Chronic Exposure to the Herbicide, Atrazine, Causes Mitochondrial Dysfunction and Insulin Resistance

There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to mitochondria, we investigated whether chronic exposure to low concentrations of ATZ might cause obesity or insulin resistance by damaging mitochondrial function. Sprague-Dawley rats (n = 48) were treated for 5 months with low concentrations (30 or 300 µg kg−1 day−1) of ATZ provided in drinking water. One group of animals was fed a regular diet for the entire period, and another group of animals was fed a high-fat diet (40% fat) for 2 months after 3 months of regular diet. Various parameters of insulin resistance were measured. Morphology and functional activities of mitochondria were evaluated in tissues of ATZ-exposed animals and in isolated mitochondria. Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level. A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of ATZ-treated rats were swollen with disrupted cristae. ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. It also suppressed the insulin-mediated phosphorylation of Akt. These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Background: Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms. Methods and Findings: Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-$\alpha$ and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs. Conclusions: Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes

EGb761, a Ginkgo Biloba Extract, Is Effective Against Atherosclerosis In Vitro, and in a Rat Model of Type 2 Diabetes

BACKGROUND: EGb761, a standardized Ginkgo biloba extract, has antioxidant and antiplatelet aggregation and thus might protect against atherosclerosis. However, molecular and functional properties of EGb761 and its major subcomponents have not been well characterized. We investigated the effect of EGb761 and its major subcomponents (bilobalide, kaemferol, and quercetin) on preventing atherosclerosis in vitro, and in a rat model of type 2 diabetes. METHODS AND RESULTS: EGb761 (100 and 200 mg/kg) or normal saline (control) were administered to Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, for 6 weeks (from 3 weeks before to 3 weeks after carotid artery injury). Immunohistochemical staining was performed to investigate cell proliferation and apoptosis in the injured arteries. Cell migration, caspase-3 activity and DNA fragmentation, monocyte adhesion, and ICAM-1/VCAM-1 levels were explored in vitro. Treatment with EGb761 dose-dependently reduced intima-media ratio, proliferation of vascular smooth muscle cells (VSMCs) and induced greater apoptosis than the controls. Proliferation and migration of VSMCs in vitro were also decreased by the treatment of EGb761. Glucose homeostasis and circulating adiponectin levels were improved, and plasma hsCRP concentrations were decreased in the treatment groups. Caspase-3 activity and DNA fragmentation increased while monocyte adhesion and ICAM-1/VCAM-1 levels decreased significantly. Among subcomponents of EGb761, kaemferol and quercetin reduced VSMC migration and increased caspase activity. CONCLUSIONS: EGb761 has a protective role in the development of atherosclerosis and is a potential therapeutic agent for preventing atherosclerosis

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 x 10(-8)) with GDM, mapping to/near MTNR1B (P = 4.3 x 10(-54)), TCF7L2 (P = 4.0 x 10(-16)), CDKAL1 (P = 1.6 x 10(-4)), CDKN2A-CDKN2B (P = 4.1 x 10(-9)) and HKDC1 (P = 2.9 x 10(-8)). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.Peer reviewe

Abnormal liver function test predicts type 2 diabetes: a community-based prospective study

Increased activities of liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and -glutamyltranspeptidase (GGT) are indicators of hepatocellular injury. Increased activity of these markers is associated with insulin resistance (1), metabolic syndrome, and type 2 diabetes (2–9). However, most of these studies were performed in Western countries (2– 5,7,9), and the two studies from Japan and Korea were not community based (6,8). In this prospective communitybased study, we evaluated the relationships between markers of liver function and the onset of type 2 diabetes after adjusting for potential risk factors including inflammatory markers

Visceral fatness and insulin sensitivity in women with a previous history of gestational diabetes mellitus

OBJECTIVE: The purpose of this study was to investigate the insulin sensitivity and visceral fatness in women with previous gestational diabetes mellitus (GDM), who are prone to develop type 2 diabetes. RESEARCH DESIGN AND METHODS: A 75-g oral glucose tolerance test (OGTT) performed 1 year postpartum identified 21 GAD(-) women with previous GDM and impaired glucose tolerance (GDM-IGT). Sixty age- and BMI-matched women with normal glucose tolerance (GDM-NGT) were selected by 1:3 matching to the GDM-IGT group. Another 18 women with normal glucose metabolism during a previous pregnancy and no family history of diabetes were recruited as the normal control group. Age and BMI matching was performed using a range of +/-1.0 years and +/-1.0 kg/m(2), respectively. Total body fat was measured by tetrapolar bioelectrical impedance, and visceral fat was determined using a single cut of a computed tomography scan. Insulin sensitivity was determined by the minimal model technique using the frequently sampled intravenous glucose tolerance test. RESULTS: One year postpartum, visceral fat was greater in the GDM-IGT group than in the age- and BMI-matched GDM-NGT or normal control groups. The insulin sensitivity index was lower in the GDM-IGT group than in the GDM-NGT or normal control groups. beta-Cell function, as measured by the acute insulin response to glucose, was also lower in GDM-IGT. CONCLUSIONS: High body fat content, especially visceral fat content, and a low insulin response to glucose seem to contribute simultaneously to the development of impaired glucose metabolism in Korean women with previous GDM

Effective heights and tangential momentum accommodation coefficients of gaseous slip flows in deep reactive ion etching rectangular microchannels

he behavior of a rarefied, compressible flow in long, constant cross section channels provides an opportunity to study complex gas dynamics in a simple geometry that allows analytical solutions. The problem of a rarefied, compressible flow in near unity aspect ratio rectangular cross section channels has been all but ignored despite it being a common flow geometry. We present analytical expressions for the mass flow rate in long, straight and uniform rectangular cross section microchannels in the slip flow regime. Using these analytical expressions, we extract the tangential momentum accommodation coefficient (TMAC) as well as the effective channel dimensions to account for a slight curvature of one of the walls of the rectangle. These expressions are effective in near unity aspect ratio rectangular microchannels made by deep reactive ion etching. The dependence of the flow behavior on the channel height to width aspect ratio is discussed as is the effect of the slight deviation from a rectangular cross section. The obtained TMAC results are consistent with values found by previous researchers using similar materials. Finally, a method of determining TMACs in channels consisting of non-homogenous materials or processing methods is presented

Gaseous slip flow of a rectangular microchannel with non-uniform slip boundary conditions

This article presents analytical expressions of velocity and mass flow rate in terms of Fourier series for gaseous slip flows in long, straight, and uniform rectangular microchannels in the case of different first-order slip boundary conditions on each wall of the microchannels. The derived velocity expressions were in good agreement with those presented by Ebert and Sparrow (J Basic Eng 87:1018, 1965), when the slip boundary conditions on each wall of the microchannels were identical. The computed first-order dimensionless mass flow rate was also in very good agreement with the dimensionless mass flow rate for the planar channel reported by Arkilic et al. (J Microelectromec Syst 6:167, 1997) as the channel aspect ratio approached zero. Using the derived first-order dimensionless mass flow expression and the previously reported mass flow data, we found the unknown tangential momentum accommodation coefficient (TMAC) of nitrogen on a glass surface in a rectangular microchannel made by anodic bonding. The effects of the channel aspect ratio and Knudsen number on the velocity fields were discussed. The uncertainty level of the estimation of TMAC from mass flow rate measurements was also discussed, along with the effects of the channel aspect ratio and Knudsen number on the uncertainty level.close5

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

P>Objective Several population-based studies in iodine-deficient areas have shown an association between smoking and thyroid function. There are no population-based studies about the effects of smoking in iodine-sufficient areas. We examined the effect of smoking on thyroid function and the association with iodine intake in Korea, an area with sufficient iodine intake, much more than recommended by the World Health Organization (WHO). Design Of 5018 subjects in a population-based cohort, we included 3399 who had no history of thyroid disease were not taking thyroid medication and whose blood samples were available for measurement of thyroid function. Measurements Thyroid function test, questionnaire about smoking status and dietary intake. Results Of 3399 subjects, 397(11 center dot 7%) had subclinical hypothyroidism (SCH). Female sex was an independent risk factor for SCH. Multivariate analysis in female subjects showed the following were independent risk factors for SCH: older age, positive antithyroid peroxidase (anti-TPO) antibody status and iodine intake, whereas current smoking was inversely related with SCH. However, in male subjects, only age showed a weak association with SCH. When the interaction between smoking and other risk factors was analysed, smoking showed no association with anti-TPO antibody status, whereas it showed a significant negative interaction with iodine intake (odds ratio, 0 center dot 930; 95% CI, 0 center dot 869-0 center dot 996; P = 0 center dot 037). Furthermore, the risk for SCH was observed only in the never-smoker group; however, it was abolished in current- and ex-smoker groups. Conclusion Cigarette smoking was associated with a lower prevalence of SCH in a negative interaction with iodine intake.Cho NH, 2009, CLIN ENDOCRINOL, V71, P679, DOI 10.1111/j.1365-2265.2009.03586.xEffraimidis G, 2009, J CLIN ENDOCR METAB, V94, P1324, DOI 10.1210/jc.2008-1548Ittermann T, 2008, EUR J ENDOCRINOL, V159, P761, DOI 10.1530/EJE-08-0386Makepeace AE, 2008, CLIN ENDOCRINOL, V69, P648, DOI 10.1111/j.1365-2265.2008.03239.xde Benoist B, 2008, FOOD NUTR BULL, V29, P195Vejbjerg P, 2008, EUR J EPIDEMIOL, V23, P423, DOI 10.1007/s10654-008-9255-1HAMPL R, 2008, ENDOCR REGUL, V42, P53Vanderver GB, 2007, THYROID, V17, P741, DOI 10.1089/thy.2006.0332Asvold BO, 2007, ARCH INTERN MED, V167, P1428Dillingham BL, 2007, THYROID, V17, P131, DOI 10.1089/thy.2006.02.06Laurberg P, 2006, EUR J ENDOCRINOL, V155, P219, DOI 10.1530/eje.1.02210Jorde R, 2006, EXP CLIN ENDOCR DIAB, V114, P343, DOI 10.1055/s-2006-924264Teng WP, 2006, NEW ENGL J MED, V354, P2783, DOI 10.1056/NEJMoa054022Messina M, 2006, THYROID, V16, P249Lim S, 2005, DIABETES RES CLIN PR, V70, P126, DOI 10.1016/j.diabres.2005.02.020Sharma RB, 2005, J IMMUNOL, V174, P7740Andersen S, 2005, AM J CLIN NUTR, V81, P656Belin RM, 2004, J CLIN ENDOCR METAB, V89, P6077, DOI 10.1210/jc.2004-0431Shin C, 2004, J HUM HYPERTENS, V18, P717, DOI 10.1038/sj.jhh.1001732YOUNJHIN A, 2004, KOREAN J COMMUNITY N, V9, P173Strieder TGA, 2003, CLIN ENDOCRINOL, V59, P396Knudsen N, 2002, ARCH INTERN MED, V162, P439, DOI 10.1001/archinte.162.4.439Hollowell JG, 2002, J CLIN ENDOCR METAB, V87, P489, DOI 10.1210/jc.87.2.489Rasmussen LB, 2002, BRIT J NUTR, V87, P61, DOI 10.1079/BJN2001474Rasmussen LB, 2001, EUR J CLIN NUTR, V55, P287, DOI 10.1038/sj.ejcn.1601156Chang HC, 2000, TOXICOL APPL PHARM, V168, P244, DOI 10.1006/taap.2000.9019Canaris GJ, 2000, ARCH INTERN MED, V160, P526Kim JY, 1998, YONSEI MED J, V39, P355Laurberg P, 1998, J CLIN ENDOCR METAB, V83, P765Rasooly L, 1998, AUTOIMMUNITY, V27, P213Divi RL, 1996, CHEM RES TOXICOL, V9, P16PARK HY, 1995, J KOREAN SOC ENDOCRI, V10, P386PRUMMEL MF, 1993, JAMA-J AM MED ASSOC, V269, P479FUKAYAMA H, 1992, ACTA ENDOCRINOL-COP, V127, P520BERGHOUT A, 1987, CLIN ENDOCRINOL, V26, P273MAHMOUD I, 1986, EXP MOL PATHOL, V44, P259TUNBRIDGE WMG, 1977, CLIN ENDOCRINOL, V7, P481