Search

How functional genetics research can be applied to improving crop yields is a timely challenge. One of the most direct methods is to produce larger inflorescences with higher productivity, which should be accompanied by a balance between stem cell proliferation and lateral organ initiation in meristems. Unbalanced proliferation of stem cells causes the fasciated inflorescences, which reflect the abnormal proliferation of meristems, derived from the Latin word ‘fascis’, meaning ‘bundle’. Maize, a model system for grain crops, has shown tremendous yield improvements through the mysterious transformation of the female inflorescence during domestication. In this review, we focus on maize inflorescence architecture and highlight the patterns of fasciation, including recent progress.

Background: ST-elevation myocardial infarction (STEMI) poses significant morbidity, mortality and economic burden in people with diabetes. We sought to determine the impact of diabetes on the short-term outcome and hospital costs post-percutaneous coronary intervention (PCI) for STEMI. Methods: STEMI hospitalizations were selected in the Nationwide Readmissions Database from 2010 to 2014. From the patients who underwent PCI, we examined the 30-day readmission, in-hospital mortality, and total cost according to the presence of diabetes, prior stroke, and prior MI. All statistical analyses were performed using R statistical software version 4.1.2. Results: Among 539,171 index STEMI hospitalizations for primary PCI, 10.1% were readmitted within 30 days and 4.6% died in hospital. The readmission rates were 10.2%, 12.9%, 14.4%, 17.5%, and 18.4% in the reference (i.e., no diabetes, prior MI or stroke) , diabetes-only, diabetes and MI, diabetes and stroke, diabetes, MI, and stroke groups, respectively (P Conclusion: Within 30 days of PCI for STEMI, diabetes increases readmission rate, in-hospital mortality, and financial burden with and without prior CVD. These findings underscore the importance of aggressive optimization in STEMI patients with diabetes. Disclosure Y. Kang: None. S. Jang: None.

The aim of this study was to investigate the association of nonalcoholic fatty liver disease (NAFLD) with diabetes and the impact of waist circumference (WC) changes in subjects with prediabetes. We enrolled 6240 subjects with prediabetes who underwent health check-ups in 2007 and revisited our hospital at least once for a follow-up examination between 2008 and 2013. Subjects were stratified by WC changes into three groups. The relative risks (RRs) for diabetes according to the NAFLD status and WC change were evaluated. The prevalence of NAFLD was 45.4% (2830/6240). During follow-up, the incidence of diabetes was 8.1% (505/6240). Subjects with NAFLD had a higher incidence of diabetes and the adjusted RRs were 1.81 (95% confidence interval [CI], 1.47 to 2.21), after adjustment for potential confounding factors. The adjusted RRs were related to WC changes. The adjusted RRs for diabetes according to tertiles of WC change (first, second, and third tertile) were 1.64 (95% CI, 1.08 to 2.49), 1.73 (95% CI, 1.28 to 2.34), and 2.04 (95% CI, 1.42 to 2.93), respectively. NAFLD has significantly increased risk of incident diabetes in subjects with prediabetes. The risk for diabetes is gradually increased with tertiles of WC change.

Introduction This study aimed to investigate the efficacy and clinical factors affecting the glycemic response to dulaglutide in type 2 diabetes (T2D) in a real-world clinical setting. Methods We conducted a retrospective study of 234 patients at the Asan Medical Center, Republic of Korea, who had T2D and initiated dulaglutide from June 2016 to December 2017. The primary outcome was the change in glycated hemoglobin (HbA1c) concentration between baseline and 6 months after the initiation of therapy. Multivariate regression analysis was used to determine the clinical parameters contributing to a superior glycemic response to dulaglutide. Results The mean age of the patients was 53, and 50% were male. Their mean baseline HbA1c, body mass index and duration of diabetes were 8.8%, 27.6 kg/m2 and 10.2 years, respectively. The change in HbA1c between baseline and 6 months was − 0.92% (95% CI: − 1.1% to − 0.74%, p

OBJECTIVES The hemoglobin glycation index (HGI) quantifies interindividual variations in glycated hemoglobin (HbA1c) and is associated with diabetic complications and metabolic diseases. However, information on the association between HGI and non-alcoholic fatty liver disease (NAFLD) in healthy subjects is limited, particularly in Asian populations. This study aimed to investigate the association between HGI and NAFLD in a healthy Korean cohort. DESIGN Subjects were stratified in quartiles according to their HGI level. NAFLD was diagnosed by hepatic ultrasonography, hepatic steatosis index and fatty liver index. Multiple logistic regression analysis was performed to evaluate the association between HGI quartiles and the risk of NAFLD. PATIENTS Data from subjects without diabetes who underwent liver ultrasonography during routine health examinations were retrospectively reviewed. RESULTS Data from 14 465 subjects were included in the analysis. The prevalence of NAFLD increased significantly with each HGI quartile (24.8%, 29.7%, 32.6% and 40.6% in quartiles 1-4, respectively; P

