strength in elderly people.

Sarcopenia, the age-related decline in muscle mass, affects the muscle strength and muscle quality, and these changes decrease functional capacity. The prevalence of thyroid dysfunction increases with age, and changes in thyroid hormone level lead to neuromuscular deficits. We investigated the effects of subclinical hypothyroidism on the muscle mass, strength or quality in elderly people. One thousand one hundred eighteen subjects aged > or = 65 yr were randomly selected from a local population and classified into a euthyroid (280 men and 358 women), subclinically hypothyroid (61 men and 75 women), or overtly hypothyroid (7 men and 16 women) group. Although women with subclinical hypothyroidism had a higher prevalence of sarcopenia, defined according to the ratio of appendicular skeletal muscle mass to the square of height, muscle mass, strength or quality did not differ in relation to thyroid status in men or in women. Multivariate analysis including age, diabetes, hypertension, acute coronary event, alcohol, smoking, presence of pain, physical activity score, and lipid profile, showed that thyroid-stimulating hormone level was not associated with muscle mass, strength or quality. In conclusion, subclinical hypothyroidism has little influences on muscle mass, strength or quality, and may not be associated with sarcopenia.

A Randomized Trial Evaluating the Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec With or Without Metformin, in Adults With Type 2 Diabetes (ONSET 9).

OBJECTIVE: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp), both with insulin degludec with or without metformin, in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, treat-to-target trial randomized participants to faster aspart (n = 546) or IAsp (n = 545). All available information, regardless of treatment discontinuation or use of ancillary treatment, was used for evaluation of effect. RESULTS: Noninferiority for the change from baseline in HbA1c 16 weeks after randomization (primary end point) was confirmed for faster aspart versus IAsp (estimated treatment difference [ETD] -0.04% [95% CI -0.11; 0.03]; -0.39 mmol/mol [-1.15; 0.37]; P < 0.001). Faster aspart was superior to IAsp for change from baseline in 1-h postprandial glucose (PPG) increment using a meal test (ETD -0.40 mmol/L [-0.66; -0.14]; -7.23 mg/dL [-11.92; -2.55]; P = 0.001 for superiority). Change from baseline in self-measured 1-h PPG increment for the mean over all meals favored faster aspart (ETD -0.25 mmol/L [-0.42; -0.09]); -4.58 mg/dL [-7.59; -1.57]; P = 0.003). The overall rate of treatment-emergent severe or blood glucose (BG)-confirmed hypoglycemia was statistically significantly lower for faster aspart versus IAsp (estimated treatment ratio 0.81 [95% CI 0.68; 0.97]). CONCLUSIONS: In combination with insulin degludec, faster aspart provided effective overall glycemic control, superior PPG control, and a lower rate of severe or BG-confirmed hypoglycemia versus IAsp in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen.

Estimated Association Between Cytokines and the Progression to Diabetes: 10-year Follow-Up From a Community-Based Cohort.

CONTEXT: The long-term association between multiple cytokines and progression to diabetes is still uncertain. OBJECTIVE: To identify which cytokines could predict progression to prediabetes and type 2 diabetes over 10 years. METHODS: The study included 912 participants aged 40 to 69 years at baseline from the Ansung cohort, part of the Korea Genome Epidemiology Study. At baseline, a 75-g oral glucose tolerance test and 8 cytokines were measured: plasminogen activator inhibitor 1 (PAI-1), resistin, interleukin 6, leptin, monocyte chemoattractant protein 1, tumor necrosis factor alpha, retinol binding protein 4 (RBP4), and adiponectin. People with normal glucose tolerance (NGT, n = 241) and prediabetes (n = 330) were followed-up biennially for 10 years. Multinomial logistic regression analysis was used to evaluate the predictability of cytokines on the new-onset prediabetes and type 2 diabetes. RESULTS: At 10 years, 38 (15.8%) and 82 (34.0%) of those with NGT had converted to prediabetes and type 2 diabetes, respectively. Of those with prediabetes, 228 (69.1%) had converted to type 2 diabetes. In people with NGT or prediabetes at baseline, the highest tertile of RBP4 was associated with a 5.48-fold and 2.43-fold higher risk of progression to type 2 diabetes, respectively. The odds for converting from NGT to prediabetes in the highest tertile of PAI-1 and the lowest tertile of adiponectin were 3.23 and 3.37, respectively. In people with prediabetes at baseline, those in the highest tertile of resistin were 2.94 time more likely to develop type 2 diabetes (all P < 0.05). CONCLUSIONS: In this 10-year prospective study, NGT with higher serum RBP4 and PAI-1, and with lower adiponectin were associated with new-onset prediabetes and type 2 diabetes.

