Hyun Min Kim

Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

IGF-1 receptor (IGF-1R) signaling is implicated in cardiac hypertrophy and longevity. However, the role of IGF-1R in age-related cardiac remodeling is only partially understood. We therefore sought to determine whether the deletion of the IGF-1R in cardiomyocytes might delay the development of aging-associated myocardial pathologies by examining 2-year-old male cardiomyocyte-specific IGF-1R knockout (CIGF1RKO) mice. Aging was associated with the induction of IGF-1R expression in hearts. Cardiomyocytes hypertrophied with age in wild-type (WT) mice. In contrast, the cardiac hypertrophic response associated with aging was blunted in CIGF1RKO mice. Concomitantly, fibrosis was reduced in aged CIGF1RKO compared with aged WT hearts. Expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and receptor activator of nuclear factor-κB ligand was increased in aged WT hearts, but this increase was attenuated in aged CIGF1RKO hearts. Phosphorylation of Akt was increased in aged WT, but not in aged CIGF1RKO, hearts. In cultured cardiomyocytes, IGF-1 induced senescence as demonstrated by increased senescence-associated β-galactosidase staining, and a phosphoinositide 3-kinase inhibitor inhibited this effect. Furthermore, inhibition of phosphoinositide 3-kinase significantly prevented the increase in IL-1α, IL-1β, receptor activator of nuclear factor-κB ligand, and p21 protein expression by IGF-1. These data reveal an essential role for the IGF-1-IGF-1R-Akt pathway in mediating cardiomyocyte senescence.

The Effects of Green Tea on Obesity and Type 2 Diabetes

Obesity and type 2 diabetes are major public health issues worldwide, contributing to increased cardiovascular morbidity and mortality. The proportions of people with obesity and/or type 2 diabetes have increased and recently reaching epidemic levels in Asia [1]. Although pharmacologic modality is the mainstay treatment of diabetes, remedies using plants (e.g., garlic, psyllium, and green tea) have stimulated a new interest in research [2]. Green tea (Camellia sinensis) is one of the worlds most popular beverages, especially in Asian countries including Korea, China, and Japan. Because of the high rate of green tea consumption in these populations, even small effects on an individual basis could have a large public health impact [3]. A population-based, prospective cohort study has shown that green tea consumption is associated with reduced mortality due to all causes and cardiovascular disease as well [4], and randomized controlled trials have indicated that green tea is effective in decreasing blood pressure, low density lipoprotein cholesterol, oxidative stress, and a marker of chronic inflammation [5]. Various studies have shown the beneficial effects of green tea, not only on cardiovascular diseases but also on obesity and type 2 diabetes itself [6,7]. In a retrospective cohort study performed in Japan, a 33% risk reduction of developing type 2 diabetes was found in subjects consuming six or more cups of green tea daily compared to those consuming less than 1 cup per week [6]. Wu et al. [7] reported that Taiwanese subjects who had habitually consumed tea for more than 10 years showed lower body fat composition and smaller waist circumference. Evidences from epidemiological studies suggest the possibility of green tea being a novel strategy for treatment or prevention of obesity and diabetes. However, a limited number of clinical trials using green tea, green tea extracts (GTEs), or its main ingredient catechin have shown disappointing results in controlling hyperglycemia in type 2 diabetic patients or protecting the condition in healthy subjects. MacKenzie et al. [8] showed no significant difference in glucose control after 3 months of ingestion of decaffeinated GTE in type 2 diabetic patients in a double-blinded, placebo-controlled, randomized trial. Similarly, Nagao et al. [9] showed that plasma glucose levels and A1c did not improve after 12 weeks of supplementation with catechin in patients with type 2 diabetes [9]. However, they showed that the addition of catechin decreased A1c level and increased serum insulin level compared to the placebo group in a subgroup of patients who have been treated with insulin therapy. Also, Hsu et al. [10] showed no difference in glycemic control or lipid parameters after 16 weeks of green tea supplementation. Ryu et al. [11] showed that 4 weeks of green tea consumption did not affect inflammation, adiponectin levels, or insulin resistance in type 2 diabetic patients, and they suggested that those mechanisms were unlikely to explain the benefits in cardiovascular risk or mortality by tea consumption observed in epidemiological studies. Despite these equivocal results, several mechanisms have been proposed to explain the positive effect of green tea on glucose metabolism or obesity. Epigallocatechin gallate (EGCG), the most abundant form of catechin in green tea, has been known to be the main attributable factor of beneficial effects of green tea [12]. EGCG inhibits adipocyte proliferation and differentiation in 3T3-L1 cells [13], increases fat oxidation [14], and increases expression of GLUT-4 in adipose tissue of an animal model [15]. In human studies, clear increases in energy expenditure were documented [16]. Also, some suggested the protective function of EGCG for cytokine-induced β-cell destruction mediated by inhibition of nuclear factor-κB activation [17]. Recently, Tian et al. [18] showed that green tea polyphenols had antiobesity effect by up-regulating adiponectin levels in rats. They suggested that the involved mechanisms were the inhibition of Erk activation, alleviation of peroxisome proliferator-activated receptor γ (PPARγ) phosphorylation, and increases in the PPARγ expression [18]. Park et al. [19] revealed the ambivalent role of gallated catechin (GC) in green tea, including EGCG, in glucose tolerance. GC acutely reduces blood glucose levels mainly through its activities in the alimentary tract while increasing the glucose level when in the circulation by blocking normal glucose uptake into the tissues. They suggested the development of nonabsorbable derivatives of GC with only positive luminal effect as a prevention strategy of type 2 diabetes and obesity. As mentioned above, many researches are being performed to define the precise molecular mechanisms of green tea and ultimately, its clinical application in obesity and type 2 diabetes. In this study, Bae and his colleagues [20] demonstrated the possibility of GTE as an antiobestic and/or antidiabetic agent when coadministered with another dietary supplement poly-γ-glutamic acid (γ-PGA) in db/db mice, potentially through the action of intestinal GTE. γ-PGA is a main constituent of the viscous material in Korean chungkookjang and Japanese natto. The study presents the results of nuclear magnetic resonance spectroscopy that γ-PGA can interact with EGCG, and this possible complex formation may delay the absorption of GCs to systemic circulation from the intestine, resulting in decreased blood glucose level. The protective effects of GTE+γ-PGA regimen on body weight gain and development of glucose intolerance were much better than treatment with either GTE or γ-PGA alone. Therefore, they suggest that GTE+γ-PGA treatment may be a promising preventative and therapeutic tool for obesity and type 2 diabetes. Future studies, especially in human, are warranted to confirm these benefits in patients with diabetes or healthy subjects, as well as to define the precise molecular mechanisms of action of green tea supplementation.

1,5-anhydroglucitol as a useful marker for assessing short-term glycemic excursions in type 1 diabetes

Background Type 1 diabetes is associated with more severe glycemic variability and more frequent hypoglycemia than type 2 diabetes. Glycemic variability is associated with poor glycemic control and diabetic complications. In this study, we demonstrate the clinical usefulness of serum 1,5-anhydroglucitol (1,5-AG) for assessing changes in glycemic excursion in type 1 diabetes. Methods Seventeen patients with type 1 diabetes were enrolled in this study. A continuous glucose monitoring system (CGMS) was applied twice at a 2-week interval to evaluate changes in glycemic variability. The changes in serum glycemic assays, including 1,5-AG, glycated albumin and hemoglobin A1c (HbA1c), were also evaluated. Results Most subjects showed severe glycemic excursions, including hypoglycemia and hyperglycemia. The change in 1,5-AG level was significantly correlated with changes in the glycemic excursion indices of the standard deviation (SD), mean amplitude of glucose excursion (MAGE), lability index, mean postmeal maximum glucose, and area under the curve for glucose above 180 mg/dL (r=-0.576, -0.613, -0.600, -0.630, and -0.500, respectively; all P<0.05). Changes in glycated albumin were correlated with changes in SD and MAGE (r=0.495 and 0.517, respectively; all P<0.05). However, changes in HbA1c were not correlated with any changes in the CGMS variables. Conclusion 1,5-AG may be a useful marker for the assessment of short-term changes in glycemic variability. Furthermore, 1,5-AG may have clinical implications for the evaluation and treatment of glycemic excursions in type 1 diabetes.

Optical characteristics and longevity of quantum dot-coated white LED

For improving the light quality of a white LED, the feasibility of QDs was seriously considered and their longevity as well as efficiency was evaluated. For that purpose, the most similar combination of phosphors to the commercial light-converting system was selected and fabricated as the hybrid phosphor of Lu3Al5O12:Ce3+ and CdSe/ZnS QDs in remote type. To ensure competitive, a frame of reference with Lu3Al5O12:Ce3+ and (Sr,Ca)AlSiN3:Eu2+ was made and two cases were compared. When the hybrid phosphor with QDs was used, it was found that the luminous flux was increased by 20%, compared to the conventional combination of inorganic phosphor in commercial level. Also, CRI value can be controlled up to 90. But, the LED PKG reliability of a white LED with QDs in remote type still needs to be improved. The luminous flux of the hybrid phosphor with QDs was decreased to 91% within 1000 hours under the operating condition of 85°C and 85% of relative humidity, while that of conventional combination of inorganic phosphors was kept in stable luminescence. Substantial variation of color coordinates were observed. By tracking the changes of the R9 value over the time, it was found that the quantum structure had not been sustained during the operation. More work on the stability of QDs in phosphor plate should be done for device application.

Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK.

Background/Objectives:Activation of Notch signaling pathologically enhances lipogenesis and gluconeogenesis in the liver causing non-alcoholic fatty liver disease (NAFLD) and diabetes. Delta-like 1 homolog (DLK1), an imprinted gene that can modulate adipogenesis and muscle development in mice, was found as an inhibitory regulator of Notch signaling. Therefore, we investigated the metabolic effect of exogenous DLK1 in vitro and in vivo.Subjects/Methods:A soluble DLK1 peptide was generated with fusion between a human Fc fragment and extracellular domain of DLK1. Male db/db mice were randomly assigned to two groups: vehicle treated and DLK1-treated group (25 mg kg−1, intraperitoneal injection, twice a week for 4 weeks). Primary mice hepatocytes and HepG2 cells were used for in vitro experiments.Results:After 4 weeks of DLK1 administration, hepatic triglyceride content and lipid droplets in liver tissues, as well as serum levels of liver enzymes, were markedly decreased in db/db mice. DLK1 treatment induced phosphorylation of AMPK and ACC and suppressed nuclear expression of SREBP-1c in the mouse liver or hepatocytes, indicating regulation of fatty acid oxidation and synthesis pathways. Furthermore, DLK1-treated mice showed significantly lower levels of fasting and random glucose, with improved glucose and insulin tolerance compared with the vehicle-treated group. Macrophage infiltration and proinflammatory cytokine levels in the epididymal fat were decreased in DLK1-treated db/db mice. Moreover, DLK1 suppressed glucose production from hepatocytes, which was blocked after co-administration of an AMPK inhibitor, compound C. DLK1-treated hepatocytes and mouse liver tissues showed lower PEPCK and G6Pase expression. DLK1 triggered AKT phosphorylation followed by cytosolic translocation of FOXO1 from the nucleus in hepatocytes.Conclusions:The present study demonstrated that exogenous administration of DLK1 reduced hepatic steatosis and hyperglycemia via AMPK activation in the liver. This result suggests that DLK1 may be a novel therapeutic approach for treating NAFLD and diabetes.

Optimal Candidates for the Switch from Glimepiride to Sitagliptin to Reduce Hypoglycemia in Patients with Type 2 Diabetes Mellitus

Background Sitagliptin is a novel antidiabetic agent with a low risk for hypoglycemia. We investigated the efficacy and safety of sitagliptin when patients switched from a sulfonylurea to sitagliptin and identified good candidates for the switch. Methods Sixty-one patients with type 2 diabetes switched from glimepiride with metformin to sitagliptin with metformin due to clinical hypoglycemia. Serum glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour postprandial plasma glucose (2h-PPG) before and 12 and 24 weeks after the drug switch were checked. Results HbA1c and FPG levels did not change 12 or 24 weeks after the switch; however, the 2h-PPG level decreased from 218.0±67.5 mg/dL at baseline to 197.1±69.9 mg/dL at 12 weeks and 192.3±67.4 mg/dL at 24 weeks after switching drugs (P=0.045, P=0.018, respectively). All but one patient no longer experienced hypoglycemia after discontinuing glimepiride. In a multivariate logistic regression analysis, a high homeostasis model assessment of insulin resistance and low baseline HbA1c level were independent predictors of an HbA1c ≤7% after switching to sitagliptin. Conclusion Glycemic control was not aggravated in patients 24 weeks after the drug switch, and symptomatic hypoglycemia decreased significantly. Patients with dominant insulin resistance may be good candidates for switching from a sulfonylurea to sitagliptin to reduce hypoglycemia.

Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts

While deletion of Akt1 results in a smaller heart size and Akt2-/- mice are mildly insulin resistant, Akt1-/-/Akt2-/- mice exhibit perinatal lethality, indicating a large degree of functional overlap between the isoforms of the serine/threonine kinase Akt. The present study aimed to determine the cooperative contribution of Akt1 and Akt2 on the structure and contractile function of adult hearts. To generate an inducible, cardiomyocyte-restricted Akt2 knockout (KO) model, Akt2flox/flox mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline Akt1-/- mice to generate the following genotypes:Akt1+/+; Akt2flox/flox (WT), Akt2flox/flox; α-MHC-MCM (iAkt2 KO), Akt1-/-, and Akt1-/-; Akt2flox/flox; α-MHC-MCM mice (Akt1-/-/iAkt2 KO). At 28 days after the first tamoxifen injection, Akt1-/-/iAkt2 KO mice developed contractile dysfunction paralleling increased atrial and brain natriuretic peptide (ANP and BNP) levels, and repressed mitochondrial gene expression. Neither cardiac fibrosis nor apoptosis were detected in Akt1-/-/iAkt2 KO hearts. To explore potential molecular mechanisms for contractile dysfunction, we investigated myocardial microstructure before the onset of heart failure. At 3 days after the first tamoxifen injection, Akt1-/-/iAkt2 KO hearts showed decreased expression of connexin43 (Cx43) and connexin-interacting protein zonula occludens-1 (ZO-1). Furthermore, Akt1/2 silencing significantly decreased both Cx43 and ZO-1 expression in cultured neonatal rat cardiomyocytes in concert with reduced beating frequency. Akt1 and Akt2 are required to maintain cardiac contraction. Loss of Akt signaling disrupts gap junction protein, which might precipitate early contractile dysfunction prior to heart failure in the absence of myocardial remodeling, such as hypertrophy, fibrosis, or cell death.

Effects of telmisartan on fat distribution: a meta-analysis of randomized controlled trials

Abstract Objectives: Several meta-analyses have confirmed the positive metabolic effects of telmisartan, an angiotensin II receptor blocker that can also act as a partial peroxisome proliferator-activated receptor-γ agonist, compared to those of other angiotensin II receptor blockers. These effects include decreased fasting glucose, glycosylated hemoglobin, interleukin-6, and tumor necrosis factor-α levels. However, no systemic analysis of telmisartan’s effects on body fat distribution has been performed. We performed a meta-analysis of randomized controlled telmisartan trials to investigate its effects on body weight, fat distribution, and visceral adipose reduction. Research design and methods: A literature search was performed using Embase, MEDLINE, and the Cochrane Library between January 1966 and November 2013. Randomized controlled trials in English and meeting the following criterion were included: random assignment of hypertensive participants with overweight/obesity, metabolic syndrome, or glucose intolerance to telmisartan or control therapy group. Results: Of 651 potentially relevant reports, 15 satisfied the inclusion criterion. While visceral fat area was significantly lower in the telmisartan group than in the control group (weighted mean difference = −18.13 cm2, 95% C.I. = −27.16 to −9.11, Pχ2 = 0.19, I2 = 41%), subcutaneous fat area was similar (weighted mean difference =2.94 cm2, 95% C.I. = −13.01 to 18.89, Pχ2 = 0.30, I2 = 17%). Total cholesterol levels were significantly different between the groups (standardized mean difference = −0.24, 95% C.I. = −0.45 to −0.03, Pχ2 = 0.0002, I2 = 67%). Limitations: Limitations include: (1) limited number of studies, especially those evaluating fat distribution; (2) different imaging modalities to assess visceral fat area (V.F.A.) and subcutaneous fat area (S.F.A.); (3) observed heterogeneity. Conclusion: The findings suggest that telmisartan affected fat distribution, inducing visceral fat reduction, and thus could be useful in hypertensive patients with obesity/overweight, metabolic syndrome, or glucose intolerance.

Effect of sodium salicylate on COX-2 expression in neonatal rat cardiomyocytes

Salicylates, one of the oldest medicinal compounds known to humans, have been reported to show anti-inflammatory effects via cyclooxygenase (COX) inhibition. However, the pathophysiological role of COX-2 in the heart is conflicting, and the role of sodium salicylate in the regulation of cardiac inflammation has not yet been elucidated. We aimed to investigate the effect of salicylate on COX-2 expression and its associated prostaglandin production using cultured neonatal rat cardiomyocytes. The cells were incubated in the presence or absence of sodium salicylate (8 mM). Treatment with sodium salicylate significantly increased COX-2 expression at both mRNA and protein levels, induced prostaglandin D2 release, and increased TNF-α mRNA expression in cardiomyocytes. In addition, salicylate treatment induced cardiomyocyte hypertrophy. Taken together, we demonstrated that salicylate induced COX-2 expression, which in turn resulted in the regulation of expression of several inflammatory mediators in cardiomyocytes.

Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation: Insulin and IGF-1 receptors in thyroid cancer development

Insulin and insulin‐like growth factor (IGF)‐1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid‐stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF‐1 receptor (IGF‐1R) in thyroid development and function has not been explored. Here, we generated thyrocyte‐specific IR and IGF‐1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid‐specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF‐1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR‐dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)‐like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF‐1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF‐1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.