Bon Jeong Ku

Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes

Despite the recent attention focused on the roles of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of type 2 diabetes, little is known about the ex vivo profile of inflammasome activation in type 2 diabetic patients. In this study, we investigated patterns of NLRP3 inflammasome activation in monocyte-derived macrophages (MDMs) from drug-naïve patients with newly diagnosed type 2 diabetes. Type 2 diabetic subjects had significantly increased mRNA and protein expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and proinflammatory cytokines in MDMs cultured with autologous sera compared with healthy controls. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, and caspase-1 cleavage were observed in MDMs from type 2 diabetic patients after stimulation with various danger molecules (ATP, high-mobility group protein B1, free fatty acids, islet amyloid polypeptide, and monosodium uric acid crystals). Mitochondrial reactive oxygen species and NLRP3 were required for IL-1β synthesis in MDMs. Finally, 2 months of therapy with the antidiabetic drug metformin significantly inhibited the maturation of IL-1β in MDMs from patients with type 2 diabetes through AMP-activated protein kinase (AMPK) activation. Taken together, these data suggest that NLRP3 inflammasome activation is elevated in myeloid cells from type 2 diabetic patients and that antidiabetic treatment with metformin contributes to modulation of inflammasome activation in type 2 diabetes.

The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.

Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus.

Recent studies have shown that activation of the signal transducer and activator of transcription‐3 (Stat3) is required for decidualization, interacting with progesterone receptor (PR) in uterus. Based on previous reports, we hypothesized that crosstalk between STAT3 and PR signaling is required for successful implantation. To identify the interaction between STAT3 and PR isoforms, we performed immunoprecipitation following transient cotransfection and found that STAT3 physically interacted with PR‐A, which is known to be important for uterine development and function, but not with PR‐B. To further investigate the role of Stat3 in uterine function, Stat3 was conditionally ablated only in the PR‐positive cells (PRcre/+ Stat3f/f; Stat3d/d). Our studies revealed that ovarian function and uterine development of Stat3d/d mice were normal. However, Stat3d/d female mice were infertile due to defective embryo implantation. Unlike Stat3f/f mice, Stat3d/d mice exhibited an unclosed uterine lumen. Furthermore, uteri of Stat3d/d mice were unable to undergo a well‐characterized hormonally induced decidual reaction. The expression of stromal PR was decreased during decidualization and preimplantation period in Stat3d/d mice, and PR target genes were significantly down‐regulated after progesterone induction. Our results suggest that STAT3 and PR crosstalk is required for successful implantation in the mouse uterus.—Lee, J. H., Kim, T. H., Oh, S. J., Yoo, J.‐Y., Akira, S., Ku, B. J., Lydon, J. P., Jeong, J.‐W. Signal transducer and activator of transcription‐3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. FASEB J. 27, 2553–2563 (2013). www.fasebj.org

Optimal hemoglobin A1C Cutoff Value for Diagnosing type 2 diabetes mellitus in Korean adults

Commonly used tests for the diagnosis of diabetes include measurements of fasting plasma glucose levels and the oral glucose tolerance test (OGTT). Recently, a hemoglobin A1C (A1C) level of 6.5% has been included as a criterion for diabetes diagnosis by the American Diabetes Association. We aimed to determine appropriate A1C cutoff values for identifying patients with diabetes or prediabetes, including impaired glucose tolerance and impaired fasting glucose among Korean adults and to determine whether these cutoffs vary according to age. We recruited 4616 adults without a history of diabetes from 10 university hospitals. A 75-g OGTT and A1C sampling were performed in all examinees. Pointwise area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy of the A1C cutoff. An A1C threshold of 6.1% proved to be the optimal limit for diagnosing diabetes, with 63.8% sensitivity and 88.1% specificity. The cutoff value increased with age (5.9% in 18-39 years, 6.2% in 40-64 years, and 6.4% in older than 65 years) and were similar for men and women. An A1C cutoff of 5.7% had reasonable sensitivity (48.6%) and specificity (65.7%) for the identification of prediabetes. Further prospective studies should be carried out to determine whether the application of age-specific diagnostic criteria is appropriate.

Serum Ferritin Is Inversely Correlated with Serum Adiponectin Level: Population-Based Cross-Sectional Study

Background: The serum concentrations of ferritin and adiponectin are associated with several metabolic disorders and have been used as predictors of insulin resistance and metabolic syndrome. But there have been no reports demonstrating a direct correlation between serum ferritin and adiponectin levels. We performed this study to evaluate the association between serum ferritin and adiponectin concentrations. Subjects and methods: We evaluated a total of 995 subjects from the Korea Rural Genomic Cohort Study in a population-based cross-sectional study. Extensive clinical and laboratory measurements, including adiponectin and ferritin concentrations, were recorded. Results: Univariate analysis revealed that the serum adiponectin level was correlated with age, sex, BMI, diastolic blood pressure, triglyceride, HDL-cholesterol, fasting blood glucose, fasting insulin, HOMA-IR, hs-CRP, and ferritin. Multivariate analysis demonstrated that the adiponectin concentration was correlated with age, BMI, fasting glucose, hs-CRP, and ferritin. The ferritin concentration was the most powerfully associated with serum adiponectin. In non-diabetic subgroups, the adiponectin level was correlated with BMI, triglyceride, HDL-cholesterol, fasting glucose, and ferritin level in multivariate analysis. In diabetic subgroups, the adiponectin level was correlated with BMI, triglyceride, hs-CRP, and ferritin level in multivariate analysis. Conclusions: The serum adiponectin concentration was correlated with conventional clinical variables, but the most powerfully associated factor was the serum ferritin level.