A subset of microRNAs in the Dlk1-Dio3 cluster regulates age-associated muscle atrophy by targeting Atrogin-1.

BACKGROUND: The microRNAs (miRNAs) down-regulated in aged mouse skeletal muscle were mainly clustered within the delta-like homologue 1 and the type III iodothyronine deiodinase (Dlk1-Dio3) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1-Dio3 cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age-related muscle atrophy. METHODS: To examine anti-atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3' untranslated region (UTR) and RNA pull-down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo, we generated adeno-associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9-GFP) bearing miR-376c-3p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80 years) were used to investigate expression levels of the conserved miRNAs in the Dlk1-Dio3 cluster. RESULTS: We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti-atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3' UTR of muscle atrophy gene-1 (Atrogin-1) encoding a muscle-specific E3 ligase. Direct interactions were identified between these miRNAs and the 3' UTR of Atrogin-1, leading to repression of Atrogin-1 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR-376c-3p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down-regulated in human muscle from individuals > 50 years old. CONCLUSIONS: Our study suggests that genetic intervention using a muscle-directed miRNA delivery system has therapeutic efficacy in preventing Atrogin-1-mediated muscle atrophy in sarcopenia.

COVID-19 and older people in Asia: Asian Working Group for Sarcopenia calls to actions.

The coronavirus disease 2019 (COVID-19) pandemic has casted a huge impact on global public health and the economy. In this challenging situation, older people are vulnerable to the infection and the secondary effects of the pandemic and need special attention. To evaluate the impacts of COVID-19 on older people, it is important to balance the successful pandemic control and active management of secondary consequences. These considerations are particularly salient in the Asian context, with its diversity among countries in terms of sociocultural heritage, healthcare setup and availability of resources. Thus, the Asian Working Group for Sarcopenia summarized the considerations of Asian countries focusing on responses and difficulties in each country, impacts of health inequity related to the COVID-19 pandemic and proposed recommendations for older people, which are germane to the Asian context. More innovative services should be developed to address the increasing demands for new approaches to deliver healthcare in these difficult times and to establish resilient healthcare systems for older people. Geriatr Gerontol Int 2020; 9999: n/a-n/a.

Prevalence of stroke and transient ischemic attack in Korean elders: findings from the Korean Longitudinal Study on Health and Aging (KLoSHA).

BACKGROUND AND PURPOSE: Studies on the epidemiology of stroke and transient ischemic attack (TIA) are very limited in Asian elderly populations. We investigate the prevalence, risk factors, and neuropsychiatric comorbidities of stroke and TIA in community-dwelling Korean elders. METHODS: Standardized face-to-face interviews, neurological examinations, and physical examinations were conducted in 714 randomly sampled community-dwelling Korean elders aged >or=65 years. Diagnoses of stroke and TIA were made according to the World Health Organization criteria. RESULTS: Age- and education-standardized prevalences of stroke, TIA, and cerebrovascular disorder (implying stroke or TIA) were estimated to be 10.1%, 8.9%, and 15.4%, respectively, in Korean elders. Hypertension and current smoking were associated with the risk of stroke, whereas atrial fibrillation, high diastolic blood pressure, high serum low-density lipoprotein cholesterol, and hypertension were associated with the risk of TIA. Cerebrovascular disorder was associated with the risk of major depressive disorder, vascular dementia, and nonamnestic mild cognitive impairment (P<0.05). CONCLUSIONS: Prevalences of stroke and TIA in Korean elders were higher than in white elders. Stroke and TIA were associated with increased risk of depression and cognitive disorders.

Progression to Gestational Diabetes Mellitus in Pregnant Women with One Abnormal Value in Repeated Oral Glucose Tolerance Tests.

BACKGROUND: Women with one abnormal value (OAV) in a 100 g oral glucose tolerance test (OGTT) during pregnancy are reported to have an increased risk of adverse pregnancy outcomes. However, there is limited data about whether women with OAV will progress to gestational diabetes mellitus (GDM) when the OGTT is repeated. METHODS: To identify clinical and metabolic predictors for GDM in women with OAV, we conducted a retrospective study and identified women with OAV in the OGTT done at 24 to 30 weeks gestational age (GA) and repeated the second OGTT between 32 and 34 weeks of GA. RESULTS: Among 137 women with OAV in the initial OGTT, 58 (42.3%) had normal, 40 (29.2%) had OAV and 39 (28.5%) had GDM in the second OGTT. Maternal age, prepregnancy body mass index, weight gain from prepregnancy to the second OGTT, GA at the time of the OGTT, and parity were similar among normal, OAV, and GDM groups. Plasma glucose levels in screening tests were different (151.8±15.7, 155.8±14.6, 162.5±20.3 mg/dL, P<0.05), but fasting, 1-, 2-, and 3-hour glucose levels in the initial OGTT were not. Compared to women with screen negative, women with untreated OAV had a higher frequency of macrosomia. CONCLUSION: We demonstrated that women with OAV in the initial OGTT significantly progressed to GDM in the second OGTT. Clinical parameters predicting progression to GDM were not found. Repeating the OGTT in women with OAV in the initial test may be helpful to detect GDM progression.

Pregnancy Outcomes of Women Additionally Diagnosed as Gestational Diabetes by the International Association of the Diabetes and Pregnancy Study Groups Criteria.

BACKGROUND: We investigated the pregnancy outcomes in women who were diagnosed with gestational diabetes mellitus (GDM) by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria but not by the Carpenter-Coustan (CC) criteria. METHODS: A total of 8,735 Korean pregnant women were identified at two hospitals between 2014 and 2016. Among them, 2,038 women participated in the prospective cohort to investigate pregnancy outcomes. Diagnosis of GDM was made via two-step approach with 50-g glucose challenge test for screening followed by diagnostic 2-hour 75-g oral glucose tolerance test. Women were divided into three groups: non-GDM, GDM diagnosed exclusively by the IADPSG criteria, and GDM diagnosed by the CC criteria. RESULTS: The incidence of GDM was 2.1% according to the CC criteria, and 4.1% by the IADPSG criteria. Women diagnosed with GDM by the IADPSG criteria had a higher body mass index (22.0±3.1 kg/m² vs. 21.0±2.8 kg/m², P<0.001) and an increased risk of preeclampsia (odds ratio [OR], 6.90; 95% confidence interval [CI], 1.84 to 25.87; P=0.004) compared to non-GDM women. Compared to neonates of the non-GDM group, those of the IADPSG GDM group had an increased risk of being large for gestational age (OR, 2.39; 95% CI, 1.50 to 3.81; P<0.001), macrosomia (OR, 2.53; 95% CI, 1.26 to 5.10; P=0.009), and neonatal hypoglycemia (OR, 3.84; 95% CI, 1.01 to 14.74; P=0.049); they were also at an increased risk of requiring phototherapy (OR, 1.57; 95% CI, 1.07 to 2.31; P=0.022) compared to the non-GDM group. CONCLUSION: The IADPSG criteria increased the incidence of GDM by nearly three-fold, and women diagnosed with GDM by the IADPSG criteria had an increased risk of adverse pregnancy outcomes in Korea.