We sought to determine the associations between hemoglobin A1c (A1c) and admission glucose with in-hospital mortality among patients with diabetes mellitus (DM) hospitalized with COVID-19. Adults hospitalized between 3/5/20 and 12/1/20 in a Connecticut health care system were included if they had prior DM diagnosis, an in-hospital A1c, and a positive RT-PCR nasopharyngeal swab for SARS-CoV-2. A1c was stratified into 200 mg/dL with mortality (in-hospital death or transition to hospice) and with intensive care unit (ICU) use. Models were adjusted for demographics and 8 relevant comorbidities. Among 733 patients (median age 67 years [interquartile range, 56-77], 48.3% female, 43.11% White, 35.47% Black, 24.97% Hispanic, 1.64% Asian), 31.7% had A1c 200 mg/dL. During hospitalization, 111 (15.1%) patients died or transitioned to hospice and 230 (31.4%) required ICU care. In 2 multi-variable adjusted analyses, neither A1c category nor high admission glucose were significantly associated with mortality (A1c 7-9% OR 1.3, CI 0.72-2.35 compared with A1c 200 OR 1.34, CI 0.72-2.35) or ICU care (A1c 7-200 OR 1.26, CI 0.9-1.78). Age (per year OR 1.06, CI 1.04-1.08), male sex (OR 1.78, CI 1.14-2.81), obesity (OR 1.85, CI 1.16-2.96) and CKD (OR 1.90, CI 1.19-3.03) were significantly associated with mortality. Only female sex (OR 0.67, CI 0.48-0.93) was significantly associated with ICU care. In our retrospective study of hospitalized patients with DM, neither A1c nor admission glucose were prognostic of COVID-19 mortality or ICU care. In those with DM, male sex, obesity and CKD predicted worse outcomes. Disclosure J. Brancale: None. A. M. Jastreboff: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Other Relationship; Spouse/Partner; Elucidata. K. J. Lipska: None. D. Athonvarangkul: None. M. Simonov: None. J. Alausa: None. L. K. Subair: None. A. M. Hajduk: None. Y. Kang: None. T. Arora: None. F. P. Wilson: Other Relationship; Self; Efference LLC, Medscape. Funding National Institutes of Health (1T32GM136651-01)

Background Nearly 25% of adrenal Cushing syndrome (CS) patients with bilateral adrenal masses have unilateral hypercortisolism, making localization crucial for surgical planning. Since there is no standardized protocol for adrenal venous sampling (AVS) in lateralizing adrenal hypercortisolism, we share our experience with a case of CS with bilateral adrenal masses in which lateralization via AVS permitted unilateral adrenalectomy. Clinical Case A 59-year-old woman with hypertension, hyperlipidemia, and prediabetes was hospitalized for worsening back pain and hypertension. Her BMI was 26.5 kg/m2, BP 173/93 mmHg, HR 73/min, she was anxious, diaphoretic, and hirsute. Glucose was 118 mg/dL and HbA1c 6.6%. Abdominal computed tomography revealed a type B aortic dissection with both right (6.1 x 3.1cm and 3.6 x 2.4cm), and left (largest 1.7 cm) sided adrenal masses. Plasma and 24 hour-urine metanephrine, normetanephrine and catecholamines, as well as plasma renin and aldosterone levels, were normal. AM cortisol on three different occasions was 21.30, 20.70, and 21.30 mcg/dL. Midnight cortisol was 17.8 mcg/dL, and 24-hour urine free cortisol on two occasions was 163 mcg (urine volume 3.4L with creatinine 1.14) and 99.2 mcg (urine volume 1.15L). After 1mg dexamethasone her AM ACTH and cortisol were

Rodent stem cells demonstrated regenerative effects in diabetic neuropathy via improvement in nerve perfusion. As a pre-clinical step, we explored if human mobilized mononuclear cells (hMNC) would have the same effects in rats. hMNC were injected into Rt. hind-limb muscles of streptozotocin-induced diabetic nude rats, and the grafts were monitored using with MRI. After 4 weeks, the effects were compared with those in the vehicle-injected Lt. hind limbs. Nerve conduction, muscle perfusion and gene expression of sciatic nerves were assessed. Induction of diabetes decreased nerve function and expression of Mpz and Met in the sciatic nerves, which are related with myelination. hMNC injection significantly improved the amplitude of compound muscle action potentials along with muscle perfusion and sciatic nerve Mpz expression. On MRI, hypointense signals were observed for 4 weeks at the graft site, but their correlation with the presence of hMNC was detectable for only 1 week. To evaluate paracrine effects of hMNC, IMS32 cells were tested with hepatocyte growth factor (HGF), which had been reported as a myelination-related factor from stem cells. We could observe that HGF enhanced Mpz expression in the IMS32 cells. Because hMNC secreted HGF, IMS32 cells were co-cultured with hMNC, and the expression of Mpz increased along with morphologic maturation. The hMNC-induced Mpz expression was abrogated by treatment of anti-HGF. These results suggest that hMNC could improve diabetic neuropathy, possibly through enhancement of myelination as well as perfusion. According to in vitro studies, HGF was involved in the hMNC-induced myelination activity, at least in part.

Objective— SFRP5 (secreted frizzled–related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans. Approach and Results— We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague–Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase–dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity ( r =0.146; P =0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [ B (SE)=7.40 (3.35); P =0.028]. Conclusions— Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.

Obesity is associated with increased severity of viral illnesses, but its impact on outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is yet to be elucidated. We sought to determine the association of obesity and other clinical factors with outcomes among patients hospitalized for severe coronavirus disease (COVID-19). This study included patients hospitalized between March 1, 2020 and September 17, 2020 in a 5-hospital health care system in Northeast United States, who had a positive RT-PCR assay of nasopharyngeal swabs for SARS-CoV-2 performed during hospitalization. Body mass index (BMI) was calculated using admission weight and height, and the WHO classification was used to define obesity. Both bivariate and multivariate logistic regression analyses were performed to determine the association of obesity and other clinical parameters with mortality (defined as in-hospital death or transition to hospice care) and intensive care use (defined by transfer to intensive care unit [ICU]). Multivariate model was adjusted for demographics and 8 pertinent comorbidities. Among 3246 patients hospitalized with COVID-19, median age was 65 years (interquartile range, 51–78), 49.9% were female, 30.5% overweight, and 43.2% had obesity (20.8%, 12.1%, and 10.4% with class I, II, and III obesity, respectively). A total of 542 (16.7%) patients died or received hospice care, and 811 (25.0%) required ICU care. In unadjusted analyses, patients with obesity had lower mortality compared with normal weight adults (13.0% vs. 23.1%) but a higher risk of ICU care (26.5% vs. 22.5%) and longer duration of ICU stays (9.5±10.6 vs. 6.6±8.5 [days]; all p-values

Aims/Introduction We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus. Materials and Methods We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly. Results A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] −0.01% [−0.1 mmol/mol], 95% confidence interval [CI] −0.25 to 0.22% [−2.7 to −2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD −0.90 mg/dL, 95% CI: −15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c

The morbidity and mortality associated with diabetic complications impose a huge socioeconomic burden worldwide. Therefore, the ultimate goal of managing diabetes mellitus (DM) is to lower the risk of macrovascular complications and highly morbid microvascular complications such as diabetic nephropathy (DN) and diabetic retinopathy (DR). Potential benefits of incretin-based therapies such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on the diabetic macrovascular complications have been recently suggested, owing to their pleiotropic effects on multiple organ systems. However, studies primarily investigating the role of these therapies in diabetic microvascular complications are rare. Nevertheless, preclinical and limited clinical data suggest the potential protective effect of incretin-based agents against DN and DR via their anti-inflammatory, antioxidative, and antiapoptotic properties. Evidence also suggests that these incretin-dependent and independent beneficial effects are not necessarily associated with the glucose-lowering properties of GLP-1 RAs and DPP-4 inhibitors. Hence, in this review, we revisit the preclinical and clinical evidence of incretin-based therapy for DR and DN, the two most common, morbid complications in individuals with DM. In addition, the review discusses a few recent studies raising concerns of aggravating DR with the use of incretin-based therapies.

Objective Although type 2 diabetes is a strong risk factor for cardiovascular disease and mortality, information on its association with mortality and life expectancy according to cardiovascular comorbidities is limited, especially in Asia. Thus, this study assessed mortality and reductions in life expectancy associated with cardiometabolic multimorbidity. Design and methods A total of 569,831 participants older than 30 years from Korean National Health Insurance Service-National Sample Cohort were enrolled between 2002 and 2006 and followed for a median of 12.0 years. They were categorized into five mutually exclusive groups according to baseline disease status, as follows: none (reference group); diabetes only; diabetes and stroke; diabetes and myocardial infarction (MI); and diabetes, stroke, and MI. Mortality rates and hazard ratios (HRs), reductions of life expectancy, and age-specific contributions to life expectancy were calculated by constructing life tables. Results The mortality rates per 1000 person-years were 6.85, 19.86, 67.17, 66.34, and 115.52 in the reference, diabetes only; diabetes and stroke; diabetes and MI; and diabetes, stroke, and MI groups, respectively. The corresponding HRs for all-cause mortality were 1.70 [95% confidence interval (CI), 1.66 to 1.75], 3.66 (95% CI, 3.32 to 4.03), 3.56 (95% CI, 3.06 to 4.14), and 4.79 (95% CI, 3.05 to 7.50) compared with the reference group. The estimated reductions in life expectancy were greater at younger ages and markedly increased with more cardiometabolic comorbidities. Conclusion Young Asians with type 2 diabetes, especially those with cardiovascular comorbidity, did not live as long than their nondiabetic equivalents. Thus, these individuals require special attention to prevent further reductions in life expectancy.

Background: Nonalcoholic fatty liver disease (NAFLD) and prediabetes are well-known risk factors for diabetes. However, few studies have been performed about the risk of diabetes in subjects with prediabetes in the presence of NAFLD. In addition, little information was known about the impact of waist circumference (WC) and body mass index (BMI) changes on the development of diabetes. In this study, we examined the association of NAFLD with diabetes and the impact of WC and BMI changes in subjects with prediabetes. Methods: We enrolled 6,240 subjects with prediabetes who underwent general routine health evaluations in 2007 and returned for follow-up examinations in 2008 -2013 at least one time. Subjects were stratified by WC and BMI changes into three groups. The relative ratios (RRs) of NAFLD for diabetes was evaluated. Results: The prevalence of NAFLD in study participants was 45.4% (2,830/6,240). Subjects with NAFLD had higher BMI, WC, HbA1c levels, blood pressure levels, blood lipid levels, and also higher ALT levels (P < 0.001). During the follow-up, the total incidence of diabetes was 8.093%. Subjects with NAFLD at baseline had a higher incidence of diabetes and the adjusted RRs were 2.181 [95% confidence interval (CI), 1.778 to 2.674]. Furthermore, the RRs were closely related to WC changes. The adjusted RRs for diabetes according to WC change (≤ 0.0 cm, 0 cm to 3.0 cm, and > 3.0 cm) were 1.953 (95% CI, 1.365 to 2.794), 1.996 (95% CI, 1.407 to 2.833), and 2.302 (95% CI, 1.598 to 3.314), respectively. Furthermore, the RRs were also closely related to BMI changes and the adjusted RRs for diabetes according to BMI change (< -0.35 kg/m2, -0.35 kg/m2 to 0.35 kg/m2, and > 0.35 kg/m2) were 1.633 (95% CI, 1.121 to 2.380), 1.995 (95% CI, 1.415 to 2.811), and 2.924 (95% CI, 2.053 to 4.165), respectively. Conclusion: There was a strong and independent association between NAFLD and diabetes in Korean subjects with prediabetes, and this relationship was closely related to WC and BMI changes. Disclosure J. Lee: None. Y. Kang: None. J. Park: None. W. Lee: None.

Objective: We aimed to evaluate the risk of incident type 2 diabetes (T2D) in metabolically healthy, obese (MHO) individuals and the role of fatty liver disease (FLD) in this potentially causal relationship. Methods: We enrolled 514,866 participants from the Korean National Health Insurance Service-National Health Screening Cohort in 2002-2015. Subjects were categorized into metabolically healthy, non-obese (MHNO), metabolically unhealthy, non-obese (MUNO), MHO, and metabolically unhealthy, obese (MUO) groups. Well-validated FLD indices were used in this study; Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), and Visceral Adiposity Index (VAI). Results: Over 5.6 years, 67,807 (27.8%) of 244,301 subjects free of T2D and liver disease besides FLD developed T2D. The risk correlated with obesity (HR, 1.35; 95% CI 1.33-1.37) and the number of metabolic risk factors; HRs for 1, 2, 3, and 4 risk factors were 1.43 (95% CI, 1.39-1.47), 1.92 (95% CI, 1.87-1.97), 2.51 (95% CI, 2.44-2.58), and 3.14 (95% CI, 3.02-3.26), respectively. Compared with the MHNO group, the risk of T2D was significantly higher in MUO (multivariate HR, 1.95; 95% CI, 1.91-2.00), MUNO (HR, 1.63; 95% CI, 1.60-1.67), and MHO (HR, 1.28; 95% CI, 1.25-1.30) individuals. Higher FLD scores among MHO individuals also exhibited a strong correlation with the incident T2D, compared with both the MHNO group and the MHO counterpart with lower FLD scores (P < 0.05 for all comparisons). Survival trees analysis based on log-rank test revealed that the best cut-off points to predict incident T2D were 25.1, 33.4, and 1.7 for FLI, HSI, and VAI, respectively. Conclusion: The number of metabolic risk factors, obesity, and FLD are significant predictors of incident T2D. Higher T2D risk in MHO individuals, with an excess risk related to higher FLD scores, necessitates more intensive monitoring and interventions in these individuals. Disclosure Y. Kang: None. Y. Cho: None. J. Yoo: None. J. Lee: None. J. Choi: None. J. Park: None. W. Lee: None. C. Jung: None.

We aimed to investigate the clinical factors affecting the therapeutic effectiveness of the sodium-glucose cotransporter-2 inhibitor empagliflozin in patients with type 2 diabetes mellitus (T2DM). We reviewed the medical records of 374 T2DM patients aged between 20 and 75 years who were prescribed empagliflozin 10 mg or 25 mg as add-on therapy for more than 90 consecutive days. Changes in hemoglobin A1c (HbA1c) from baseline levels and the reduction in body weights of the study participants were assessed. We found that younger patients (≤ 50 years), patients with the highest levels of HbA1c (>9%) at baseline, patients with an estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73 m2, and patients with a shorter duration of T2DM (< 10 years) were more likely to exhibit a better glycemic response. Multivariate linear regression analysis revealed that a shorter duration of T2DM, higher baseline levels of HbA1c, and higher eGFR were positively associated with HbA1c reduction. Higher BMI and lower HbA1c levels were predictors of a more significant reduction in body weight among patients taking empagliflozin. The glucose-lowering effect of empagliflozin was more evident in T2DM patients with higher baseline HbA1c levels, better renal function, and shorter duration of T2DM.

Objective Metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value remains controversial and may partly depend on differences in how the phenotype is defined. We aimed to investigate whether the MHO phenotype is associated with future development of incident hypertension in a Korean population according to various definitions of metabolic health. Subjects and methods The study population comprised 31 033 Koreans without hypertension. Participants were stratified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) by body mass index (cut-off value, 25·0 kg/m(2) ) and metabolic health state, using four different definitions: Adult Treatment Panel (ATP)-III, Wildman, Karelis and the homoeostasis model assessment (HOMA) criteria. Results Over the median follow-up period of 35·0 months (range, 4·5-81·4 months), 4589 of the 31 033 individuals (14·8%) developed incident hypertension. Compared with the MHNO group, the MHO group showed increased association with incident hypertension with multivariate-adjusted odds ratios of 1·56 (95% confidence interval [CI], 1·41-1·72), 1·58 (95% CI 1·42-1·75), 1·52 (95% CI 1·35-1·71) and 1·46 (95% CI 1·33-1·61), when defined by ATP-III, Wildman, Karelis and HOMA criteria, respectively. Conclusion MUO individuals showed the highest association with the incident hypertension (adjusted odds ratios up to 2·00). MHO subjects showed an approximately 1·5-fold higher association with incident hypertension than their nonobese counterpart regardless of the definition of metabolic health used. Thus, considering both metabolic health and obesity is important for the assessment of potential cardiovascular outcomes.

Objective This study investigated the effect of fatty liver disease (FLD) on the risk of incident type 2 diabetes in a population with metabolically healthy obesity (MHO). Methods The study population comprised 34,258 Koreans without type 2 diabetes. Participants were stratified by BMI (cutoff value, 25.0 kg/m2) and metabolic health state (using Wildman criteria). FLD was defined by the fatty liver index (FLI), a predictive algorithm to detect FLD. Subjects were classified into low and high FLI groups based on tertile. Results At baseline, there were significant differences in FLI between four study groups. During a median follow-up of 36.5 months, 1.7% individuals developed type 2 diabetes. The risk of incident type 2 diabetes varied for the MHO group according to the level of FLI. The risk of type 2 diabetes in the MHO with low FLI was not significantly elevated compared with the metabolically healthy individuals without obesity (MHNO) with low FLI (multivariate-adjusted HR, 1.19 [95% CI 0.66-2.14]). However, the MHO with high FLI had an elevated risk of incident type 2 diabetes (multivariate-adjusted HR, 1.99 [95% CI 1.36-2.92]). Conclusions MHO subjects have a substantially higher risk of incident type 2 diabetes than MHNO subjects. The presence of FLD assessed by FLI partially explains this increased risk.

Aims We hypothesized that transitions in metabolic health status and obesity affect the cardiovascular (CV) risk and mortality in population with metabolically healthy obesity (MHO). Methods This study enrolled 514,866 participants from the Korean National Health Insurance Service–National Sample Cohort. Changes in metabolic health status and obesity from the baseline examination in 2009–2010 to the next biannual health examination in 2011–2012 were determined. Study participants were categorized into four groups: (1) metabolically healthy, non-obese (MHNO), defined as BMI Results Among the subjects classified as MHO in 2009–2010, 45.6% were classified as MHO in 2011–2012, whereas 11.6%, 6.0%, and 36.8% were classified as MHNO, MUNO, and MUO, respectively. The risk of CV events was higher in baseline MHO group than MHNO group (HR, 1.14; 95% CI, 1.05–1.24). However, in baseline MHO group, CV mortality was not increased (HR, 0.85; 95% CI, 0.69–1.06) and all-cause mortality was even lower than that of MHNO group (HR, 0.86; 95% CI, 0.79–0.93). Compared to the stable MHO subjects, the risk of CV events was significantly higher in the subjects who transitioned from MHO to MUO with multivariate-adjusted HRs of 1.24 (95% CI: 1.00–1.54). When weight loss and progression to metabolic unhealthy phenotype occur simultaneously in the MHO population, the all-cause mortality was increased compared to the stable MHO group (HR, 1.96; 95% CI, 1.45–2.65). Conclusions Subjects with MHO constitute a heterogeneous group. Our finding supports that evolving to a metabolically unhealthy status and losing weight simultaneously is associated with the adverse outcome in the MHO population.

Background: By combining the results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major cardiovascular events (MACE) and identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. Methods: Three multicenter, randomized, double-blind, placebo-controlled CVOTs of long-acting GLP-1 RAs were included: LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and EXSCEL (Exenatide Study of Cardiovascular Event Lowering). The primary endpoint was three-point MACE (i.e., CV death, non-fatal myocardial infarction, and non-fatal stroke). Overall effect estimates were calculated as hazard ratios (HRs) and 95% confidence intervals (CIs) using the random-effects model; pre-defined subgroup analyses were performed. Results: Overall, significant risk reductions in MACE (relative risk [RR]: 0.88 [95% CI: 0.81-0.97]) and CV death (RR: 0.85 [95% CI: 0.75-0.95]) were observed. Subgroup analysis indicated significant racial differences in this CV benefit (P for test of difference < 0.001). Risk reductions were observed in subjects of black race (RR: 0.78 [95% CI: 0.60-0.99]) and Asians (RR: 0.35 [95% CI: 0.09-1.32]). However, post-hoc analysis using Bonferroni correction revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with subjects of white race (P < 0.0001). Conclusions: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in diabetic study populations, and racial difference in the CV benefit was observed. The existence of extra CV benefit in Asians and the underlying mechanisms should be investigated in the future. Disclosure Y. Kang: None. Y. Cho: None. J. Choi: None. C. Woo: None. W. Lee: None. J. Park: None. C. Jung: None.

Objectives: Fatty liver disease (FLD) is a well-known risk factor for cardiovascular disease (CVD). However, it is unclear whether FLD per se is an independent risk factor of CVD or combined unfavorable metabolic components with metabolic syndrome (MetS). In this study, we examined the independent impact of FLD on the coronary artery calcification (CAC) score progression. Methods: We examined 1,173 asymptomatic participants who underwent repeated CAC score measurement during routine health examinations. Subjects were categorized into 4 groups according to the presence (+) or absence (-) of FLD and MetS. The CAC score progression was defined as either incident CAC in a population free of CAC at baseline or increase ≥ 2.5 units between the baseline and final square root of CAC scores participants who had detectable CAC at baseline examination. Results: Among the participants, 44.8% (526), 23.2% (272), 8.8% (103) and 23.2% (272) were classified as FLD(-)/MetS(-), FLD(+)/MetS(-), FLD(-)/MetS(+), and FLD(+)/MetS(+), respectively. The proportions of subjects who developed CAC progression was 18.6% (98), 28.3% (77), 29.1% (30) and 32.0% (87) in FLD(-)/Mets(-), FLD(+)/Mets(-), FLD(-)/MetS(+), and FLD(+)/MetS(+), respectively. In logistic regression analysis, FLD(+)/MetS(+) were at significantly higher risk of CAC progression compared to FLD(-)/MetS(-) [multivariate adjusted-odds ratio (OR) 1.76, 95% confidence interval (CI) 1.18-2.62]. FLD(+)/MetS(-) also demonstrated higher risk of CAC progression [multivariate adjusted-OR 1.53, 95% CI 1.05-2.23]. Conclusions: FLD is an independent risk factor for CAC progression irrespective of the presence of metabolic syndrome. Special attention should be paid to subjects with FLD for the prevention of future cardiovascular events, even though MetS does not coexist. Disclosure Y. Cho: None. Y. Kang: None. C. Park: None. S. Park: None. W. Lee: None. J. Park: None. C. Jung: None.

Background We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). Methods This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia. Results The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (n=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. -0.9±6.0 kg, P=0.011). Conclusion The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.

It is unclear whether non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease. We examined the independent impact of NAFLD on the progression of the coronary artery calcification (CAC) score, a well-known marker of atherosclerosis progression. We examined 1,173 asymptomatic participants who underwent repeated CAC score measurement during routine health examinations. The subjects were categorised into four groups based on the presence (+) or absence (−) of NAFLD and metabolic syndrome (MetS). The progression of CAC score was defined as either incident CAC in a CAC-free population at baseline or an increase of ≥2.5 units between the baseline and the final square roots of the CAC scores of participants with detectable CAC at baseline. CAC progression was seen in 18.6% (98/526), 28.3% (77/272), 29.1% (30/103) and 32.0% (87/272) of the subjects with NAFLD(−)/MetS(−), NAFLD(+)/MetS(−), NAFLD(−)/MetS(+) and NAFLD(+)/MetS(+), respectively. The subjects with NAFLD(+)/MetS(+) and NAFLD(+)/MetS(−) had a significantly higher risk of CAC progression than those with NAFLD(−)/MetS(−) (multivariate-adjusted odds ratio [OR]: 1.76; 95% confidence interval [CI]: 1.18–2.62 and multivariate-adjusted OR: 1.53, 95% CI: 1.05–2.23, respectively). NAFLD is an independent risk factor for CAC progression, irrespective of the presence of MetS.

Although recent studies have reported cardioprotective effects of C1q/TNF-related protein 9 (CTRP9), the closet adiponectin paralog, its role on cytokine-induced endothelial inflammation is unknown. We investigated whether CTRP9 prevented inflammatory cytokine-induced nuclear factor-kappa B (NF-κB) activation and inhibited the expression of adhesion molecules and a chemokine in the vascular endothelial cell. We used human aortic endothelial cells (HAECs) to examine the effects of CTRP9 on NF-κB activation and the expression of NF-κB-mediated genes, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1). Tumor necrosis factor alpha (TNFα) was used as a representative proinflammatory cytokine. In an adhesion assay using THP-1 cells, CTRP9 reduced TNFα-induced adhesion of monocytes to HAECs. Treatment with CTRP9 significantly decreased TNFα-induced activation of NF-κB, as well as the expression of ICAM-1, VCAM-1, and MCP-1. In addition, treatment with CTRP9 significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), the downstream target of AMPK. The inhibitory effect of CTRP9 on the expression of ICAM-1, VCAM-1, and MCP-1 and monocyte adhesion to HAECs was abolished after transfection with an AMPKα1-specific siRNA. Our study is the first to demonstrate that CTRP9 attenuates cytokine-induced vascular inflammation in endothelial cells mediated by AMPK activation.

Obesity has become an important risk factor for chronic kidney disease (CKD). The metabolically healthy obese (MHO) phenotype refers to obese individuals with a favorable metabolic profile. However, its prognostic value remains controversial and may depend on the health outcome being investigated. To assess this, we examined the risk of MHO phenotype with incident CKD in a Korean population of 41,194 people without CKD. Individuals were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). Incident CKD was defined as a glomerular filtration rate of60 ml/min per 1.73 m(2) calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Over the median follow-up period of 38.7 months, 356 of the individuals developed incident CKD. Compared with the metabolically healthy nonobese (MHNO) group, the MHO group showed increased risk of incident CKD with a multivariate-adjusted hazard ratio of 1.38 (95% CI, 1.01-1.87). Nonobese but metabolically unhealthy individuals were at an increased risk of incident CKD (multivariate-adjusted hazard ratio, 1.37 (95% CI, 1.02-1.93)) than the MHNO group. Metabolically unhealthy obese individuals were at the highest risk of incident CKD. Thus, a healthy metabolic profile does not protect obese adults from incident CKD. Hence, it is important to consider metabolic health along with obesity when evaluating CKD risk.

Objective: This study sought to investigate whether the metabolically healthy obese (MHO) phenotype is associated with an increased risk of incident type 2 diabetes in a Korean population and, if so, whether systemic inflammation affects this risk in MHO individuals. Design and Methods: The study population comprised 36 135 Koreans without type 2 diabetes. Participants were stratified by body mass index (cutoff value, 25.0 kg/m2) and metabolic health state (assessed using Adult Treatment Panel-III criteria). High-sensitive C-reactive protein (hsCRP) was used as a surrogate marker of systemic inflammation. Subjects were classified into low (ie, hsCRP < 0.5 mg/L) and high (ie, hsCRP ≥ 0.5 mg/L) systemic inflammation groups. Results: During a median followup of 36.5 months (range, 4.8–81.7 mo), 635 of the 36 135 individuals (1.8%) developed type 2 diabetes. The MHO group had a significantly higher risk of incident type 2 diabetes (multivariate-adjusted hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16–2.11) than the metabolically healthy nonobese (MHNO) group. However, the risk of the MHO group varied according to the degree of systemic inflammation. Compared with the MHNO/low systemic inflammation group, the risk of type 2 diabetes in the MHO/low systemic inflammation group was not significantly elevated (multivariate-adjusted HR, 1.61; 95% CI, 0.77–3.34). However, the MHO/high systemic inflammation group had an elevated risk of incident type 2 diabetes (multivariate-adjusted HR, 3.73; 95% CI 2.36–5.88). Conclusions: MHO subjects show a substantially higher risk of incident type 2 diabetes than MHNO subjects. The level of systemic inflammation partially explains this increased risk.

Background This review evaluated the efficacy and safety of a combination therapy comprising a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in type 2 diabetes. Methods A literature search through to May 2017 was carried out of PubMed, Embase and the Cochrane Central Register of Controlled Trials. Studies were eligible if they were randomized controlled trials (RCTs) comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) against DPP4i±placebo or SGLT2i±placebo and published in English. The primary outcome was change in HbA 1c from baseline. Results Eight RCTs comparing SGLT2i/DPP4i and DPP4i, and five RCTs comparing SGLT2i/DPP4i and SGLT2i, with three RCTs involving both comparisons, were included in the present review. SGLT2i/DPP4i resulted in a greater mean HbA 1c reduction [weighted mean difference (WMD]): −0.62%] than did DPP4i alone, which was a much less marked reduction (WMD: −0.35%) than with SGLT2i alone. Also, significant differences in body weight loss from baseline were observed only with SGLT2i/DPP4i vs. DPP4i, but not vs. SGLT2i. The risk of hypoglycaemic events was low and similar between treatment groups. When subjects were stratified based on baseline HbA 1c , any reduction by SGLT2i/DPP4i in relation to DPP4i was proportional to baseline HbA 1c levels. However, compared with SGLT2i, HbA 1c reductions with SGLT2i/DPP4i were modest regardless of baseline HbA 1c . Conclusion Combination therapy with SGLT2i and DPP4i is both efficacious and safe. In particular, a marked additional glucose-lowering effect is evident when SGLT2i is combined with or added to DPP4i, and not vice versa. However, baseline HbA 1c determined the additional glucose-lowering effects of SGLT2i in combined treatment with DPP4i.

Although recent animal studies have suggested that C1q/TNF-related protein-9 (CTRP9) is more likely to be involved in the regulation of vascular function, more specifically atherosclerosis, in rodents, little is known about whether serum CTRP9 level is associated with atherosclerosis in humans.The aim of this study was to investigate whether serum CTRP9 concentration is associated with atherosclerosis by measuring brachial ankle pulse wave velocity (baPWV) in subjects with type 2 diabetes. In addition, we examined the clinical and biochemical variables associated with serum CTRP9 concentration.We measured circulating CTRP9 and total adiponectin levels in 278 subjects (169 men and 109 women; mean age of 58.3 years) with type 2 diabetes. Measurements of baPWV were performed in all subjects.Serum CTRP9 concentration was positively correlated with baPWV. This correlation was significant even after adjusting for total adiponectin levels. In multiple linear regression, serum CTRP9 concentration was independently associated with increased baPWV. Female gender, higher body mass index, and homeostatic model assessment of insulin resistance were significantly associated with elevated serum CTRP9 concentration in subjects with type 2 diabetes.Serum CTRP9 concentration was significantly and positively associated with arterial stiffness in patients with type 2 diabetes, suggesting that CTRP9 might be important in the regulation of arterial stiffness in humans.

We previously determined that AKR/J mice housed in a low-dose-rate (LDR) ((137)Cs, 0.7 mGy/h, 2.1 Gy) γ-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) ((137)Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.