Lobeglitazone and pioglitazone as add‐ons to metformin for patients with type 2 diabetes: a 24‐week, multicentre, randomized, double‐blind, parallel‐group, active‐controlled, phase III clinical trial with a 28‐week extension

We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add‐ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28‐week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was −0.74% for the lobeglitazone group and −0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, −0.16 to 0.18]. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add‐on to metformin in terms of their efficacy and safety.

GDF15 Is a Novel Biomarker for Impaired Fasting Glucose

Background Growth differentiation factor-15 (GDF15) is a protein that belongs to the transforming growth factor β superfamily. An elevated serum level of GDF15 was found to be associated with type 2 diabetes mellitus (T2DM). T2DM is an inflammatory disease that progresses from normal glucose tolerance (NGT) to impaired fasting glucose (IFG). Hence, we aimed to validate the relationship between GDF15 and IFG. Methods The participants were divided into the following three groups: NGT (n=137), IFG (n=29), and T2DM (n=75). The controls and T2DM outpatients visited the hospital for routine health check-ups. We used fasting blood glucose to detect IFG in nondiabetic patients. We checked the body mass index (BMI), C-reactive protein level, metabolic parameters, and fasting serum GDF15 level. Results Age, BMI, triglyceride, insulin, glucose, homeostatic model assessment-insulin resistance (HOMA-IR), and GDF15 levels were elevated in the IFG and T2DM groups compared to the NGT group. In the correlation analysis between metabolic parameters and GDF15, age and HOMA-IR had a significant positive correlation with GDF15 levels. GDF15 significantly discriminated between IFG and NGT, independent of age, BMI, and HOMA-IR. The serum levels of GDF15 were more elevated in men than in women. As a biomarker for IFG based on the receiver operating characteristic curve analysis, the cutoff value of GDF15 was 510 pg/mL in males and 400 pg/mL in females. Conclusion GDF15 had a positive correlation with IR independent of age and BMI, and the serum level of GDF15 was increased in the IFG and T2DM groups. GDF15 may be a novel biomarker for detecting IFG in nondiabetic patients.

Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway Is Required for Endometrial Decidualization in Mice and Human

Decidualization is a crucial change required for successful embryo implantation and the maintenance of pregnancy. During this process, endometrial stromal cells differentiate into decidual cells in response to the ovarian steroid hormones of early pregnancy. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are known to regulate cell proliferation and apoptosis in multiple cell types, including uterine endometrial cells. Aberrant activation of ERK1/2 has recently been implicated in the pathological processes of endometriosis and endometrial cancer. However, the function of ERK1/2 signaling during implantation and decidualization is still unknown. To determine the role and regulation of ERK1/2 signaling during implantation and decidualization, we examine ERK1/2 signaling in the mouse uterus during early pregnancy using immunostaining and qPCR. Interestingly, levels of phospho-ERK1/2 were highest within decidual cells located at the implantation sites. Expression levels of ERK1/2 target genes were also significantly higher at implantation sites, when compared to either inter-implantation sites. To determine if ERK1/2 signaling is also important during human endometrial decidualization, we examined levels of phospho-ERK1/2 in cultured human endometrial stromal cells during in vitro decidualization. Following treatment with a well-established decidualization-inducing steroidogenic cocktail, levels of phospho-ERK1/2 were markedly increased. Treatment with the ERK1/2 inhibitor, U0126, significantly decreased the expression of the known decidualization marker genes, IGFBP1 and PRL as well as inhibited the induction of known ERK1/2 target genes; FOS, MSK1, STAT1, and STAT3. Interestingly, the phosphorylation level of CCAAT/ enhancer binding protein β (C/EBPβ), a protein previously shown to be critical for decidualization, was significantly reduced in this model. These results suggest that ERK1/2 signaling is required for successful decidualization in mice as well as human endometrial stromal cells and implicates C/EBPβ as a downstream target of ERK1/2.

Predictive value of the preablation serum thyroglobulin level after thyroidectomy Is combined with postablation 131I whole body scintigraphy for successful ablation in patients with differentiated thyroid carcinoma

Objectives:To investigate the clinical importance of the combined use of serum thyroglobulin (Tg) levels measured just before ablation (ablation-Tg) and postablation 131I whole body scintigraphy (WBS) patterns for predicting ablation success in patients with differentiated thyroid carcinoma who received total thyroidectomy and 131I ablation therapy. Methods:We retrospectively studied the early clinical outcomes for 81 differentiated thyroid carcinoma patients treated with total thyroidectomy and high-dose 131I ablation therapy between June 2001 and July 2004. Results:Ablation success was achieved in 42 (97.7%) of the 43 patients with uptake in the thyroid bed only and ablation-Tg levels less than 10 ng/mL, whereas successful ablation was achieved in 9 (75.0%) of the 12 patients with uptake in the thyroid bed only and ablation-Tg levels equal to or greater than 10 ng/mL (P = 0.029). Among 15 patients with uptake including a lymph node and ablation-Tg levels less than 10 ng/mL, 14 patients (93.3%) showed ablation success, whereas successful ablation was achieved in only 2 (18.2%) of the 11 patients with uptake including a lymph node and ablation-Tg levels equal to or greater than 10 ng/mL (P < 0.001). Conclusions:These data indicate that the combined use of serum Tg levels measured just before ablation and the 131I WBS patterns after ablation may be an early predictor of ablation success in patients with differentiated thyroid carcinoma who received total thyroidectomy and high-dose 131I ablation therapy.

Mig-6 Suppresses Endometrial Cancer Associated with Pten Deficiency and ERK Activation

PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α-dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice, where Mig-6 was overexpressed in progesterone receptor-expressing cells, exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PR(cre/+)Pten(f/f) mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer.