Comparison of laser and traditional lancing devices for capillary blood sampling in patients with diabetes mellitus and high bleeding risk.

PURPOSE: Despite the importance of self-monitoring blood glucose (SMBG) for management of diabetes mellitus (DM), frequent blood sampling is discouraged by bleeding risk due to dual-antiplatelet agent therapy (DAPT) or thrombocytopenia. METHODS: We compared the bleeding time (BT) of sampling by using a laser-lancing-device (LMT-1000) and a conventional lancet in patients with DM and thrombocytopenia or patients undergoing DAPT. BT was measured using the Duke method, and pain and satisfaction scores were assessed using numeric rating scale (NRS) and visual analog scale (VAS). The consistency in the values of glucose and glycated-hemoglobin (HbA1c) sampled using the LMT-1000 or lancet were compared. RESULTS: The BT of sampling with the LMT-1000 was shorter than that with the lancet in patients with thrombocytopenia (60s vs. 85s, P = 0.024). The NRS was lower and the VAS was higher in laser-applied-sampling than lancet-applied sampling in the DAPT-user group (NRS: 1 vs. 2, P = 0.010; VAS: 7 vs. 6, P = 0.003), whereas the group with thrombocytopenia only showed improvement in the VAS score (8 vs. 7, P = 0.049). Glucose and HbA1c sampled by the LMT-1000 and lancet were significantly correlated in both the DAPT-user and the thrombocytopenia groups. CONCLUSION: The LMT-1000 can promote SMBG by shortening BT in subject with thrombocytopenia and by increasing satisfaction score, as well as by showing reliable glucose and HbA1c value.

Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

AIM: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. MATERIALS AND METHODS: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. RESULTS: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. CONCLUSIONS: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

Implications of fasting plasma glucose variability on the risk of incident peripheral artery disease in a population without diabetes: a nationwide population-based cohort study.

BACKGROUND: Diabetes have been known as a traditional risk factor of developing peripheral artery disease (PAD). However, the study evaluating the impact of long-term glycemic variability on the risk of developing PAD is limited, especially in a general population without diabetes. METHODS: We included 152,931 individuals without diabetes from the Korean National Health Insurance Service-Health Screening Cohort. Fasting plasma glucose (FPG) variability was measured using coefficient variance (FPG-CV), standard deviation (FPG-SD), and variability independent of the mean (FPG-VIM). RESULTS: A total of 16,863 (11.0%) incident cases of PAD were identified during a median follow-up of 8.3 years. Kaplan-Meier curves showed a progressively increasing risk of PAD in the higher quartile group of FPG variability than in the lowest quartile group (log rank P < 0.001). Multivariable Cox proportional hazard analysis showed the hazard ratio for PAD prevalence as 1.11 (95% CI 1.07-1.16, P < 0.001) in the highest FPG-CV quartile than in the lowest FPG-CV quartile after adjusting for confounding variables, including mean FPG. Similar degree of association was shown in the FPG-SD and FPG-VIM. In sensitivity analysis, the association between FPG variability and the risk of developing PAD persisted even after the participants were excluded based on previously diagnosed diseases, including stroke, coronary artery disease, congestive heart failure, chronic kidney disease, or current smokers or drinkers. Subgroup analysis demonstrated that the effects of FPG variability on the risk of PAD were more powerful in subgroups of younger age, regular exercisers, and those with higher income. CONCLUSIONS: Increased long-term glycemic variability may have a significant prognostic effect for incident PAD in individuals without diabetes.

Impact of urinary iodine concentration on blood glucose levels and blood pressure: a nationwide population-based study.

PURPOSE: Iodine is a vital trace element for systemic metabolic control as well as thyroid hormone synthesis. Though iodine has significant antioxidant and anti-inflammatory effects, reports on its effects on metabolic disorders are limited and inconsistent. METHODS: Impact of urinary iodine concentrations (UICs) on fasting blood glucose (FBG) levels and blood pressure (BP) in the general Korean population was evaluated adjusting for covariates including thyrotropin level and presence of thyroid diseases. RESULTS: The median UIC was 302.3 µg/L in all participants and was significantly lower in those with dysglycemia (303.6 µg/L in normal participants, 285.1 µg/L in participants with FBG levels of 100-125 mg/dL, and 261.8 µg/L in participants with FBG levels ≥ 126 mg/dL; p = 0.002). Similarly, the UIC was lower in participants with higher BP (311.6 µg/L in normal participants, 288.7 µg/L in prehypertensive participants, and 265.8 µg/L in hypertensive participants; p < 0.001). The multiple linear regression model showed a negative correlation between the UIC and FBG levels (p = 0.002), and the UIC and systolic BP (p < 0.001). One standard deviation increase in the UIC showed odds ratios of 0.84 (95% confidence interval [CI] = 0.73-0.98) for elevated FBG levels (≥ 100 mg/dL) and 0.94 (95% CI = 0.88-0.99) for elevated SBP (≥ 120 mm Hg) after full adjustment. CONCLUSION: Higher UICs were associated with lower FBG and BP levels, independent of thyroid function and other confounding factors in Korea, an iodine-replete country.

Association of plasma FGF21 levels with muscle mass and muscle strength in a national multicentre cohort study: Korean Frailty and Aging Cohort Study.

BACKGROUND: despite of the beneficial effects of fibroblast growth factor (FGF) 21 in several metabolic diseases, the association of plasma FGF21 with muscle mass and muscle strength is still unclear. METHODS: a total of 386 community-dwelling older adults aged 70-84 years were analysed. Appendicular skeletal muscle mass was measured using dual-energy X-ray absorptiometry and normalised to the square of height (ASM/ht2). Muscle strength was assessed using the hand grip strength (HGS) test. The definitions of low muscle mass (LMM) and low muscle strength (LMS) were based on the Asian Working Group for Sarcopenia. RESULTS: plasma FGF21 was significantly lower in participants with LMM than in those with normal muscle mass (289.7 [192.4-448.3] vs. 345.6 [238.6-503.2] pg/ml, P = 0.008). In contrast, the LMS group had a significantly higher plasma FGF21 level than the normal muscle strength group (369.7 [244.4-591.1] vs. 309.7 [205.3-444.8] pg/ml, P = 0.006). In the partial correlation analysis, following adjustment for age, sex and body mass index, FGF21 levels had no significant association with ASM/ht2, but were negatively associated with HGS (r = -0.112, P = 0.029). Furthermore, after multivariate adjustment for confounding variables, the odds ratio for the risk of LMS was 2.32 (95% confidence interval 1.20-4.46) when comparing the highest with the lowest FGF21 quartile. CONCLUSIONS: circulating FGF21 levels are negatively associated with muscle strength but are not independently correlated with muscle mass.

Sarcopenia is associated with decreased gray matter volume in the parietal lobe: a longitudinal cohort study.

BACKGROUND: Substantial evidence supports an association between physical activity and cognitive function. However, the role of muscle mass and function in brain structural changes is not well known. This study investigated whether sarcopenia, defined as low muscle mass and strength, accelerates brain volume atrophy. METHODS: A total of 1284 participants with sarcopenic measurements and baseline and 4-year follow-up brain magnetic resonance images were recruited from the Korean Genome and Epidemiology Study. Muscle mass was represented as appendicular skeletal muscle mass divided by the body mass index. Muscle function was measured by handgrip strength. The low mass and strength groups were defined as being in the lowest quintile of each variable for one's sex. Sarcopenia was defined as being in the lowest quintile for both muscle mass and handgrip strength. RESULTS: Of the 1284 participants, 12·6%, 10·8%, and 5·4% were classified as the low mass, low strength, and sarcopenia groups, respectively. The adjusted mean changes of gray matter (GM) volume during 4-year follow-up period were - 9·6 mL in the control group, whereas - 11·6 mL in the other three groups (P < 0·001). The significantly greater atrophy in parietal GM was observed in the sarcopenia group compared with the control group. In a joint regression model, low muscle mass, but not muscle strength, was an independent factor associated with a decrease of GM volume. CONCLUSIONS: Sarcopenia is associated with parietal GM volume atrophy, in a middle-aged population. Maintaining good levels of muscle mass could be important for brain health in later adulthood.

Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study.

BACKGROUND: We aimed to investigate the hazard of hospitalization for heart failure (hHF) according to the transitions in metabolic health and obesity status. METHODS: The Korean National Health Insurance Service datasets from 2002 to 2017 were used for this nationwide, longitudinal, population-based study. The hazard of hHF was analyzed according to the eight groups stratified by stability in metabolic health and transition in obesity status among initially metabolically healthy adults who underwent two cycles of health examinations in 2009-2010 and 2013-2014 (N = 7,148,763). RESULTS: During two examinations, 48.43% of the initially metabolically healthy obese (MHO) individuals and 20.94% of the initially metabolically healthy non-obese (MHNO) individuals showed changes in their metabolic health and obesity status. During a mean follow-up of 3.70 years, 3151 individuals were hospitalized for HF. When stable MHNO individuals were set as the reference, transition to metabolically unhealthy phenotype was associated with an increased hazard of hHF; the hazard ratio (HR) and 95% confidence interval (CI) in the individuals who transformed from MHO to metabolically unhealthy non-obese was 2.033 (1.579-2.616). The constant MHO group had a 17.3% increased hazard of hHF compared with the stable MHNO group [HR (95% CI) 1.173 (1.039-1.325)]. Individuals who shifted from MHO to MHNO showed a 34.3% lower hazard of hHF compared with those who maintained the MHO category [HR (95% CI) 0.657 (0.508-0.849)]. CONCLUSION: Dynamic changes in metabolic health and obesity status were observed during a relatively short interval of 3-5 years. Loss of metabolic health was significantly associated with an increased hazard of hHF. Even if metabolic health was maintained, persistent obesity remained as a risk factor for hHF, and transition from MHO to MHNO had a protective effect against hHF. Therefore, the prevention and control of obesity while maintaining metabolic health would be crucial in preventing hHF.

Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study.

BACKGROUND: Previous research regarding long-term glucose variability over several years which is an emerging indicator of glycemic control in diabetes showed several limitations. We investigated whether variability in long-term fasting plasma glucose (FG) can predict the development of stroke, myocardial infarction (MI), and all-cause mortality in patients with diabetes. METHODS: This is a retrospective cohort study using the data provided by the Korean National Health Insurance Corporation. A total of 624,237 Koreans ≥ 20 years old with diabetes who had undergone health examinations at least twice from 2005 to 2008 and simultaneously more than once from 2009 to 2010 (baseline) without previous histories of stroke or MI. As a parameter of variability of FG, variability independent of mean (VIM) was calculated using FG levels measured at least three times during the 5 years until the baseline. Study endpoints were incident stroke, MI, and all-cause mortality through December 31, 2017. RESULTS: During follow-up, 25,038 cases of stroke, 15,832 cases of MI, and 44,716 deaths were identified. As the quartile of FG VIM increased, the risk of clinical outcomes serially increased after adjustment for confounding factors including duration and medications of diabetes and the mean FG. Adjusted hazard ratios (95% confidence intervals) of FG VIM quartile 4 compared with quartile 1 were 1.20 (1.16-1.24), 1.20 (1.15-1.25), and 1.32 (1.29-1.36) for stroke, MI and all-cause mortality, respectively. The impact of FG variability was higher in the elderly and those with a longer duration of diabetes and lower FG levels. CONCLUSIONS: In diabetes, long-term glucose variability showed a dose-response relationship with the risk of stroke, MI, and all-cause mortality in this nationwide observational study.

Gamma-glutamyl transferase variability and risk of dementia: A nationwide study.

OBJECTIVES: Variability in various biomarkers has emerged as a new clinical indicator for diseases including neurodegenerative disorders. Gamma-glutamyl transferase (GGT) has a potential to be involved in the pathogenesis of dementia due to its function as a marker of oxidative stress and atherosclerosis. We investigated the association between baseline GGT, GGT variability, and dementia risk for the first time in a large population. METHODS: The Korean National Health Insurance Service datasets of claims and preventive health check-ups from 2004 to 2016 were used for this retrospective longitudinal study. The risk of incident dementia (all-cause dementia, Alzheimer's disease, and vascular dementia) was analyzed according to sex-specific quartiles of baseline GGT and GGT variability, and groups categorized by baseline GGT and GGT variability in ≥40-year-old individuals without baseline dementia (N = 6 046 442; mean follow-up 6.32 years). RESULTS: During follow-up, 166 851 cases of new dementia developed. The fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia increased in the higher quartiles of baseline GGT and GGT variability (HR [95% CI]: Q2, 1.034 [1.019-1.049]; Q3, 1.090 [1.075-1.105]; Q4, 1.212 [1.196-1.229]). The association between GGT variability quartiles and dementia risk remained significant even after adjusting for log-transformed baseline GGT level. The fully adjusted HRs for dementia was highest in the group with high baseline GGT concentration and the highest GGT variability quartile [HR (95% CI): 1.273 (1.250-1.296)]. CONCLUSIONS: Not only baseline GGT level, but also GGT variability may be an independent predictor of dementia, and might be used for risk stratification for future dementia.

Dipeptidyl peptidase-4 inhibitor compared with sulfonylurea in combination with metformin: cardiovascular and renal outcomes in a propensity-matched cohort study.

BACKGROUND: To determine the impact of dipeptidyl peptidase-4 inhibitor (DPP4i) on the risk of major cardiocerebrovascular and renal outcomes compared with sulfonylurea (SU) combined with metformin in patients with type 2 diabetes from a population-based cohort. METHODS: From a nationwide cohort in Korea (2008-2013), 23,674 patients with type 2 diabetes treated with DPP4i plus metformin or SU plus metformin were selected and matched by propensity score. Composite cardiocerebrovascular events including incident ischemic heart disease (IHD), ischemic stroke (IS), hospitalization for heart failure (HHF), and cardiocerebrovascular death, as well as renal events including incident end-stage renal disease or initiation of renal-replacement therapy were assessed by Cox proportional-hazards models. RESULTS: During a median follow-up of 19.6 months (interquartile range 7.2-36.4), 762 composite cardiocerebrovascular events and 17 end-stage renal events occurred. There was no significant difference in the risk of IHD (hazard ratio [HR], 1.00; 95% CI 0.81-1.23), IS (HR, 0.95; 95% CI 0.74-1.23), or cardiocerebrovascular death (HR, 0.74; 95% CI 0.46-1.18) in the DPP4i group compared to that in the SU group. Likewise, DPP4i therapy was not associated with the risk of end-stage renal outcomes (HR, 1.23; 95% CI 0.41-3.62). However, the risk of HHF was significantly higher in the DPP4i group than in the SU group (HR, 1.47; 95% CI 1.07-2.04). CONCLUSIONS: This real-world database analysis showed that DPP4i therapy did not increase the overall risk of major cardiovascular and renal outcomes compared to SU therapy. However, the DPP4i-associated risk of HHF remained significant.

Erratum to "Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism".

[This corrects the article DOI: 10.1155/2018/6209140.].

Predictive Factors for Efficacy of AST-120 Treatment in Diabetic Nephropathy: a Prospective Single-Arm, Open-Label, Multi-Center Study.

BACKGROUND: Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS: A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS: Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 µol/L to 1.91 ± 0.72 µol/L; P = 0.002) but not in the non-responder group. CONCLUSION: The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.

Differential relationship between waist circumference and mortality according to age, sex, and body mass index in Korean with age of 30-90 years; a nationwide health insurance database study.

BACKGROUND: A recent concept is that obesity, assessed by body mass index (BMI), is not always a sign of poor health. Thus, in order to use obesity metrics in clinical decision making, it is important to clarify the relationship between waist circumference (WC), a proxy for abdominal obesity, and mortality. METHODS: Data were used from 8,796,759 subjects aged between 30 and 90 years, who had participated in the Korea National Health Screening Examination between January 1, 2009 and December 31, 2009 and survived at least 1 year post screening. Data from a mean follow-up time of an additional 5.3 years (time at risk) were analyzed for the relationship between WC and mortality according to age, sex, and BMI category. RESULTS: An increased WC of more than 90 cm in men and 85 cm in women showed a definite negative influence on mortality. However, the detailed relationship between WC and mortality was J-shaped or U-shaped according to age, sex, and BMI category. In the normal BMI group, the optimal WC range with the lowest mortality was < 70 cm in men and 70-75 cm in women, whereas in obese individuals a WC between 80 and 90 cm in men and 75 and 85 cm in women showed the lowest mortality. The association between increased WC and higher mortality tended to be more obvious in normal-weight women than in normal-weight men or obese women. Furthermore, in normal-weight and obese women, the effect of increased WC on mortality was more critical for subjects aged < 60 years rather than those aged ≥ 60 years. CONCLUSIONS: Abdominal obesity, as measured by WC, showed a significant negative association on mortality, and its association with mortality was different according to age, sex, and BMI category. Therefore, WC should be considered in the assessment of obesity-related health risks, and individualized cut-off points for the definition of a healthy WC according to age, sex, and BMI category are necessary.

The association of low muscle mass with soluble receptor for advanced glycation end products (sRAGE): The Korean Sarcopenic Obesity Study (KSOS).

BACKGROUND: Advanced glycation end products (AGEs) are accumulated with aging in various tissues of humans. The soluble receptor for AGEs (sRAGE) exerts a protective role against the development of aging-related chronic disorders by neutralizing the action of AGEs. We investigated the implication of sRAGE on low muscle mass in Asian men and women. METHODS: This cross-sectional study included a 390-participant, nondiabetic subcohort recruited within the framework of the Korean Sarcopenic Obesity Study, an ongoing prospective cohort study. Low muscle mass was defined based on the distribution of appendicular skeletal muscle mass divided by body mass index, as proposed by the Foundation for the National Institutes Sarcopenia Project. RESULTS: Serum sRAGE levels were significantly lower in participants with low muscle mass than in participants without low muscle mass (0.76 [0.60-1.00] ng/mL vs 0.87 [0.67-1.15] ng/mL, P = .005). In age- and sex-adjusted correlation analyses, appendicular skeletal muscle mass divided by body mass index was associated with sRAGE (r = 0.109, P = .037). Furthermore, decreased circulating levels of sRAGE are independently associated with low muscle mass (odds ratio = 0.254, P = .002) after adjusting for confounding factors, including insulin resistance and inflammatory markers. CONCLUSIONS: The present study shows that a low circulating level of sRAGE may be an independent risk factor for the presence of low muscle mass.

Long-term effects on glycaemic control and ß-cell preservation of early intensive treatment in patients with newly diagnosed type 2 diabetes: A multicentre randomized trial.

AIM: To determine the effects of early intensive glycaemic control with intensive insulin treatment (IIT) or initial combined oral antidiabetic drug (COAD) therapy on long-term glycaemic control and the preservation of ß-cell function in people with type 2 diabetes mellitus (T2DM). METHODS: Newly diagnosed drug-naïve patients with T2DM from 8 outpatient diabetes centres were randomized to receive either IIT (n = 50; glargine/glulisine) or COAD (n = 47; glimepiride/metformin) as intensive treatment until the termination criteria to ensure euglycaemia were met. After intensive treatment, the patients completed a follow-up period with either lifestyle modification (LSM) alone or rescue therapy to maintain target glycated haemoglobin levels of <7% (53 mmol/mol) up to week 104. The primary outcomes were analysed after excluding participants who were anti-glutamic acid decarboxylase autoantibody-positive. RESULTS: Both intensive treatment methods were effective for short-term glycaemic control, but improvements in the disposition index (DI) were significantly greater in the IIT group than in the COAD group (P = .021). During the follow-up period after intensive treatment, the two groups significantly differed in rescue method regarding the maintenance of comparable levels of glycaemic control (P = .010) and more participants who received IIT exhibited well-controlled glycaemia with LSM alone. Additionally, the IIT group maintained a higher DI than the COAD group during the follow-up period. Cox regression analysis showed that the IIT method was associated with a 52.5% lower risk of failing to maintain drug-free glycaemic remission compared with the COAD method (P = .015). CONCLUSIONS: The findings indicate that outpatient clinic-based IIT to ensure euglycaemia in newly diagnosed patients with T2DM might be an effective initial therapeutic option for improvements in ß-cell function and glycaemic control over the long term, without serious adverse events.

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.

Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism.

Sestrin2 (sesn2) is an endogenous antioxidant protein that has recently gained attention for its potential to treat various inflammatory diseases. However, the relationship of sesn2 with cardiomyopathy is still unclear. In H9c2 cells, sesn2 knockdown reduced the level of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, downregulated antioxidant genes including catalase and superoxide dismutase (SOD2), and increased reactive oxygen species (ROS) production upon lipopolysaccharide (LPS) treatment. LPS-mediated cell death and the expression of matrix metalloproteinase (MMP) 2 and MMP9 were significantly increased by sesn2 knockdown. However, these increases were prevented by treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator. Consistent with the in vitro results, AMPK phosphorylation was decreased in heart tissue from sesn2 knockdown mice compared to heart tissue from control C57BL/6 mice, which was associated with decreased expression of antioxidant genes and increased LPS-mediated cell death signaling. Furthermore, the decrease in AMPK phosphorylation caused by sesn2 knockdown increased LPS-mediated expression of cardiac fibrotic factors, including collagen type I and type III, in addition to MMP2 and MMP9, in heart tissue from C57BL/6 mice. These results suggest that sesn2 is a novel potential therapeutic target for cardiomyopathy under inflammatory conditions.

Increased Vascular Disease Mortality Risk in Prediabetic Korean Adults Is Mainly Attributable to Ischemic Stroke.

BACKGROUND AND PURPOSE: Prediabetes is a known risk factor for vascular diseases; however, its differential contribution to mortality risk from various vascular disease subtypes is not known. METHODS: The subjects of the National Health Insurance Service in Korea (2002-2013) nationwide cohort were stratified into normal glucose tolerance (fasting glucose <100 mg/dL), impaired fasting glucose (IFG) stage 1 (100-109 mg/dL), IFG stage 2 (110-125 mg/dL), and diabetes mellitus groups based on the fasting glucose level. A Cox regression analysis with counting process formulation was used to assess the mortality risk for vascular disease and its subtypes-ischemic heart disease, ischemic stroke, and hemorrhagic stroke. RESULTS: When adjusted for age, sex, and body mass index, IFG stage 2, but not stage 1, was associated with significantly higher all-cause mortality (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.18-1.34) and vascular disease mortality (HR, 1.27; 95% CI, 1.08-1.49) compared with normal glucose tolerance. Among the vascular disease subtypes, mortality from ischemic stroke was significantly higher (HR, 1.60; 95% CI, 1.18-2.18) in subjects with IFG stage 2 but not from ischemic heart disease and hemorrhagic stroke. The ischemic stroke mortality associated with IFG stage 2 remained significantly high when adjusted other modifiable vascular disease risk factors (HR, 1.51; 95% CI: 1.10-2.09) and medical treatments (HR, 1.75; 95% CI, 1.19-2.57). CONCLUSIONS: Higher IFG degree (fasting glucose, 110-125 mg/dL) was associated with increased all-cause and vascular disease mortality. The increased vascular disease mortality in IFG stage 2 was attributable to ischemic stroke, but not ischemic heart disease or hemorrhagic stroke in Korean adults.

Knockdown of sestrin2 increases pro-inflammatory reactions and ER stress in the endothelium via an AMPK dependent mechanism.

BACKGROUND & OBJECTIVE: Sestrin2 (sesn2) has recently gained attention as an important regulator for various metabolic disorders. Sesn2 is involved in AMP-activated protein kinase (AMPK) activation, which leads to anti-inflammatory and anti-oxidative responses. However, the role of sesn2 in the endothelium has not yet been clarified. METHODS: To evaluate sesn2-mediated anti-atherosclerotic effects, siRNA to silence sesn2 expression was introduced to human umbilical vein endothelial cells (HUVECs), THP-1 cells and C57BL/6 mice. Lipopolysaccharide (LPS) was administrated to sesn2-knockdown cells and mice to induce atherosclerotic signals. RESULTS: Knockdown of sesn2 was involved with atherosclerotic reactions caused by LPS treatment through decrease of AMPK phosphorylation. In sesn2-knockdown HUVECs and THP-1 cells, LPS-mediated nuclear factor kappa B (NF-κB) phosphorylation and secretion of pro-inflammatory cytokines were both significantly increased. In HUVECs, expression of adhesion molecules and LPS-stimulated adhesion of THP-1 cells to the endothelium were significantly increased after sesn2-knockdown. Furthermore, LPS-induced reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and cell toxicity were all significantly elevated after sesn2-knockdown in HUVECs. Interestingly, all these pro-atherosclerotic effects were fully abrogated by treatment with an AMPK activator. In aortic tissue samples from C57BL/6 mice, sesn2-knockdown using siRNA oligomers resulted in reduced AMPK phosphorylation and induction of LPS-mediated NF-κB phosphorylation, leading to up-regulation of adhesion molecules and ER stress-related signaling. CONCLUSION: Knockdown of sesn2 aggravates atherosclerotic processes by increasing pro-inflammatory reactions and ER stress in the endothelium via an AMPK-dependent mechanism, suggesting that sesn2 might be a novel therapeutic target for atherosclerosis.

Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin-Angiotensin System Blockade: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. APPROACH AND RESULTS: This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. CONCLUSIONS: Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion.