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Su P, Chen C, Sun Y. Physiopathology of polycystic ovary syndrome in endocrinology, metabolism and inflammation. J Ovarian Res 2025; 18:34. [PMID: 39980043 PMCID: PMC11841159 DOI: 10.1186/s13048-025-01621-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 02/08/2025] [Indexed: 02/22/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by elevated androgen levels, ovarian cysts, and impaired ovulation in females. This condition is closely linked with various reproductive health issues and has significant impacts on endocrine and metabolic pathways. Patients with PCOS commonly exhibit hyperandrogenaemia and insulin resistance, leading to complications such as acne, hirsutism, weight fluctuations, and metabolic disturbances, as well as an increased risk for type 2 diabetes, cardiovascular disease, and endometrial cancer. Although extensive research has identified several mechanistic aspects of PCOS, a thorough understanding of its pathophysiology remains incomplete. This review aims to provide a detailed analysis of the physiological and pathological aspects of PCOS, covering endocrine, metabolic, and inflammatory dimensions, to better elucidate its etiological framework.
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Affiliation(s)
- Pingping Su
- Wenzhou Graduate Joint Training Base, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gynecology, Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, China
| | - Chao Chen
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yun Sun
- Department of Gynecology, Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, China.
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Peters JC, Breen JA, Pan Z, Nicklas J, Cornier MA. A Randomized, Crossover Trial Assessing Appetite, Energy Metabolism, Blood Biomarkers, and Ad Libitum Food Intake Responses to a Mid-Morning Pecan Snack vs. an Equicaloric High-Carbohydrate Snack in Healthy Volunteers with Overweight/Obesity. Nutrients 2024; 16:2084. [PMID: 38999832 PMCID: PMC11243619 DOI: 10.3390/nu16132084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND The differential effects of pecans versus other popular snack foods on appetite and blood markers of metabolism and satiety have not been well studied. This study investigated the effects of a single mid-morning snack of pecans or tortilla chips on subjective appetite, food intake, blood measures of hormones and metabolites, and resting energy expenditure. METHODS Twenty participants with overweight and obesity were enrolled in a within-participants, randomized crossover trial. Participants had indwelling catheters placed for blood sampling and were fed a standardized breakfast, followed two hours later by a 250 kcal snack of either pecans or tortilla chips, and then by a self-selected lunch. Visual analog scale (VAS) appetite measures, blood markers, and energy expenditure were taken at intervals after food consumption. RESULTS VAS ratings, energy, food intake and macronutrient composition did not differ between treatment conditions, but glucose and insulin were significantly more elevated after tortilla chips. Free fatty acids (FFA), triglycerides (TG), peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) were higher after consuming pecans compared to tortilla chips. CONCLUSIONS Pecan consumption improves postprandial glucose and insulin profiles which would be beneficial to individuals at risk of developing type 2 diabetes. Further studies are needed to investigate whether increased relative secretion of PYY and GLP-1 after eating pecans versus tortilla chips may affect subjective appetite and energy intake if consumed chronically.
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Affiliation(s)
- John C. Peters
- Anschutz Health and Wellness Center, 12348 E. Montview Blvd., MailStop C263, Aurora, CO 80045, USA; (J.A.B.); (J.N.)
- Division of Endocrinology, Diabetes and Metabolism, University of Colorado Denver, Anschutz Medical Campus, 12801 E. 17th Ave., RC1 South Rm 7103, Aurora, CO 80045, USA
| | - Jeanne Anne Breen
- Anschutz Health and Wellness Center, 12348 E. Montview Blvd., MailStop C263, Aurora, CO 80045, USA; (J.A.B.); (J.N.)
| | - Zhaoxing Pan
- Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 13123 E. 16th Ave., B065, Aurora, CO 80045, USA;
| | - Jacinda Nicklas
- Anschutz Health and Wellness Center, 12348 E. Montview Blvd., MailStop C263, Aurora, CO 80045, USA; (J.A.B.); (J.N.)
- Division of General Internal Medicine, University of Colorado Denver, Anschutz Medical Campus, 12801 E. 17th Ave., RC1 South Rm 7103, Aurora, CO 80045, USA
| | - Marc-Andre Cornier
- Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., CSB 822, Charleston, SC 29425, USA;
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Rodrigues S, Bortolotto LA, Beyl RA, Singh P. Severity of sleep apnea impairs adipose tissue insulin sensitivity in individuals with obesity and newly diagnosed obstructive sleep apnea. FRONTIERS IN SLEEP 2023; 2:1295301. [PMID: 39434962 PMCID: PMC11493395 DOI: 10.3389/frsle.2023.1295301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/23/2024]
Abstract
Introduction Obstructive sleep apnea (OSA) is a common sleep disorder associated with increased risk for the development of type 2 diabetes. While studies have examined the effects of sleep on whole-body insulin sensitivity, little is known about the effects of sleep on adipose tissue insulin sensitivity in patients with OSA. We analyzed if the severity of OSA, measured by apnea-hypopnea index (AHI), is associated with adipose tissue insulin sensitivity. Methods We examined the relationship between sleep parameters and adipose tissue insulin sensitivity in non-diabetic participants with obesity and newly diagnosed OSA who underwent overnight polysomnography and a 2 h oral glucose tolerance test during which circulating free fatty acids were measured. In total, 16 non-diabetic participants with obesity and newly diagnosed OSA (sex, 81.3% males; mean age, 50.9 ± 6.7 y; BMI, 36.5 ± 2.9 kg/m2; AHI, 43 ± 20 events/h) were included in the analysis. Results In our study participants, AHI is inversely associated with free-fatty acid suppression during oral glucose challenge (R = -0.764, p = 0.001). This relationship persisted even after statistical adjustment for age (R = -0.769, p = 0.001), body mass index (R = -0.733, p = 0.002), waist-to-hip ratio (R = -0.741, p = 0.004), or percent body fat mass (R = -0.0529, p = 0.041). Furthermore, whole-body insulin sensitivity as determined by the Matsuda index was associated with percent REM sleep (R = 0.552, p = 0.027) but not AHI (R = -0.119, p = 0.660). Conclusion In non-diabetic patients with OSA, the severity of sleep apnea is associated with adipose tissue insulin sensitivity but not whole-body insulin sensitivity. The impairments in adipose tissue insulin sensitivity may contribute to the development of type 2 diabetes.
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Affiliation(s)
- Sara Rodrigues
- Pennington Biomedical Research Center, Baton Rouge, LA, United States
- Unidade de Hipertensao, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Luiz Aparecido Bortolotto
- Unidade de Hipertensao, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Robbie A. Beyl
- Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Prachi Singh
- Pennington Biomedical Research Center, Baton Rouge, LA, United States
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Effect of Pemafibrate on Hemorheology in Patients with Hypertriglyceridemia and Aggravated Blood Fluidity Associated with Type 2 Diabetes or Metabolic Syndrome. J Clin Med 2023; 12:jcm12041481. [PMID: 36836015 PMCID: PMC9962113 DOI: 10.3390/jcm12041481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 02/07/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Persistent high serum triglyceride (TG) and free fatty acid (FFA) levels, which are common in metabolic syndrome and type 2 diabetes, are risk factors for cardiovascular events because of exacerbated hemorheology. To explore the effects of pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, on hemorheology, we performed a single-center, nonrandomized, controlled study in patients with type 2 diabetes (HbA1c 6-10%) or metabolic syndrome, with fasting TG levels of ≥ 150 mg/dL and a whole blood transit time of > 45 s on a microarray channel flow analyzer (MCFAN). Patients were divided into a study group, receiving 0.2 mg/day of pemafibrate (n = 50) for 16 weeks, and a non-pemafibrate control group (n = 46). Blood samples were drawn 8 and 16 weeks after entry to the study to evaluate whole blood transit time as a hemorheological parameter, leukocyte activity by MCFAN, and serum FFA levels. No serious adverse events were observed in either of the groups. After 16 weeks, the pemafibrate group showed a 38.6% reduction in triglycerides and a 50.7% reduction in remnant lipoproteins. Pemafibrate treatment did not significantly improve whole blood rheology or leukocyte activity in patients with type 2 diabetes mellitus or metabolic syndrome complicated by hypertriglyceridemia and exacerbated hemorheology.
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Vigil P, Meléndez J, Petkovic G, Del Río JP. The importance of estradiol for body weight regulation in women. Front Endocrinol (Lausanne) 2022; 13:951186. [PMID: 36419765 PMCID: PMC9677105 DOI: 10.3389/fendo.2022.951186] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022] Open
Abstract
Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders.
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Affiliation(s)
- Pilar Vigil
- Reproductive Health Research Institute (RHRI), Santiago, Chile
| | - Jaime Meléndez
- Reproductive Health Research Institute (RHRI), Santiago, Chile
| | - Grace Petkovic
- Arrowe Park Hospital, Department of Paediatrics, Wirral CH49 5PE, Merseyside, United Kingdom
| | - Juan Pablo Del Río
- Unidad de Psiquiatría Infantil y del Adolescente, Clínica Psiquiátrica Universitaria, Universidad de Chile, Santiago, Chile
- Millennium Nucleus to Improve the Mental Health of Adolescents and Youths, Millennium Science Initiative, Santiago, Chile
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Peschel G, Grimm J, Müller M, Höring M, Krautbauer S, Weigand K, Liebisch G, Buechler C. Sex-specific changes in triglyceride profiles in liver cirrhosis and hepatitis C virus infection. Lipids Health Dis 2022; 21:106. [PMID: 36280840 PMCID: PMC9590217 DOI: 10.1186/s12944-022-01715-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/11/2022] [Indexed: 12/05/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection is associated with serum lipid abnormalities, which partly normalize following direct-acting antiviral (DAA) therapy. Here, associations of serum triglycerides (TGs) with viral genotype and markers of liver disease severity were evaluated in patients with chronic HCV. Methods The study included the serum of 177 patients with chronic HCV. TGs were quantified by flow injection analysis Fourier transform mass spectrometry. Laboratory values and noninvasive scores for liver fibrosis assessment were determined. The nonparametric Kruskal‒Wallis test, one-way ANOVA, multiple linear regression and Student’s t test were used as appropriate. P values were adjusted for multiple comparisons. Results HCV-infected women had lower serum TGs than men, and thus, a sex-specific analysis was performed. None of the 46 TG species analyzed differed in the serum of female patients with and without liver cirrhosis. In contrast, in the serum of male patients with liver cirrhosis, TGs with 53, 56 and 58 carbon atoms and three to eight double bonds were diminished. These polyunsaturated TGs were also low in males with a high fibrosis-4 score. TGs with 7 or 8 double bonds negatively correlated with the model of end-stage liver disease score in males. In addition, TGs with 49, 51 and 53 carbon atoms were reduced in male patients infected with genotype 3a in comparison to genotype 1a. TGs with 56 carbon atoms were lower in genotype 3a-infected males than in genotype 1b-infected males. TGs did not differ in females by genotype. Genotype 3-related changes disappeared at the end of therapy with DAAs. Overall, the levels of serum TGs did not change during DAA therapy in either sex. Consequently, the serum TGs of males with liver cirrhosis were lower than those of males without cirrhosis at the end of therapy. Such a difference was not apparent in females. Conclusions The decline in TGs observed only in male patients with liver cirrhosis and male patients infected with genotype 3 illustrates sex-specific changes in lipid metabolism in chronic HCV. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-022-01715-w.
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Affiliation(s)
- Georg Peschel
- grid.411941.80000 0000 9194 7179Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany ,Department of Internal Medicine, Klinikum Fürstenfeldbruck, 82256 Fürstenfeldbruck, Germany
| | - Jonathan Grimm
- grid.411941.80000 0000 9194 7179Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Martina Müller
- grid.411941.80000 0000 9194 7179Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Marcus Höring
- grid.411941.80000 0000 9194 7179Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, 93053 Regensburg, Germany
| | - Sabrina Krautbauer
- grid.411941.80000 0000 9194 7179Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, 93053 Regensburg, Germany
| | - Kilian Weigand
- grid.411941.80000 0000 9194 7179Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany ,grid.502406.50000 0004 0559 328XDepartment of Gastroenterology, Gemeinschaftsklinikum Mittelrhein, 56073 Koblenz, Germany
| | - Gerhard Liebisch
- grid.411941.80000 0000 9194 7179Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, 93053 Regensburg, Germany
| | - Christa Buechler
- grid.411941.80000 0000 9194 7179Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany
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Făgărășan I, Rusu A, Cristea M, Bala CG, Vulturar DM, Cristea C, Todea DA. Predictors of New-Onset Diabetes in Hospitalized Patients with SARS-CoV-2 Infection. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:13230. [PMID: 36293811 PMCID: PMC9603418 DOI: 10.3390/ijerph192013230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 06/16/2023]
Abstract
The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is one of the world's most disruptive health crises. The presence of diabetes plays an important role in the severity of the infection, and a rise in newly diagnosed diabetes cases has been identified. The aim of this retrospective study was to determine the incidence of new-onset diabetes (NOD) and predictive factors with their cut-off values for patients hospitalized with COVID-19. All patients (n = 219) hospitalized for COVID-19 during three consecutive months were included. NOD was diagnosed in 26.48% of patients. The severity of the infection, hospital admission values for fasting plasma glucose, lactate dehydrogenase (LDH), PaO2/FiO2 ratio, the peak values for leucocytes, neutrophils, C-reactive protein, triglycerides, and the need for care in the intensive care unit were predictors for the occurrence of NOD in univariate analysis, while only LDH level remained a significant predictor in the multivariable analysis. In conclusion, the results of the study showed a high incidence of NOD in patients hospitalized with COVID-19 and identified LDH levels at hospital admission as a significant predictor of NOD during SARS-CoV-2 infection. However, the persistence of NOD after the COVID-19 infection is not known, therefore, the results must be interpreted with caution.
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Affiliation(s)
- Iulia Făgărășan
- Department of Pneumology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400332 Cluj-Napoca, Romania
| | - Adriana Rusu
- Department of Diabetes and Nutrition Diseases, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Maria Cristea
- Faculty of Electrical Engineering, Technical University of Cluj-Napoca, 26–28 G. Barițiu Street, 400027 Cluj-Napoca, Romania
| | - Cornelia-Gabriela Bala
- Department of Diabetes and Nutrition Diseases, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Damiana-Maria Vulturar
- Department of Pneumology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400332 Cluj-Napoca, Romania
| | - Ciprian Cristea
- Faculty of Electrical Engineering, Technical University of Cluj-Napoca, 26–28 G. Barițiu Street, 400027 Cluj-Napoca, Romania
| | - Doina-Adina Todea
- Department of Pneumology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400332 Cluj-Napoca, Romania
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Yoon H. Relationship between Metabolic Syndrome, Metabolic Syndrome Score, Insulin Resistance and Beta Cell Function in Korean Adults with Obesity. KOREAN JOURNAL OF CLINICAL LABORATORY SCIENCE 2020. [DOI: 10.15324/kjcls.2020.52.4.327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Hyun Yoon
- Department of Clinical Laboratory Science, Wonkwang Health Science University, Iksan, Korea
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Bai D, Wu Y, Deol P, Nobumori Y, Zhou Q, Sladek FM, Liu X. Palmitic acid negatively regulates tumor suppressor PTEN through T366 phosphorylation and protein degradation. Cancer Lett 2020; 496:127-133. [PMID: 33039560 DOI: 10.1016/j.canlet.2020.10.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/19/2020] [Accepted: 10/06/2020] [Indexed: 01/22/2023]
Abstract
Chronic elevated free fatty (FFA) levels are linked to metabolic disorders and tumorigenesis. However, the molecular mechanism by which FFAs induce cancer remains poorly understood. Here, we show that the tumor suppressor PTEN protein levels were decreased in high fat diet (HFD) fed mice. As palmitic acid (PA, C16:0) showed a significant increase in the HFD fed mice, we further investigated its role in PTEN down regulation. Our studies revealed that exposure of cells to high doses of PA induced mTOR/S6K-mediated phosphorylation of PTEN at T366. The phosphorylation subsequently enhanced the interaction of PTEN with the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which promoted polyubiquitination of PTEN and protein degradation. Consistent with PTEN degradation, exposure of cells to increased concentrations of PA also promoted PTEN-mediated AKT activation and cell proliferation. Significantly, a higher level of S6K activation, PTEN T366 phosphorylation, and AKT activation were also observed in the livers of the HFD fed mice. These results provide a molecular mechanism by which a HFD and elevated PA regulate cell proliferation through inactivation of tumor suppressor PTEN.
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Affiliation(s)
- Dongmei Bai
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Yong Wu
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Poonamjot Deol
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA
| | - Yumiko Nobumori
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Qi Zhou
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA
| | - Xuan Liu
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA.
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Song Y, Søndergaard E, Jensen MD. Unique Metabolic Features of Adults Discordant for Indices of Insulin Resistance. J Clin Endocrinol Metab 2020; 105:5837675. [PMID: 32413132 PMCID: PMC7286305 DOI: 10.1210/clinem/dgaa265] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/11/2020] [Indexed: 01/01/2023]
Abstract
PURPOSE Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Adipose Insulin Resistance index (ADIPO-IR) values are often concordant. In this study we evaluated whether there are groups discordant for HOMA-IR and ADIPOpalmitate-IR and, if so, what are their defining characteristics. METHODS The body composition, basal metabolic rate (BMR), fasting plasma lipids, insulin, glucose, and free fatty acid (FFA) palmitate concentrations data of 466 volunteers from previous research studies were abstracted and analyzed. The middle 2 population quartiles for HOMA-IR and Adipose Insulin Resistance index palmitate concentration (ADIPOpalmitate-IR) defined medium HOMA-IR and ADIPOpalmitate-IR (MH and MA), the top and bottom quartiles were defined as high/low HOMA (HH/LH), and high/low ADIPOpalmitate as HA/LA. Because ADIPOpalmitate-IR was significantly greater in women than in men, we established sex-specific quartiles for each index. We identified groups discordant for HOMA-IR and ADIPO-IR (HHMA, LHMA, MHHA, and MHLA). RESULTS Body fat and fasting triglycerides (TGs) were significantly greater with higher indices in the concordant groups (HHHA > MHMA > LHLA). MHHA differed from MHLA by visceral fat (P < .01) and fasting TGs (P < .05), whereas HHMA differed (P < .01) from LHMA by BMR. By multivariate regression, the group factor contributed to BMR (P < .01) and visceral fat (P < .05). CONCLUSIONS Adults discordant for HOMA-IR and ADIPO-IR have unique features including differences in visceral fat, TGs, and BMR. This suggests different forms of insulin resistance are present, which should be considered when studying insulin resistance in the future.
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Affiliation(s)
- Yilin Song
- Division of Endocrinology, Diabetes and Metabolism, Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, US
| | - Esben Søndergaard
- Division of Endocrinology, Diabetes and Metabolism, Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, US
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark
| | - Michael D Jensen
- Division of Endocrinology, Diabetes and Metabolism, Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, US
- Correspondence and Reprint Requests: Michael D. Jensen, MD, Mayo Clinic, Endocrine Research Unit, 200 1st Street SW, Rm 5-194 Joseph, Rochester, MN 55905. E-mail:
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Abstract
INTRODUCTION The Diabetes Prevention Program study results indicated that metformin therapy was not as beneficial as a lifestyle modification for delaying the development of type 2 diabetes in individuals at high risk of the disease. A key feature in the etiology of type 2 diabetes mellitus, which appears in the prediabetic phase, is a significant deficiency, compared to healthy controls, in highly flexible poly-cis-unsaturated fatty acyl chains in membrane phospholipids. This deficiency lowers membrane flexibility, which in turn, reduces the amount of all functional Class I glucose transporters, and thereby reduces glucose-mediated ATP production. This leads to an increase in essentially saturated free fatty acid (FFA) levels for fatty-acid-mediated ATP production, which will set up a vicious cycle of raising the levels of essentially saturated FFAs and lowering the level of transmembrane glucose transport. Metformin suppresses hepatic gluconeogenesis, which reduces the plasma glucose concentration. CONCLUSION We hypothesize that chronic metformin treatment leads to an additional increase in essentially saturated FFAs, which causes an additional rise in membrane stiffness and hypoxia. So we propose that all these metformin-mediated activities accelerated the onset of type 2 diabetes in the participants of the metformin group in the Diabetes Prevention Program study, compared to the participants of the lifestyle-intervention group in this study. We propose that the biochemical reactions, involved in the fatty-acid-mediated ATP production, play an important part in the increase of the observed essentially saturated FFA concentrations. These statements should also extend to the metformin therapy of individuals with type 2 diabetes.
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Affiliation(s)
- Rob N M Weijers
- Teaching Hospital, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
| | - Dick J Bekedam
- Department of Obstetrics and Gynecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
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Moran M, Cheng X, Shihabudeen Haider Ali MS, Wase N, Nguyen N, Yang W, Zhang C, DiRusso C, Sun X. Transcriptome analysis-identified long noncoding RNA CRNDE in maintaining endothelial cell proliferation, migration, and tube formation. Sci Rep 2019; 9:19548. [PMID: 31863035 PMCID: PMC6925215 DOI: 10.1038/s41598-019-56030-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 12/05/2019] [Indexed: 12/22/2022] Open
Abstract
Obesity is a leading risk factor for type-2 diabetes. Diabetes often leads to the dysregulation of angiogenesis, although the mechanism is not fully understood. Previously, long noncoding RNAs (lncRNAs) have been found to modulate angiogenesis. In this study, we asked how the expression levels of lncRNAs change in endothelial cells in response to excessive palmitic acid treatment, an obesity-like condition. Bioinformatics analysis revealed that 305 protein-coding transcripts were upregulated and 70 were downregulated, while 64 lncRNAs were upregulated and 46 were downregulated. Gene ontology and pathway analysis identified endoplasmic reticulum stress, HIF-1 signaling, and Toll-like receptor signaling as enriched after palmitic acid treatment. Moreover, we newly report enrichment of AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling, and cysteine and methionine metabolism by palmitic acid. One lncRNA, Colorectal Neoplasia Differentially Expressed (CRNDE), was selected for further investigation. Palmitic acid induces CRNDE expression by 1.9-fold. We observed that CRNDE knockdown decreases endothelial cell proliferation, migration, and capillary tube formation. These decreases are synergistic under palmitic acid stress. These data demonstrated that lncRNA CRNDE is a regulator of endothelial cell proliferation, migration, and tube formation in response to palmitic acid, and a potential target for therapies treating the complications of obesity-induced diabetes.
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Affiliation(s)
- Matthew Moran
- Department of Biochemistry, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | - Xiao Cheng
- Department of Biochemistry, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | | | - Nishikant Wase
- Department of Biochemistry, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | - Nghi Nguyen
- Department of Biochemistry, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | - Weilong Yang
- Center for Plant Science Innovation, School of Biological Sciences, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | - Chi Zhang
- Center for Plant Science Innovation, School of Biological Sciences, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | - Concetta DiRusso
- Department of Biochemistry, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA.,Nebraska Center for Integrated Biomolecular Communication, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA
| | - Xinghui Sun
- Department of Biochemistry, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA. .,Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska - Lincoln, Lincoln, Nebraska, 68588, USA.
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13
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Shalash MAM, Rohoma KH, Kandil NS, Abdel Mohsen MA, Taha AAF. Serum sclerostin level and its relation to subclinical atherosclerosis in subjects with type 2 diabetes. J Diabetes Complications 2019; 33:592-597. [PMID: 31129005 DOI: 10.1016/j.jdiacomp.2019.04.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/18/2019] [Accepted: 04/21/2019] [Indexed: 01/20/2023]
Abstract
BACKGROUND Sclerostin, a Wnt-signalling inhibitor, is an established negative regulator of bone formation. However, data regarding its potential importance in vascular disease are less clear. Common carotid artery media thickness (CIMT) assessment and plaque identification using ultrasound imaging are well-recognized tools for identifying and monitoring atherosclerosis. The aim of the present study is to examine the relationship between serum sclerostin and subclinical atherosclerosis (as evidenced by CIMT). METHODS This cross-sectional study included 50 subjects with T2DM and 20 subjects as a control group. Multivariable linear regression models were used to assess the association of sclerostin with subclinical atherosclerosis. RESULTS Serum sclerostin levels in T2DM patients were significantly higher compared to the control group (167.16 ± 63.60 versus 85.98 ± 23.74 pg/ml, P < 0.0001). A concentration of ≥162.5 pg/ml showed a sensitivity of 90% and a specificity of 86.67% to detect an increased risk of subclinical atherosclerosis. Univariate analysis revealed a significant positive correlation between serum sclerostin and CIMT (r = 0.635, P < 0.001). Sclerostin concentrations remained independently associated with CIMT (β = 63.188 [6.919-119.456], P = 0.017) after adjusting for age and gender. CONCLUSION Our data suggest a positive correlation between serum sclerostin level and subclinical atherosclerosis in subjects with type 2 diabetes mellitus.
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Affiliation(s)
- Magui Abdel Moneim Shalash
- Department of Internal Medicine (Unit of Diabetes and Metabolism), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Kamel Hemida Rohoma
- Department of Internal Medicine (Unit of Diabetes and Metabolism), Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Noha Said Kandil
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | | | - Aya Abdul Fattah Taha
- Department of Internal Medicine (Unit of Diabetes and Metabolism), Faculty of Medicine, Alexandria University, Alexandria, Egypt
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14
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Awadalla H, Noor SK, Elmadhoun WM, Bushara SO, Almobarak AO, Sulaiman AA, Ahmed MH. Comparison of serum lipid profile in type 2 diabetes with and without adequate diabetes control in Sudanese population in north of Sudan. Diabetes Metab Syndr 2018; 12:961-964. [PMID: 29954711 DOI: 10.1016/j.dsx.2018.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 06/05/2018] [Indexed: 10/14/2022]
Abstract
BACKGROUND Diabetes mellitus (DM) is a major health problem in Sudan and is a leading cause of morbidity and mortality. Dyslipidemia is a major complication of diabetes and an important risk factor for cardiovascular disease (CVD). The objective of this study was to determine the prevalence of dyslipidemia and its co-relation with the glycemic control in individuals with diabetes in River Nile State, Sudan. METHODS Individuals with diabetes attended, Naserudin Karamalla Diabetic (NKDM) Centre, in Atbara teaching hospital during study period, who volunteered to participate were included. Only those on treatment for DM for at least one year were included. Venous samples were collected for cholesterol, triglycerides, HDL, LDL, blood glucose and Glycosylated hemoglobin. Participants were interviewed using standardized pretested questionnaire to record medical history and sociodemographic characteristics. Blood pressure, body mass index (BMI) and waist circumference were measured. RESULTS A total of 188 individuals were included. The mean age was 49.5 + 13.9 and (128) 68.1% were females. Most patients were having DM for at least 3-5 years 69 (36.7%). Poor diabetes control (HbA1c >7) was recorded in 87.2%, hypercholesterolemia, hypertriglyceridemia and high LDL were identified in 36.6%, 27.7% and 26.6% respectively. In addition, HDL was low in 61.2% of patients. CONCLUSION Low HDL is a prominent feature in two thirds of individuals with diabetes, while high cholesterol and high triglyceride were seen in over one quarter.
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Affiliation(s)
- Heitham Awadalla
- Department of community Medicine, Faculty of Medicine, University of Khartoum, Sudan
| | - Sufian K Noor
- Department of Medicine, Nile Valley University, Atbara, Sudan
| | | | - Sarra O Bushara
- Department of Medicine, Nile Valley University, Atbara, Sudan
| | - Ahmed O Almobarak
- Department of Pathology, Faculty of Medicine, University of Medical Sciences and Technology, Khartoum, Sudan
| | - Amel Abdalrhim Sulaiman
- Research & Information Unit, Public Health Administration - MOH, Qassim Region, Saudi Arabia
| | - Mohamed H Ahmed
- Department of Medicine and HIV metabolic clinic, Milton Keynes University Hospital NHS Foundation Trust, Eaglestone, Milton Keynes, Buckinghamshire, UK.
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15
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Postprandial glycaemic and lipaemic responses to chronic coffee consumption may be modulated by CYP1A2 polymorphisms. Br J Nutr 2018; 119:792-800. [DOI: 10.1017/s0007114518000260] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AbstractThere is much epidemiological evidence suggesting a reduced risk of development of type 2 diabetes (T2D) in habitual coffee drinkers, however to date there have been few longer-term interventions, directly examining the effects of coffee intake on glucose and lipid metabolism. Previous studies may be confounded by inter-individual variation in caffeine metabolism. Specifically, the rs762551 SNP in the CYP1A2 gene has been demonstrated to influence caffeine metabolism, with carriers of the C allele considered to be of a ‘slow’ metaboliser phenotype. This study investigated the effects of regular coffee intake on markers of glucose and lipid metabolism in coffee-naïve individuals, with novel analysis by rs762551 genotype. Participants were randomised to either a coffee group (n 19) who consumed four cups/d instant coffee for 12 weeks or a control group (n 8) who remained coffee/caffeine free. Venous blood samples were taken pre- and post-intervention. Primary analysis revealed no significant differences between groups. Analysis of the coffee group by genotype revealed several differences. Before coffee intake, the AC genotype (‘slow’ caffeine metabolisers, n 9) displayed higher baseline glucose and NEFA than the AA genotype (‘fast’ caffeine metabolisers, n 10, P<0·05). Post-intervention, reduced postprandial glycaemia and reduced NEFA suppression were observed in the AC genotype, with the opposite result observed in the AA genotype (P<0·05). These observed differences between genotypes warrant further investigation and indicate there may be no one-size-fits-all recommendation with regard to coffee drinking and T2D risk.
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16
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Yasu T, Mutoh A, Wada H, Kobayashi M, Kikuchi Y, Momomura S, Ueda S. Renin-Angiotensin System Inhibitors Can Prevent Intravenous Lipid Infusion-Induced Myocardial Microvascular Dysfunction and Leukocyte Activation. Circ J 2018; 82:494-501. [PMID: 28954968 DOI: 10.1253/circj.cj-17-0809] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
BACKGROUND Levels of triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to endothelial dysfunction through renin-angiotensin system (RAS) activation and oxidative stress. The present study investigated how systemic FFA loading affected myocardial microcirculation during hyperemia via RAS. METHODS AND RESULTS Eight healthy men received candesartan, perindopril, or a placebo for 2 days in a double-blind crossover design, and then myocardial microcirculation during hyperemia induced by a 2-h infusion of lipid/heparin was assessed using dipyridamole stress-myocardial contrast echocardiography (MCE). Leukocyte activity and hemorheology were also assessed ex vivo using a microchannel flow analyzer, serum levels of oxidative stress markers, and IκB-α expression in mononuclear cells. Serum FFA elevation by the infusion of lipid/heparin significantly decreased myocardial capillary blood velocity and myocardial blood flow during hyperemia. Both candesartan and perindopril significantly prevented the FFA-induced decrease in capillary blood velocity and myocardial blood flow during hyperemia. Systemic FFA loading also caused an increase in the number of adherent leukocytes and prolonged the whole blood passage time. These effects were blocked completely by candesartan and partially by perindopril. Both agents prevented the FFA-induced enhancement of oxidative stress and IκB-α degradation in mononuclear cells. CONCLUSIONS Both candesartan and perindopril can prevent FFA-induced myocardial microcirculatory dysfunction during hyperemia via modulation of leukocyte activation and microvascular endothelial function.
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Affiliation(s)
- Takanori Yasu
- Department of Cardiovascular Medicine & Nephrology, Dokkyo Medical University Nikko Medical Center
| | - Akiko Mutoh
- Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus Graduate School of Medicine
| | - Hiroshi Wada
- Department of First Integrated Medicine, Saitama Medical Center, Jichi Medical University
| | - Mayumi Kobayashi
- Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus Graduate School of Medicine
| | | | - Shinichi Momomura
- Department of First Integrated Medicine, Saitama Medical Center, Jichi Medical University
| | - Shinichiro Ueda
- Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus Graduate School of Medicine
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17
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Feng R, Luo C, Li C, Du S, Okekunle AP, Li Y, Chen Y, Zi T, Niu Y. Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: a case - control study. Lipids Health Dis 2017; 16:165. [PMID: 28870233 PMCID: PMC5584533 DOI: 10.1186/s12944-017-0551-1] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 08/15/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) given its association with obesity and diabetes may perhaps exert distinct free fatty acids (FFA) pattern, but the understanding of this phenomenon is limited. To this effect, we evaluated FFA profiles among healthy subjects and NAFLD patients stratified by body weight, to identify FFA valuable for early diagnosis of NAFLD. METHODS Serum FFA profiles of healthy and NAFLD (lean, overweight and obese) subjects was determined using gas chromatography-mass spectrometry (GC-MS) and distinctions in FFA patterns were evaluated using one-way ANOVA while Receiver operating characteristics (ROC) and logistic regression models were used to explore FFA significant for diagnosing NAFLD. RESULTS NAFLD patients presented significantly higher (P < 0.05) serum FFA profiles compared to healthy controls (HC). While total FFA profiles were insignificantly different between lean (2093.33 ± 558.11 μg/ml) and overweight (2420.81 ± 555.18 μg/ml) NAFLD patients, obese NAFLD (2739.01 ± 810.35 μg/ml) presented most significantly elevated (P < 0.05) total FFA profiles compared with HC. Of the four FFA; myristic acid (14:0), palmitoleic acid (16:1), γ-linolenic acid (γ-18:3) and cis-7,10,13,16,19-docosapentaenoic acid (22:5), selected in ROC analysis given their high Youden's index and AUC, only 14:0; 5.58(1.37, 22.76) and 16:1; 4.36(1.34, 14.13) had statistical significant odd ratios. CONCLUSION Our findings suggest 14:0 and 16:1 are promising for early diagnosis of NAFLD.
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Affiliation(s)
- Rennan Feng
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China.
| | - Chao Luo
- STD & AIDS Center, Harbin Center for Disease Control and Prevention, Harbin, Heilongjiang Province, 150056, China
| | - Chunlong Li
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150081, China
| | - Shanshan Du
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China
| | - Akinkunmi Paul Okekunle
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China
| | - Yanchuan Li
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China
| | - Yang Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China
| | - Tianqi Zi
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China
| | - Yucun Niu
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, 150081, China
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18
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Yoon H, Jeong DK, Lee KS, Kim HS, Moon AE, Park J. Relationship between metabolic syndrome and metabolic syndrome score and beta cell function by gender in Korean populations with obesity. Endocr J 2016; 63:785-793. [PMID: 27350719 DOI: 10.1507/endocrj.ej16-0106] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The present study was conducted to assess the relationships between metabolic syndrome and metabolic syndrome score (MSS) and beta cell function by gender in Korean populations with obesity. This study included 1,686 adults aged 20 or older using the 2010 Korea National Health and Nutrition Examination Survey (KNHANES) data, which represent national data in Korea. The key study results were as follows: First, in men, after adjusting for related variables (including body mass index), metabolic syndrome (p=0.005) and MSS (p=0.018) were inversely associated with the homeostatic model assessment of beta cell function (HOMA-B) values. Second, in women, after adjusting for related variables, metabolic syndrome (p=0.616) and MSS (p=0.929) were not associated with HOMA-B levels. In conclusion, metabolic syndrome and MSS were inversely associated with beta cell function in Korean men with obesity, but not in Korean women with obesity.
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Affiliation(s)
- Hyun Yoon
- Department of Biomedical Laboratory Science, Hanlyo University, Gwangyang-si, Jeollanam-do 57764, South Korea
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19
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Weijers RNM. Membrane flexibility, free fatty acids, and the onset of vascular and neurological lesions in type 2 diabetes. J Diabetes Metab Disord 2016; 15:13. [PMID: 27123439 PMCID: PMC4847252 DOI: 10.1186/s40200-016-0235-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 04/10/2016] [Indexed: 12/13/2022]
Abstract
Free fatty acids released from human adipose tissue contain a limited amount of non-esterified poly-cis-unsaturated fatty acids. In cases of elevated plasma free fatty acids, this condition ultimately leads to a shift from unsaturated to saturated fatty-acyl chains in membrane phospholipids. Because this shift promotes the physical attractive van der Waals interactions between phospholipid acyl chains, it increases stiffness of both erythrocyte and endothelial membranes, which causes a reduction in both insulin-independent and insulin-dependent Class 1 glucose transporters, a reduction in cell membrane functionality, and a decreased microcirculatory blood flow which results in tissue hypoxia. Against the background of these processes, we review recently published experimental phospholipid data obtained from Drosophila melanogaster and from human erythrocytes of controls and patients with type 2 diabetes, with and without retinopathy, along the way free fatty acids interfere with eye and kidney function in patients with type 2 diabetes and give rise to endoplasmic reticulum stress, reduced insulin sensitivity, and ischemia.
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Affiliation(s)
- Rob N M Weijers
- Teaching Hospital, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
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20
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Lorenzo C, Hanley AJ, Rewers MJ, Festa A, Haffner SM. Lipoprotein heterogeneity may help to detect individuals with insulin resistance. Diabetologia 2015; 58:2765-73. [PMID: 26341113 DOI: 10.1007/s00125-015-3743-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 08/10/2015] [Indexed: 01/10/2023]
Abstract
AIMS/HYPOTHESIS The triacylglycerol (TG)-to-HDL-cholesterol ratio has been shown to detect insulin resistance. However, the added predictive value of a more comprehensive assessment of lipoprotein composition is unknown. METHODS We analysed cross-sectional data from 882 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Lipoproteins were measured by nuclear magnetic resonance (NMR) spectroscopy. Determined by the frequently sampled intravenous glucose tolerance test, insulin resistance was defined as the lowest sex-specific quartile of insulin sensitivity. RESULTS The AUC of the receiver operating characteristic curve of HDL-cholesterol and TG levels for detecting insulin resistance was similar to that of the TG-to-HDL-cholesterol ratio (0.676 vs 0.673; p = 0.685), but smaller than the AUC of NMR-detected lipoproteins (0.676 vs 0.745; p < 0.001). NMR lipoproteins added discriminative value to HDL-cholesterol and TG levels (net reclassification improvement of 40.0%; p < 0.001; and integrated discrimination improvement of 9.5%; p < 0.001), with net benefit within predicted probabilities of between 10% and 50% by Vickers' decision-curve analysis. We also demonstrated additive value to demographic variables, BMI and levels of fasting glucose, TG, and HDL-cholesterol (net reclassification improvement of 14.0%; p < 0.001; and integrated discrimination improvement of 4.5%; p < 0.001). CONCLUSIONS/INTERPRETATION NMR lipoproteins, which can be measured in the fasting state, add information to the TG and HDL-cholesterol ratio across a broad range on insulin resistance. Depending on the other risk factors of insulin resistance that are incorporated, NMR lipoproteins permit the correct reclassification of an additional 14-40% of individuals.
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Affiliation(s)
- Carlos Lorenzo
- Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
| | - Anthony J Hanley
- Department of Nutritional Sciences, and the Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Department of Medicine, and the Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University Colorado School of Medicine, Aurora, CO, USA
| | | | - Steven M Haffner
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
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21
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Shen M, Kumar SPDS, Shi H. Estradiol regulates insulin signaling and inflammation in adipose tissue. Horm Mol Biol Clin Investig 2015; 17:99-107. [PMID: 25372734 DOI: 10.1515/hmbci-2014-0007] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 02/28/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Obesity-associated low-grade inflammation at white adipose tissue (WAT) leads to metabolic defects. Sex steroid hormone estrogen may be protective against high-fat diet (HFD)-induced obesity and insulin resistance. This has been tested by many previous studies utilizing rodent models of ovariectomy (OVX) and/or treatment of estradiol (E2), the major biologically active form of estrogen. Body weight and adiposity are increased by OVX and reduced following E2 treatment, however. Thus, the protective roles of E2 may be secondary effects to the changes in body weight and adiposity. We hypothesize that E2 directly prevents inflammation and maintains insulin sensitivity in WAT independent of energy status using mice with similar body weights and adiposity. MATERIALS AND METHODS Four groups of female C57BL/6 mice were used, including sham-operated mice treated with vehicle for E2 and fed with either a low-fat diet (LFD; Sham-Veh-LFD) or a HFD (Sham-Veh-HFD), and HFD-fed OVX mice treated with either vehicle (OVX-Veh-HFD) or E2 (OVX-E2-HFD). Body weight and abdominal parametrial WAT mass, insulin signaling, and expression levels of genes related to low-grade inflammation in WAT were compared between these groups pair-fed with equal amounts of calories for a period of 4 days. RESULTS Body weights and WAT mass were similar in all four groups. OVX-Veh-HFD mice had impaired insulin signaling associated with rapid activation of inflammation, whereas OVX-E2-HFD group maintained insulin sensitivity without showing inflammation in WAT. CONCLUSIONS E2 directly contributed to the maintenance of insulin sensitivity during the early phase of development of metabolic dysfunction, possibly via preventing low-grade inflammation in WAT.
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22
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Velloso LA, Folli F, Saad MJ. TLR4 at the Crossroads of Nutrients, Gut Microbiota, and Metabolic Inflammation. Endocr Rev 2015; 36:245-71. [PMID: 25811237 DOI: 10.1210/er.2014-1100] [Citation(s) in RCA: 187] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity is accompanied by the activation of low-grade inflammatory activity in metabolically relevant tissues. Studies have shown that obesity-associated insulin resistance results from the inflammatory targeting and inhibition of key proteins of the insulin-signaling pathway. At least three apparently distinct mechanisms-endoplasmic reticulum stress, toll-like receptor (TLR) 4 activation, and changes in gut microbiota-have been identified as triggers of obesity-associated metabolic inflammation; thus, they are expected to represent potential targets for the treatment of obesity and its comorbidities. Here, we review the data that place TLR4 in the center of the events that connect the consumption of dietary fats with metabolic inflammation and insulin resistance. Changes in the gut microbiota can lead to reduced integrity of the intestinal barrier, leading to increased leakage of lipopolysaccharides and fatty acids, which can act upon TLR4 to activate systemic inflammation. Fatty acids can also trigger endoplasmic reticulum stress, which can be further stimulated by cross talk with active TLR4. Thus, the current data support a connection among the three main triggers of metabolic inflammation, and TLR4 emerges as a link among all of these mechanisms.
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Affiliation(s)
- Licio A Velloso
- Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
| | - Franco Folli
- Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
| | - Mario J Saad
- Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
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23
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Weijers RNM. Unsaturation index and type 2 diabetes: Unknown, unloved. World J Meta-Anal 2015; 3:89-92. [DOI: 10.13105/wjma.v3.i2.89] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Revised: 01/28/2015] [Accepted: 04/07/2015] [Indexed: 02/05/2023] Open
Abstract
A useful parameter for interpreting analyses of membrane fatty-acid composition is the unsaturation index (UI), a measure of unsaturation that is calculated as the mean number of cis double bonds per fatty-acid residue multiplied by 100. The UI is a fundamental parameter that contains information about many membrane biophysical properties and behavior. UI is a crucial index for type 2 diabetes (T2D) and other disorders, yet it is not properly considered in the scientific community. The goal of the present editorial is to familiarize the scientific T2D community with the UI. The idea of early systemic cell-membrane disease necessitates new thinking and suggests that UI should feature prominently on the research agenda.
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Tereshina EV, Ivanenko SI. Age-related obesity is a heritage of the evolutionary past. BIOCHEMISTRY (MOSCOW) 2015; 79:581-92. [PMID: 25108322 DOI: 10.1134/s0006297914070013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In the process of human aging, an increase in the total amount of fat is observed mainly due to accumulation of lipids in non-adipose tissues. Insulin resistance, provoked by the intracellular accumulation of triglycerides, is often associated with development of such age-related diseases as atherosclerosis, type 2 diabetes, cancer, osteoporosis, and also with systemic inflammation and lipo- and glucose toxicity. Accumulation of lipids and lipophilic compounds is a biological phenomenon common for both prokaryotes and eukaryotes. Initially, it arose as an adaptation to starvation and shortage of nitrogen-containing nutrients, but later it converted into a depot of membrane material, needed on recommencement of cell division. In rodents and humans, the accumulation of non-metabolized fat in non-adipose tissues can be regarded as an adaptation to changes in the internal medium on a certain stage of ontogenesis as a result of age-related dysfunction of adipose tissue.
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Affiliation(s)
- E V Tereshina
- World Wide Medical Assistance, Oberwil B. Zug, 6317, Switzerland.
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25
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Rojas JM, Bruinstroop E, Printz RL, Alijagic-Boers A, Foppen E, Turney MK, George L, Beck-Sickinger AG, Kalsbeek A, Niswender KD. Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation. Mol Metab 2015; 4:210-21. [PMID: 25737956 PMCID: PMC4338317 DOI: 10.1016/j.molmet.2015.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 12/29/2014] [Accepted: 01/09/2015] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous system (CNS) neuropeptide Y (NPY); in fact, a single intracerebroventricular (icv) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion and does so, in large part, via signaling through the CNS NPY Y1 receptor. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism. METHODS Chow-fed Zucker fatty (ZF) rats were pair-fed by matching their caloric intake to that of lean controls and effects on body weight, plasma TG, and liver content of TG and phospholipid (PL) were compared to ad-libitum (ad-lib) fed ZF rats. Additionally, lean 4-h fasted rats with intact or disrupted hepatic sympathetic innervation were treated with icv NPY or NPY Y1 receptor agonist to identify novel hepatic mechanisms by which NPY promotes VLDL particle maturation and secretion. RESULTS Manipulation of plasma TG levels in obese ZF rats, through pair-feeding had no effect on liver TG content; however, hepatic PL content was substantially reduced and was tightly correlated with plasma TG levels. Treatment with icv NPY or a selective NPY Y1 receptor agonist in lean fasted rats robustly activated key hepatic regulatory proteins, stearoyl-CoA desaturase-1 (SCD-1), ADP-ribosylation factor-1 (ARF-1), and lipin-1, known to be involved in remodeling liver PL into TG for VLDL maturation and secretion. Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation. CONCLUSIONS These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is dependent on the Y1 receptor and sympathetic signaling to the liver.
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Key Words
- AGPAT, 1-acyl-glycerol-3-phosphate acyltransferase
- ARF-1, ADP-ribosylation factor-1
- ApoB, apolipoprotein B
- CNS, central nervous system
- Cyto, cytoplasmic
- DAG, diacylglycerol
- DGAT, diacylglycerol acyltransferase
- ER, endoplasmic reticulum
- FFA(s), free fatty acid(s)
- GAPDH, glyceraldehyde 3-phosphate dehydrogenase
- HDAC-1, histone deacetylase-1
- Lipin-1
- NE, norepinephrine
- NPY Y1 receptor
- NPY, neuropeptide Y
- Nuc, nuclear
- PA, phosphatidic acid
- PAP-1, phosphatidic acid phosphatase-1
- PF, pair-fed
- PL, phospholipid
- PLD, phospholipase D
- POMC, proopiomelanocortin
- Phospholipid
- RPL13A, ribosomal protein L13a
- RT-PCR, real-time PCR
- SCD-1, stearoyl-CoA desaturase-1
- SNS, sympathetic nervous system
- Sham, sham-denervation
- Sx, sympathetic denervation
- Sympathetic denervation
- TG, triglyceride
- Triglyceride
- VLDL
- VLDL, very low-density lipoprotein
- Veh, vehicle
- ZF, Zucker fatty
- ad-lib, ad-libitum
- icv, intracerebroventricular
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Affiliation(s)
- Jennifer M. Rojas
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Eveline Bruinstroop
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Richard L. Printz
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Aldijana Alijagic-Boers
- Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Science, Amsterdam, The Netherlands
| | - Ewout Foppen
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Maxine K. Turney
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Leena George
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Annette G. Beck-Sickinger
- Institute of Biochemistry, Faculty of Bioscience, Pharmacy and Psychology, Leipzig University, Leipzig, Germany
| | - Andries Kalsbeek
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Science, Amsterdam, The Netherlands
| | - Kevin D. Niswender
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
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Diet-induced obesity modulates epigenetic responses to ionizing radiation in mice. PLoS One 2014; 9:e106277. [PMID: 25171162 PMCID: PMC4149562 DOI: 10.1371/journal.pone.0106277] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 08/05/2014] [Indexed: 01/16/2023] Open
Abstract
Both exposure to ionizing radiation and obesity have been associated with various pathologies including cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and other risk factors, such as obesity. In order to evaluate radiation responses in obese animals, C3H and C57BL/6J mice fed a control normal fat or a high fat (HF) diet were exposed to fractionated doses of X-rays (0.75 Gy ×4). Bone marrow micronucleus assays did not suggest a modulation of radiation-induced genotoxicity by HF diet. Using MSP, we observed that the promoters of p16 and Dapk genes were methylated in the livers of C57BL/6J mice fed a HF diet (irradiated and non-irradiated); Mgmt promoter was methylated in irradiated and/or HF diet-fed mice. In addition, methylation PCR arrays identified Ep300 and Socs1 (whose promoters exhibited higher methylation levels in non-irradiated HF diet-fed mice) as potential targets for further studies. We then compared microRNA regulations after radiation exposure in the livers of C57BL/6J mice fed a normal or an HF diet, using microRNA arrays. Interestingly, radiation-triggered microRNA regulations observed in normal mice were not observed in obese mice. miR-466e was upregulated in non-irradiated obese mice. In vitro free fatty acid (palmitic acid, oleic acid) administration sensitized AML12 mouse liver cells to ionizing radiation, but the inhibition of miR-466e counteracted this radio-sensitization, suggesting that the modulation of radiation responses by diet-induced obesity might involve miR-466e expression. All together, our results suggested the existence of dietary effects on radiation responses (especially epigenetic regulations) in mice, possibly in relationship with obesity-induced chronic oxidative stress.
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Pari L, Rajarajeswari N, Saravanan S, Rathinam A. Antihyperlipidemic effect of coumarin in experimental type 2 diabetic rats. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.bionut.2014.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Wu Y, Zhou H, Wu K, Lee S, Li R, Liu X. PTEN phosphorylation and nuclear export mediate free fatty acid-induced oxidative stress. Antioxid Redox Signal 2014; 20:1382-95. [PMID: 24063548 PMCID: PMC3936505 DOI: 10.1089/ars.2013.5498] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIM Oxidative stress induced by free fatty acids (FFA) contributes to metabolic syndrome-associated development of cardiovascular diseases, yet molecular mechanisms remain poorly understood. This study aimed at establishing whether phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and its subcellular location play a role in FFA-induced endothelial oxidative stress. RESULTS Exposing human endothelial cells (ECs) with FFA activated mammalian target of rapamycin (mTOR)/S6K pathway, and upon activation, S6K directly phosphorylated PTEN at S380. Phosphorylation of PTEN increased its interaction with its deubiquitinase USP7 in the nucleus, leading to PTEN deubiquitination and nuclear export. The reduction of PTEN in the nucleus, in turn, decreased p53 acetylation and transcription, reduced the expression of the p53 target gene glutathione peroxidase-1 (GPX1), resulting in reactive oxygen species (ROS) accumulation and endothelial damage. Finally, C57BL/6J mice fed with high-fat atherogenic diet (HFAD) showed PTEN nuclear export, decreased p53 and GPX1 protein expressions, elevated levels of ROS, and significant lesions in aortas. Importantly, inhibition of mTOR or S6K effectively blocked these effects, suggesting that mTOR/S6K pathway mediates HFAD-induced oxidative stress and vascular damage via PTEN/p53/GPX1 inhibition in vivo. INNOVATION Our study demonstrated for the first time that S6K directly phosphorylated PTEN at S380 under high FFA conditions, and this phosphorylation mediated FFA-induced endothelial oxidative stress. Furthermore, we showed that S380 phosphorylation affected PTEN monoubiquitination and nuclear localization, providing the first example of coordinated regulation of PTEN nuclear localization via phosphorylation and ubiquitination. CONCLUSION Our studies provide a novel mechanism by which hyperlipidemia causes vascular oxidative damage through the phosphorylation of PTEN, blocking of PTEN nuclear function, and inhibition of p53/GPX1 activity.
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Affiliation(s)
- Yong Wu
- 1 Department of Biochemistry, University of California , Riverside, California
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29
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Senthil Kumar SPD, Shen M, Spicer EG, Goudjo-Ako AJ, Stumph JD, Zhang J, Shi H. Distinct metabolic effects following short-term exposure of different high-fat diets in male and female mice. Endocr J 2014; 61:457-70. [PMID: 24646677 PMCID: PMC4045093 DOI: 10.1507/endocrj.ej13-0455] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Obesity-associated hepatic lipid accumulation and chronic low-grade inflammation lead to metabolic defects. Saturated fatty acids (SFA) are a risk factor for, whereas unsaturated fatty acids (UFA) are thought to be protective against, developing metabolic diseases. Sex differences exist in the regulation of metabolism. We tested the hypothesis that diets high in SFA, mono-UFA (MUFA), or poly-UFA (PUFA) had early, sex-distinct effects that differentially contribute to long-term metabolic disturbance such as fatty liver and insulin resistance. Metabolic changes including body and fat mass, circulating leptin and glucose levels, plasma lipid profile, hepatic lipid accumulation, expression levels of genes related to lipid metabolism and low-grade inflammation, and tissue insulin sensitivity were compared between male and female mice fed with a low-fat chow, or high-fat SFA, MUFA, or PUFA for a short period of four days. SFA and MUFA males increased adiposity associated with increased liver lipid accumulation and rapid activation of inflammation in adipose and muscle tissues, whereas PUFA males did not show lipid accumulation or tissue inflammation compared to chow males. All SFA and UFA males displayed tissue insulin resistance. In contrast, female high-fat diet groups had normal liver lipid content and maintained tissue insulin sensitivity without showing tissue inflammation. Therefore, sex differences existed during early phase of development of metabolic dysfunction. The beneficial effects of PUFA, but not MUFA, were corroborated in protection of obesity, hyperlipidemia, fatty liver, and low-grade inflammation. The benefit of MUFA and PUFA in maintaining tissue insulin sensitivity in males, however, was questioned.
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Affiliation(s)
| | - Minqian Shen
- Cell, Molecular, and Structural Biology, Miami University, Ohio, 45056, United States
| | - Elizabeth G Spicer
- Department of Nursing, School of Engineering and Applied Sciences, Miami University, Ohio, 45056, United States
| | - Ashley J Goudjo-Ako
- Program in Physiology and Neuroscience, Department of Biology, Miami University, Ohio, 45056, United States
| | - Justin D Stumph
- Program in Physiology and Neuroscience, Department of Biology, Miami University, Ohio, 45056, United States
| | - Jing Zhang
- Department of Statistics, Miami University, Ohio, 45056, United States
| | - Haifei Shi
- Cell, Molecular, and Structural Biology, Miami University, Ohio, 45056, United States
- Program in Physiology and Neuroscience, Department of Biology, Miami University, Ohio, 45056, United States
- Corresponding author: Haifei Shi, Department of Biology, Miami University, 700 E High St., Oxford, Ohio, 45056, United States, 001-513-529-3162 (Phone), 001-513-529-6900 (Fax),
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30
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McGill JB, Vlajnic A, Knutsen PG, Recklein C, Rimler M, Fisher SJ. Effect of gender on treatment outcomes in type 2 diabetes mellitus. Diabetes Res Clin Pract 2013; 102:167-74. [PMID: 24183259 DOI: 10.1016/j.diabres.2013.10.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 07/30/2013] [Accepted: 10/01/2013] [Indexed: 02/08/2023]
Abstract
AIM To evaluate the effect of gender on clinical outcomes in people with type 2 diabetes mellitus (T2DM) receiving antidiabetes therapy. METHODS This is a pooled analysis from nine similarly designed phase 3 and 4 randomized, controlled studies evaluating insulin glargine and an active comparator (NPH insulin, insulin lispro, premixed insulin, oral antidiabetes drugs, dietary intervention) in adults with T2DM. Impact of gender on outcomes including HbA1c, fasting plasma glucose (FPG), weight-adjusted insulin dose, and hypoglycemia incidence was evaluated after 24 weeks of treatment. RESULTS Overall, 1651 male and 1287 female individuals were included; 49.8% and 50.2% were treated with insulin glargine or comparators, respectively. Females receiving insulin glargine were less likely than males to achieve a glycemic target of HbA1c≤7.0% (53mmol/mol) (54.3% vs 60.8%, respectively, p=0.0162); there was no difference between females and males receiving comparators (52.7% vs 51.3%, respectively, p=0.4625). Females had significantly greater reductions in FPG (3.1mg/dL, p=0.0458), required significantly higher insulin doses (0.03IU/kg, p=0.0071), and had significantly higher annual rates of symptomatic (p<0.0001), glucose-confirmed (<50 and <70mg/dL) symptomatic (p=0.0005 and p<0.0001), and severe hypoglycemia (p=0.0020) than males. CONCLUSIONS Females in this analysis had smaller reductions in HbA1c and were less likely to reach glycemic goals despite higher insulin doses and more hypoglycemic events than males. Differences in gender responses to therapy should be considered when individualizing treatment for people with T2DM.
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Affiliation(s)
- J B McGill
- Washington University School of Medicine, St. Louis, MO, USA.
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31
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Jian ZH, Lung CC, Ko PC, Sun YH, Huang JY, Ho CC, Ho CY, Chiang YC, Chen CJ, Liaw YP. The association between the apolipoprotein A1/ high density lipoprotein -cholesterol and diabetes in Taiwan - a cross-sectional study. BMC Endocr Disord 2013; 13:42. [PMID: 24093822 PMCID: PMC3851878 DOI: 10.1186/1472-6823-13-42] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 09/18/2013] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Traditional lipid indices have been associated with type 2 diabetes, but it remains uncertain which lipid index is the best discriminator for diabetes. In this study, we aimed to assess lipoproteins, traditional lipid variables, and other variables to discover their association with diabetes in the Taiwanese population. METHODS Data from a nationwide cross-sectional population-based survey of 3087 men and 3373 women in 2002 were analyzed in this study. All participants were assessed for anthropometry, glycosylated hemoglobin, fasting sugar and lipid profiles with triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoprotein A1 (ApoA1) and B (ApoB). The ratio of LDL-C/HDL-C, ApoB/ApoA1, ApoB/LDL-C and ApoA1/HDL-C and other variables were analyzed to determine their potential roles in type 2 diabetes in the Taiwanese population. The Odds ratios (ORs) of the risk variables for diabetes were estimated using logistic regression and were adjusted for confounding factors. RESULTS The increased ratio of ApoA1/HDL-C was significantly associated with diabetes in men (top tertile vs. lowest: OR 2.98; 95% CI: 1.12 - 7.92; P-trend = 0.030) and women (top tertile vs. lowest: OR 2.15; 95% CI: 1.00 - 4.59; P-trend = 0.047). A modest increased diabetic risk was evident with ApoB/LDL-C in women (top tertile vs. lowest: OR 2.03; 95% CI: 1.07- 3.85; P-trend = 0.028), but not in men (top tertile v. lowest: OR 1.69; 95% CI: 0.79- 3.62; P-trend = 0.198). CONCLUSIONS ApoA1/HDL-C had a significant linear association with diabetes in both sexes and was superior to other lipid and lipoprotein variables among the general Taiwanese population.
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Affiliation(s)
- Zhi-Hong Jian
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Chia-Chi Lung
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical, University Hospital, Taichung City 40201, Taiwan
| | - Pei-Chieh Ko
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Yi-Hua Sun
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Department of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Jing-Yang Huang
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Chien-Chang Ho
- Department of Health and Leisure Management, Yuanpei University, Hsinchu, Taiwan
| | - Chia-Yo Ho
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Yi-Chen Chiang
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Yung-Po Liaw
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical, University Hospital, Taichung City 40201, Taiwan
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Dihydropyridine calcium channel blockers inhibit non-esterified-fatty-acid-induced endothelial and rheological dysfunction. Clin Sci (Lond) 2013; 125:247-55. [PMID: 23535137 DOI: 10.1042/cs20120311] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Circulating NEFAs (non-esterified fatty acids) from adipose tissue lipolysis lead to endothelial dysfunction and insulin resistance in patients with the metabolic syndrome or Type 2 diabetes mellitus. The aim of the present study was to test the hypothesis that DHP (dihydropyridine) CCBs (calcium channel blockers) prevent NEFA-induced endothelial and haemorheological dysfunction independently of their antihypertensive properties. Using a double-blind cross-over study design, nifedipine, amlodipine, diltiazem or placebo were administered to eight healthy subjects for 2 days before each study day. On the study days, the following were assessed before and after the infusion of lipid and heparin to raise serum NEFAs: endothelial function, by measuring FBF (forearm blood flow) responses to ACh (acetylcholine); leucocyte activation, by ex vivo measurement of plasma MPO (myeloperoxidase) levels, adherent leucocyte numbers and whole blood transit time through microchannels; and oxidative stress, by determining plasma levels of d-ROMs (derivatives of reactive oxygen metabolites). Effects of the CCBs on NF-κB (nuclear factor κB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in vitro. Elevated NEFAs reduced the responses to ACh and significantly increased whole blood transit time, adherent leucocyte numbers and d-ROMs. Nifedipine and amlodipine, but not diltiazem, prevented NEFA-induced endothelial dysfunction, leucocyte activation and enhancement of oxidative stress without affecting BP (blood pressure), whereas all these drugs prevented NEFA-induced p65 activation in vitro. These results suggest that DHP CCBs, independent of their antihypertensive properties in humans, prevent NEFA-induced endothelial and haemorheological dysfunction through inhibition of NEFA-induced leucocyte activation, although the sensitivity to drugs of leucocyte Ca2+ channels may differ among cells.
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Manning PJ, Sutherland WHF, Williams SM, Walker RJ, Berry EA, De Jong SA, Ryalls AR. The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis 2013; 23:543-549. [PMID: 22402059 DOI: 10.1016/j.numecd.2011.11.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 11/01/2011] [Accepted: 11/17/2011] [Indexed: 12/31/2022]
Abstract
The metabolic syndrome is associated with abnormal glucose and lipid metabolism, insulin resistance, increased oxidative stress and pro-inflammatory activity that increase the risk of type 2 diabetes and cardiovascular disease. The aim of this study was to investigate the effect of treatment with the antioxidant α-lipoic acid (ALA) with or without vitamin E supplementation, on markers of insulin resistance and systemic inflammation and plasma nonesterified fatty acid (NEFA) concentrations in individuals with the metabolic syndrome. In a randomized, double-blind, placebo-controlled trial, subjects with the metabolic syndrome received ALA (600 mg/day, n = 34), vitamin E (100 IU/day, n = 36), both ALA and vitamin E (n = 41), or matching placebo (n = 40) for 1 year. Fasting circulating concentrations of glucose and insulin were measure every 3 months and NEFA, markers of inflammation, adiponectin and vitamin E were measured at 6 monthly intervals. Plasma NEFA concentrations decreased [-10 (-18, 0)%] at a marginal level of significance (p = 0.05) in those who received ALA alone compared with placebo and decreased [-8 (-14, -1)% (95% CI)] significantly (P = 0.02) in participants who were randomised to ALA with and without vitamin E compared with those who did not receive ALA. Fasting glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and markers of inflammation did not change significantly during the study. These data suggest that prolonged treatment with ALA may modestly reduce plasma NEFA concentrations but does not alter insulin or glucose levels in individuals with the metabolic syndrome.
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Affiliation(s)
- P J Manning
- Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
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Lorenzo C, Hanley AJ, Rewers MJ, Haffner SM. The association of alanine aminotransferase within the normal and mildly elevated range with lipoproteins and apolipoproteins: the Insulin Resistance Atherosclerosis Study. Diabetologia 2013; 56:746-57. [PMID: 23344727 PMCID: PMC3615715 DOI: 10.1007/s00125-012-2826-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 12/14/2012] [Indexed: 01/01/2023]
Abstract
AIMS/HYPOTHESIS Markers of liver injury, such as alanine aminotransferase (ALT), have been associated with atherogenic lipoprotein changes. We examined the extent to which this association was explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. METHODS In this analysis we included 824 non-diabetic participants (age 40-69 years) in the Insulin Resistance Atherosclerosis Study. No participants reported excessive alcohol intake or treatment with lipid-lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and lipoprotein heterogeneity by nuclear magnetic resonance (NMR) spectroscopy. RESULTS ALT had a positive relationship with triacylglycerols, LDL-to-HDL-cholesterol ratio and apolipoprotein B (ApoB) after adjusting for demographic variables (p < 0.001 for all three relationships). ALT was also associated with the following NMR lipoproteins: positively with large VLDL (p < 0.001), intermediate-density lipoprotein (IDL) (p < 0.001) and small LDL subclass particles (p < 0.001), and VLDL particle size (p < 0.001); and negatively with large LDL subclass particles (p < 0.05) and LDL (p < 0.001) and HDL particle sizes (p < 0.01). ALT remained associated with IDL and small LDL subclass particles and ApoB after adjusting for glucose tolerance, adiposity, directly measured insulin sensitivity and C-reactive protein. CONCLUSIONS/INTERPRETATION ALT is associated with a wide range of atherogenic lipoprotein changes, which are partially explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. Because of the significant variability in the relationship between ALT and liver fat, further studies are needed to assess the extent of the lipoprotein changes using a direct measure of liver fat.
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Affiliation(s)
- C Lorenzo
- Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
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35
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Xie W, Zhai Z, Yang Y, Kuang T, Wang C. Free fatty acids inhibit TM-EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome. J Thromb Thrombolysis 2013; 34:468-74. [PMID: 22903729 DOI: 10.1007/s11239-012-0793-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Metabolic syndrome is associated with significant hypercoagulable prothrombotic tendency; however, the mechanism for the prothrombotic state is not completely understood. We hypothesize that higher circulating plasma free fatty acids (FFAs) in metabolic syndrome inhibit the endothelial thrombomodulin (TM)-endothelial protein C receptor (EPCR) pathway, thereby promoting thrombus formation. Human umbilical vein endothelial cells were cultured in media supplemented with various doses of palmitic acid (PA), in the presence or absence of JNK inhibitor, and the expression of TM and EPCR was measured by western blot. The thrombotic state of high fat fed C57BL/6J mice was examined by tail bleeding time and deep venous thrombosis (DVT) model. As a result, PA inhibited the expression of TM and EPCR in endothelial cells, and this effect was blunted by inhibiting JNK signaling. High fat diet fed mice had higher level of circulating FFAs and exhibited prothrombotic state, evidenced by increased tail bleeding time and enlarged thrombotic size in DVT model, compared to the control diet fed mice. Hence, FFAs inhibit TM-EPCR-Protein C system in endothelial cells through activating JNK signaling, which may be a mechanism for the prothrombotic state in metabolic syndrome.
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Affiliation(s)
- Wanmu Xie
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China
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Mashili F, Chibalin AV, Krook A, Zierath JR. Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes. Diabetes 2013; 62:457-65. [PMID: 23043161 PMCID: PMC3554355 DOI: 10.2337/db12-0337] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is involved in cytokine- and nutrient-induced insulin resistance. The role of STAT3 in the development of skeletal muscle insulin resistance and type 2 diabetes (T2D) pathogenesis is incompletely defined. We tested the hypothesis that STAT3 signaling contributes to skeletal muscle insulin resistance in T2D. Protein abundance and phosphorylation of STAT3 signaling molecules were determined in skeletal muscle biopsy specimens from BMI- and age-matched overweight individuals with normal glucose tolerant (NGT) and T2D patients. The direct role of STAT3 in the development of lipid-induced skeletal muscle insulin resistance was determined using small interfering (si)RNA. Phosphorylated STAT3, phosphorylated Janus kinase 2 (JAK2), and suppressor of cytokine signaling 3 (SOCS3) protein abundance was increased in skeletal muscle from T2D patients. STAT3 phosphorylation positively correlated with free fatty acid level and measures of insulin sensitivity in NGT but not T2D patients. Palmitate exposure led to a constitutive phosphorylation of STAT3, increased protein abundance of SOCS3, and development of insulin resistance in L6 myotubes. These effects were prevented by siRNA-mediated STAT3 silencing. In summary, STAT3 is constitutively phosphorylated in skeletal muscle from T2D patients. STAT3 gene silencing prevents lipid-induced insulin resistance in cultured myotubes. Collectively, our results implicate excessive STAT3 signaling in the development of skeletal muscle insulin resistance in T2D.
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Affiliation(s)
- Fredirick Mashili
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Alexander V. Chibalin
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Anna Krook
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Juleen R. Zierath
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Corresponding author: Juleen R. Zierath,
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The clinical availability of non alcoholic fatty liver disease as an early predictor of the metabolic syndrome in Korean men: 5-year's prospective cohort study. Atherosclerosis 2013; 227:398-403. [PMID: 23390894 DOI: 10.1016/j.atherosclerosis.2013.01.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 01/01/2013] [Accepted: 01/02/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVES There were many studies for the clinical association between non alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS). However, while most of studies have focused on the unilateral effects of MetS on NAFLD, studies for reverse association were comparatively rare. Therefore, we carried out a prospective cohort study to evaluate the longitudinal effects of NAFLD on the development of MetS according to the degree of NAFLD. PATIENTS AND METHODS A total of 46,874 men, who had participated in a medical health check-up program in 2005, were enrolled in this study. Out of them, a Mets-free cohort of 11,926 without excluding conditions was followed up until 2010. All participants were classified into 3 groups by their NAFLD status (normal, mild, moderate to severe). The baseline values of metabolic components and the development rates of MetS were compared according to the degree of NAFLD. Cox proportional hazards model was used to measure the hazard ratios (HRs) for MetS according to the degree of NAFLD. RESULTS During 41,912.1 person-years of follow-up, 1861 incident cases of MetS developed between 2006 and 2010. Even after adjusting for multiple covariates, the HRs (95% CI) for MetS were higher in the mild group (1.49; 1.30-1.70) and moderate to severe group (2.00; 1.46-2.73) compared to normal group, respectively (P for trend <0.001). These associations were apparent in the clinically relevant subgroup analyses. CONCLUSIONS NAFLD was independent risk factor for MetS during the 5-yr follow-up period.
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Bush NC, Basu R, Rizza RA, Nair KS, Khosla S, Jensen MD. Insulin-mediated FFA suppression is associated with triglyceridemia and insulin sensitivity independent of adiposity. J Clin Endocrinol Metab 2012; 97:4130-8. [PMID: 22933539 PMCID: PMC3485612 DOI: 10.1210/jc.2012-2285] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
CONTEXT A central/visceral fat distribution and excess free fatty acid (FFA) availability are associated with dyslipidemia and insulin resistance. However, these two characteristics often coexist, making it difficult to detect the independent contributions of each. Whether FFA suppression is more closely linked to metabolic abnormalities is not clear. OBJECTIVE The aim of the study was to examine the relationship between FFA suppression, body fat distribution, and fitness as contributors toward insulin resistance and hypertriglyceridemia. DESIGN We measured systemic palmitate turnover using an iv infusion of [9,10-(3)H]palmitate; upper body sc adipose tissue (UBSQ) and visceral adipose tissue (VAT) with dual-energy x-ray absorptiometry and a single-slice abdominal computed tomography scan; fitness with a graded exercise treadmill test; and insulin sensitivity with both the iv glucose tolerance test (IVGTT) (SI(IVGTT)) and mixed meal tolerance test (SI(Meal)). SETTING The study was conducted at a General Clinical Research Center. PARTICIPANTS Baseline data were obtained from 140 elderly adults (age, 60-88 yr; 83 males) and 60 young adults (age, 18-31 yr; 31 males) who participated in a previously published trial assessing the effects of 2-yr supplementation of dehydroepiandrosterone or testosterone on body composition, glucose metabolism, and bone density. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES We measured fasting plasma triglyceride (TG) concentrations, SI(IVGTT), and SI(Meal). RESULTS Using multivariate regression analysis, the strongest combined predictors of TG concentrations were VAT, postmeal nadir FFA concentrations, sex, and age. The best predictors of SI(IVGTT) were IVGTT nadir palmitate concentration, VAT, UBSQ fat, fitness, and age, whereas the best predictors of SI(Meal) were meal nadir palmitate concentration, UBSQ fat, fitness, and sex. CONCLUSIONS FFA suppression is associated with both fasting TG concentrations and insulin sensitivity, independent of measures of adiposity.
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Affiliation(s)
- Nikki C Bush
- Mayo Clinic, Endocrine Research Unit, 200 First Street SW, Room 5-194 Joseph, Rochester, Minnesota 55905, USA
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Dobretsov GE, Syrejshchikova TI, Smolina NV, Uzbekov MG. Effects of fatty acids on human serum albumin binding centers. Bull Exp Biol Med 2012; 153:323-6. [PMID: 22866302 DOI: 10.1007/s10517-012-1706-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Albumin is a carrier of nonesterified long-chain fatty acids and many other ligands. The status of its binding centers was studied for various proportions of nonesterified long-chain fatty acids and albumin as exemplified by palmitic acid. The status of the binding center was tested by recording K-35 probe fluorescence decay in the subnanosecond band. This method showed the work of three types of centers. Palmitic acid enhanced binding activity of all centers, though to a different degree: if the palmitic acid/albumin proportion increased to 2-3, the probe binding to type 1 centers (located in the drug center I region) increased 1.5 times, while binding to type 3 centers increased more than 3-fold. Modification of these centers by nonesterified long-chain fatty acids was similar in the isolated human albumin preparation and in diluted blood serum. Hence, K-35 probe showed the actual status of various albumin centers, their binding capacity depending to a different measure on the fatty acid charge of albumin.
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Affiliation(s)
- G E Dobretsov
- Institute of Physicochemical Medicine, the Russian Academy of Sciences, Moscow, Russia
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Zhang Z, Xue HL, Liu Y, Wang WJ. Yi-Qi-Zeng-Min-Tang, a Chinese medicine, ameliorates insulin resistance in type 2 diabetic rats. World J Gastroenterol 2011; 17:987-95. [PMID: 21448349 PMCID: PMC3057160 DOI: 10.3748/wjg.v17.i8.987] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Revised: 11/17/2010] [Accepted: 11/24/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of the Chinese herbal decoction, Yi-Qi-Zeng-Min-Tang (YQZMT), on insulin resistance in type 2 diabetic rats.
METHODS: Sprague-Dawley rats were divided into two dietary regiments by feeding either normal pellet diet (NPD) or high fat diet (HFD). Four weeks later, the HFD-fed rats were injected intraperitoneally with low-dose streptozotocin (STZ). Rats with non-fasting blood glucose level ≥ 16.67 mmol/L were considered type 2 diabetic and further divided into five subgroups: the type 2 diabetes model group, low-dose, medium-dose and high-dose YQZMT groups, and rosiglitazone group. Age-matched NPD-fed rats served as controls. YQZMT or rosiglitazone were administered for 8 wk. Intraperitoneal glucose and insulin tolerance tests were performed before and after the treatment to measure the glucose tolerance and insulin sensitivity. Serum levels of biochemical parameters, adipocytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), as well as free fatty acids (FFAs), were also analyzed.
RESULTS: There was significant elevation of insulin resistance and serum levels of fasting glucose (12.82 ± 1.08 mmol/L vs 3.60 ± 0.31 mmol/L, P < 0.01), insulin (7197.36 ± 253.89 pg/mL vs 4820.49 ± 326.89 pg/mL, P < 0.01), total cholesterol (TC) (8.40 ± 0.49 mmol/L vs 2.14 ± 0.06 mmol/L, P < 0.01), triglyceride (2.24 ± 0.12 mmol/L vs 0.78 ± 0.05 mmol/L, P < 0.01), low-density lipoprotein cholesterol (LDL-c) (7.84 ± 0.51 mmol/L vs 0.72 ± 0.04 mmol/L, P < 0.01) and decrease in high-density lipoprotein cholesterol (HDL-c) (0.57 ± 0.03 mmol/L vs 1.27 ± 0.03 mmol/L, P < 0.01) in the low-dose STZ and high-fat diet induced type 2 diabetic group when compared with the control group. Administration of YQZMT induced dose- and time-dependent changes in insulin resistance, glucose and lipid profile, and reduced levels of FFA, TNF-α and IL-6 in the type 2 diabetic rats. After the treatment, compared with the diabetic group, the insulin resistance was ameliorated in the high-dose YQZMT (2.82 g/100 g per day) group, with a significant reduction in serum glucose (12.16 ± 1.00 mmol/L vs 17.65 ± 2.22 mmol/L, P < 0.01), homeostasis model assessment of basal insulin resistance (22.68 ± 2.37 vs 38.79 ± 9.02, P < 0.05), triglyceride (0.87 ± 0.15 mmol/L vs 1.99 ± 0.26 mmol/L, P < 0.01), TC (3.31 ± 0.52 mmol/L vs 6.50 ± 1.04 mmol/L, P < 0.01) and LDL-c (2.47 ± 0.50 mmol/L vs 6.00 ± 1.07 mmol/L, P < 0.01), and a significant increase in HDL-c (0.84 ± 0.08 mmol/L vs 0.50 ± 0.03 mmol/L, P < 0.01). But the body weight was not changed significantly.
CONCLUSION: YQZMT, which ameliorates insulin resistance and does not cause increase in body weight, may be a suitable therapeutic adjunct for the treatment of type 2 diabetes.
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Yang Y, Kozloski M. Sex differences in age trajectories of physiological dysregulation: inflammation, metabolic syndrome, and allostatic load. J Gerontol A Biol Sci Med Sci 2011; 66:493-500. [PMID: 21350248 DOI: 10.1093/gerona/glr003] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
There is a paucity of knowledge from population data about sex differences and their age variation in physiological determinants of longevity. This study fills this gap using nationally representative samples of 38,000 individuals aged 17+ from the National Health and Nutrition Examination Survey (1988-2006). It examines sex differences in the age trajectories of 14 markers of physiological functions across multiple systems and three summary indices including inflammation burden, metabolic syndrome, and allostatic load. Statistical analyses show substantial sex differences, age variations, and sex by age interaction effects for all variables examined. These patterns remain robust after adjustment of risk factors and shed light on the biological base of the reduction of sex difference in mortality in the post-reproductive life span.
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Affiliation(s)
- Yang Yang
- Lineberger Comprehensive Cancer Center, Department of Sociology, Carolina Population Center, University of North Carolina, Chapel Hill, NC 27517, USA.
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Rosenson RS, Helenowski IB, Tangney CC. Heterogeneous postprandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy. Cardiovasc Drugs Ther 2010; 24:439-47. [PMID: 20922563 DOI: 10.1007/s10557-010-6264-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5 h) versus late (8 h) postprandial triglyceride responses. METHODS Fifty-five subjects with fasting hypertriglyceridemia (≥1.7 mmol/L (150 mg/ dL) and <5.8 mmol/L (500 mg/dL)) and ≥2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160 mg/d) or placebo for 12 weeks in a double-blind controlled clinical trial. A standardized fat load (50 g/m(2)) was given orally after a 12 h fast. Blood specimens were obtained at 0 h (fasting), 3.5 h, and 8 h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. RESULTS Fenofibrate was more effective in late peakers (n = 8) when compared to early peakers (n = 15) with respect to reducing postprandial triglyceride concentrations (-67% vs. -34%, p = 0.0024) and large VLDL (-76% vs. -31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. CONCLUSIONS Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate.
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Affiliation(s)
- Robert S Rosenson
- Mount Sinai Heart, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1070, New York, NY 10017, USA.
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Goulet ED, Khursigara Z, Gougeon R, Morais JA. Postprandial insulin sensitivity and thermogenesis in frail elderly women. Appl Physiol Nutr Metab 2010; 35:526-33. [DOI: 10.1139/h10-041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The frailty syndrome is associated with inflammation, hypercortisolemia, and cardiovascular diseases, all of which are linked with insulin resistance. But whether frailty is characterized by insulin resistance is unclear, especially in the postprandial state. The prevalence of underweight with frailty is high. We wondered whether hypermetabolism associated with inflammation and hypercortisolemia could increase the thermic effect of food (TEF) and contribute to the frailty-associated body weight loss. In this study, we determined whether insulin sensitivity and TEF responses differ between frail and healthy elderly persons following a meal. Ten healthy and 13 frail elderly women were recruited and studied during the 5 h following the ingestion of a standardized liquid mixed-meal test. Areas under the curve (AUC) for glucose and insulin, and the product of AUC glucose × AUC insulin × 10−6 (PGI) were used as indices of insulin sensitivity. TEF was measured by indirect calorimetry. Following the meal, glucose and insulin AUCs and PGI were significantly higher in frail than in healthy elderly women and, except for the insulin AUC; these differences remained significant after adjustment for age, body weight, and physical activity. Physical activity, determined by questionnaire, was the single best predictor of PGI, explaining 27% of its variance. There was no difference in TEF between groups, and it did not correlate with any significant variable measured. Our results suggest that postprandial insulin resistance is higher in frail than in healthy elderly women, and TEF is similar, indicating that both processes do not contribute to the propensity for body weight loss.
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Affiliation(s)
- Eric D.B. Goulet
- McGill Nutrition and Food Science Centre, McGill University Health Center–Royal Victoria Hospital, Montreal, QC H3A 1A1, Canada
| | - Zareen Khursigara
- McGill Nutrition and Food Science Centre, McGill University Health Center–Royal Victoria Hospital, Montreal, QC H3A 1A1, Canada
| | - Réjeanne Gougeon
- McGill Nutrition and Food Science Centre, McGill University Health Center–Royal Victoria Hospital, Montreal, QC H3A 1A1, Canada
| | - José A. Morais
- McGill Nutrition and Food Science Centre, McGill University Health Center–Royal Victoria Hospital, Montreal, QC H3A 1A1, Canada
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Eidelman O, Jozwik C, Huang W, Srivastava M, Rothwell SW, Jacobowitz DM, Ji X, Zhang X, Guggino W, Wright J, Kiefer J, Olsen C, Adimi N, Mueller GP, Pollard HB. Gender dependence for a subset of the low-abundance signaling proteome in human platelets. HUMAN GENOMICS AND PROTEOMICS : HGP 2010; 2010:164906. [PMID: 20981232 PMCID: PMC2958630 DOI: 10.4061/2010/164906] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Accepted: 01/05/2010] [Indexed: 11/23/2022]
Abstract
The incidence of cardiovascular diseases is ten-times higher in males than females, although the biological basis for this gender disparity is not known. However, based on the fact that antiplatelet drugs are the mainstay for prevention and therapy, we hypothesized that the signaling proteomes in platelets from normal male donors might be more activated than platelets from normal female donors. We report here that platelets from male donors express significantly higher levels of signaling cascade proteins than platelets from female
donors. In silico connectivity analysis shows that the 24 major hubs in platelets from male donors focus on pathways associated with megakaryocytic expansion and platelet activation. By contrast, the 11 major hubs in platelets from female donors were found to be either negative or neutral for platelet-relevant processes. The difference may suggest a biological mechanism for gender discrimination in cardiovascular disease.
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Affiliation(s)
- Ofer Eidelman
- Department of Anatomy, Physiology and Genetics, USU Center for Medical Proteomics, Uniformed Services University, School of Medicine, USUHS, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
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Ley SH, Harris SB, Connelly PW, Mamakeesick M, Gittelsohn J, Wolever TM, Hegele RA, Zinman B, Hanley AJ. Association of apolipoprotein B with incident type 2 diabetes in an aboriginal Canadian population. Clin Chem 2010; 56:666-70. [PMID: 20110448 DOI: 10.1373/clinchem.2009.136994] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Expanding evidence indicates that apolipoprotein B (apo B) is superior to LDL cholesterol as a marker of vascular disease. Although traditional lipid measures are known to predict type 2 diabetes, limited data are available regarding apo B. We assessed the association of apo B with incident type 2 diabetes and compared it with traditional lipid variables as a risk predictor in aboriginal Canadians. METHODS Of an initial cohort of 606 individuals without diabetes in 1993-1995, 540 were contacted for the 10-year follow-up evaluation in 2003-2005. Fasting and 2-h postload glucose concentrations were obtained at baseline and follow-up to determine incident type 2 diabetes. Baseline fasting serum lipids were measured with standard laboratory procedures. RESULTS The cumulative 10-year incidence of type 2 diabetes was 17.5%. High concentrations of apo B, triglycerides, and LDL cholesterol, and low concentrations of HDL cholesterol were individually associated with incident type 2 diabetes in univariate analyses. Comparing C statistics of univariate models showed apo B to be a superior determinant of incident diabetes compared with LDL (P = 0.026) or HDL (P = 0.004) cholesterol. With multivariate adjustment including waist circumference, apo B (odds ratio, 1.50; 95% CI, 1.11-2.02) and triglycerides (odds ratio, 1.49; 95% CI, 1.12-1.98) remained associated with incident diabetes, whereas LDL and HDL cholesterol became nonsignificant. CONCLUSIONS The association of plasma apo B with incident type 2 diabetes and its better prediction of risk compared with LDL or HDL cholesterol suggest the potential for the use of apo B in type 2 diabetes risk communication and prevention.
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Affiliation(s)
- Sylvia H Ley
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
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Singh H, Brindle NPJ, Zammit VA. High glucose and elevated fatty acids suppress signaling by the endothelium protective ligand angiopoietin-1. Microvasc Res 2010; 79:121-7. [PMID: 20079751 DOI: 10.1016/j.mvr.2010.01.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 01/07/2010] [Indexed: 11/19/2022]
Abstract
Pre-diabetes is characterized by hyperglycemia and dyslipidemia; it is associated with increased cardiovascular disease and endothelial dysfunction. Angiopoietin-1 (Ang1), a ligand for endothelial receptor, is a potent vascular protective factor important in maintaining normal endothelial function. The aim of the study was to examine the influence of elevated glucose and fatty acid concentrations on angiopoietin signaling in human cardiac microvascular endothelial cells. Incubation with 30 mM glucose caused 50% suppression in the ability of Ang1 to activate Tie2-receptor phosphorylation without any decrease in Tie2 expression or increased internalization in microvascular endothelial cells. Examination of downstream signaling revealed inhibition of Ang1-dependent Akt phosphorylation. By contrast, Ang1 activation of Erk1/2 signaling was not affected by hyperglycemia. Similar suppression of Ang1-dependent activation of Akt by hyperglycemia was observed in large vessel human endothelial cells. Incubation of microvascular endothelial cells with 200 microM palmitic acid significantly inhibited Ang1-dependent Akt phosphorylation without affecting phosphorylation of the Tie-2 receptor or of ERK1/2. Therefore, contrary to hyperglycemia, palmitate acted exclusively downstream of the receptor. The present findings suggest a mechanism by which increased glucose or fatty acids may suppress vascular protection by Ang1 and predispose to endothelial dysfunction and vascular disease.
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Affiliation(s)
- Harprit Singh
- University of Leicester, Department of Cardiovascular Sciences, RKCSB, PO Box 65, Leicester LE2 7LX, UK
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Chung Y, Dunson DB. Nonparametric Bayes Conditional Distribution Modeling With Variable Selection. J Am Stat Assoc 2009; 104:1646-1660. [PMID: 23580793 PMCID: PMC3620660 DOI: 10.1198/jasa.2009.tm08302] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This article considers a methodology for flexibly characterizing the relationship between a response and multiple predictors. Goals are (1) to estimate the conditional response distribution addressing the distributional changes across the predictor space, and (2) to identify important predictors for the response distribution change both within local regions and globally. We first introduce the probit stick-breaking process (PSBP) as a prior for an uncountable collection of predictor-dependent random distributions and propose a PSBP mixture (PSBPM) of normal regressions for modeling the conditional distributions. A global variable selection structure is incorporated to discard unimportant predictors, while allowing estimation of posterior inclusion probabilities. Local variable selection is conducted relying on the conditional distribution estimates at different predictor points. An efficient stochastic search sampling algorithm is proposed for posterior computation. The methods are illustrated through simulation and applied to an epidemiologic study.
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Affiliation(s)
- Yeonseung Chung
- Department of Biostatistics, Harvard School of Public Health, 655 Huntington Ave. SPH2, 4th Floor, Boston, MA 02115 ()
| | - David B. Dunson
- Department of Statistical Science, Duke University, 218 Old Chemistry Building, Box 90251, Durham, NC 27707 ()
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Bitzur R, Cohen H, Kamari Y, Shaish A, Harats D. Triglycerides and HDL cholesterol: stars or second leads in diabetes? Diabetes Care 2009; 32 Suppl 2:S373-7. [PMID: 19875584 PMCID: PMC2811435 DOI: 10.2337/dc09-s343] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Rafael Bitzur
- Bert W. Strassburger Lipid Center, Chaim Sheba Medical Center, Tel Hashomer, Israel.
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Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 2009; 297:R587-92. [PMID: 19439618 DOI: 10.1152/ajpregu.90762.2008] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Factors comprising the metabolic syndrome occur with increased incidence in postmenopausal women. To investigate the effects of ovarian failure on the progression of the metabolic syndrome, female B(6)C(3)F(1) mice were treated with 4-vinylcyclohexene diepoxide (VCD) and fed a high-fat (HF) diet for 16 wk. VCD destroys preantral follicles, causing early ovarian failure and is a well-characterized model for the gradual onset of menopause. After 12 wk on a HF diet, VCD-treated mice had developed an impaired glucose tolerance, whereas cycling controls were unaffected [12 wk AUC HF mice 13,455 +/- 643 vs. HF/VCD 17,378 +/- 1140 mg/dl/min, P < 0.05]. After 16 wk on a HF diet, VCD-treated mice had significantly higher fasting insulin levels (HF 5.4 +/- 1.3 vs. HF/VCD 10.1 +/- 1.4 ng/ml, P < 0.05) and were significantly more insulin resistant (HOMA-IR) than cycling controls on a HF diet (HF 56.2 +/- 16.7 vs. HF/VCD 113.1 +/- 19.6 mg/dl x microU/ml, P < 0.05). All mice on a HF diet gained more weight than mice on a standard diet, and weight gain in HF/VCD mice was significantly increased compared with HF cycling controls. Interestingly, even without a HF diet, progression into VCD-induced menopause caused a significant increase in cholesterol and free fatty acids. Furthermore, in mice fed a standard diet (6% fat), insulin resistance developed 4 mo after VCD-induced ovarian failure. Insulin resistance following ovarian failure (menopause) was prevented by estrogen replacement. Studies here demonstrate that ovarian failure (menopause) accelerates progression into the metabolic syndrome and that estrogen replacement prevents the onset of insulin resistance in VCD-treated mice. Thus, the VCD model of menopause provides a physiologically relevant means of studying how sex hormones influence the progression of the metabolic syndrome.
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Affiliation(s)
- Melissa J Romero-Aleshire
- Dept. of Physiology, College of Medicine, 1656 E Mabel St, Univ. of Arizona, Tucson, AZ 85724-5218, USA
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