Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21709


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    Regulation of TGF β1 signaling pathway by Store Operated Calcium Entry in Mesangial Cells: A mechanism for controlling Extracellular Matrix Protein Expression in Kidney
    (2016-03-23) Wang, Yanxia; Li, Weizu; Ma, Rong; Chaudhari, Sarika
    Excessive extracellular matrix (ECM) proteins accumulation in glomerulus is one of the consistent pathological changes seen in kidney diseases, such as diabetic nephropathy. The Orai1-mediated store operated Ca2+ entry (SOCE) is associated with many physiological and pathological processes in a variety of cells, including glomerular mesangial cells (MCs) which are a major source of ECM proteins. Previously, we demonstrated in vivo and in vitro that SOCE is enhanced in MCs in diabetes. Also, in cultured human MCs, activation of store–operated Ca2+ channels significantly decreased fibronectin protein expression and collagen IV mRNA expression while inhibition of the channels significantly increased the expression of fibronectin and collagen IV. In vivo knockdown of Orai1 in MCs in mice using the targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV. However, the downstream mechanism underlying the SOCE effect is not known. Transforming growth factor- β1 (TGFβ1)-Smad3 pathway plays a critical role in ECM protein expression and renal fibrosis. The present study was conducted to test the hypothesis that SOCE suppressed ECM protein expression by inhibiting TGF β1-Smad3 pathway in MCs. In cultured human MCs, TGFβ1- induced activation of Smad3 in terms of its phosphorylation and translocation was examined in presence and absence of thapsigargin (TG, 1 µM), a classical activator of store-operated Ca2+ channel. We found that treatment with TGFβ1 (5 ng/ml for 15 hours) significantly increased the expression level of Phospho-Smad3 (p-Smad3) evaluated by Western blot. However, this response was markedly inhibited by TG treatment. Consistently, immunocytochemistry and Western blot showed that TGF β1 significantly increased the expression of nuclear Smad3. Again, this TGFβ1-induced nuclear translocation of Smad3 was prevented by pre-treatment with TG. Importantly, the TG effect was reversed by La3+ (5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca2+ channel. Furthermore, knockdown of Orai1 using siRNA approach significantly augmented TGFβ1-induced p-Smad3 expression. Taken together, our results indicate that SOCE in MCs negatively regulates the TGFβ1/Smad3 signaling pathway which may in turn suppress the ECM proteins and thus could be a potential therapeutic target of kidney disease with glomerular fibrosis like diabetic nephropathy.
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    Whole Blood NMR Relaxometry for the Detection of Insulin Resistance
    (2016-03-23) Deodhar, Sneha; Mishra, Ina; Cistola, David; Patel, Vipulkumar
    Time-domain nuclear magnetic resonance relaxometry (TD-NMR) is a practical method for measuring the physical and dynamical properties of complex, heterogeneous samples. In prior work, we showed that TD-NMR measurements of human plasma or serum report on an individual’s metabolic status, particularly with respect to insulin resistance. The relationship between plasma water transverse relaxation time (T2) and insulin resistance is mediated by subtle subclinical shifts in protein and lipoprotein levels in the circulation. The previous test required separation of blood cells in order to conduct T2 measurements on isolated plasma or serum. We hypothesized that this separation may not be required, as it is conceivable that similar metabolic relationships could be gleaned from T2 measurements on water in whole blood. To test this hypothesis, we conducted an observational, cross-sectional study of over 30 asymptomatic, non-diabetic human subjects who were recruited though an approved IRB protocol. Antecubital venous blood was drawn into lavender-top tubes containing EDTA as the anticoagulant. The blood samples, prior to NMR measurements, were allowed to spontaneously settle in the tube thereby creating two phases: a liquid supernatant (plasma) and blood cell pellet. The NMR relaxation constants T1 and T2 were determined using a Bruker mq20 Minispec NMR instrument operating at 20MHz. The data were collected using inversion recovery and modified Carr-Purcell-Meiboom-Gill pulse sequences, respectively. The NMR time-decay curves were transformed using an inverse-Laplace algorithm in order to extract T2 values. In addition, we measured over 100 diagnostic biomarkers on each subject and correlated the NMR measurements with established markers of metabolic function. The supernatant water T2 values from whole blood were compared to those obtained from fractionated plasma samples and to the other 100-plus biomarkers. The associations were quantified using parametric and non-paramertic correlations and the Student t-test. Statistically-significant bivariate correlations were observed between whole blood water T2 and and lipid biomarkers, which are associated with insulin resistance and metabloic disease.
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    Redox imbalance and aberrant mitochondrial enzymatic activities in diabetic lung
    (2016-03-23) Jin, Zhen; Yan, Liang-Jun; Wu, Jinzi
    The lung is a known target of diabetic injury, but the underlying mechanisms of damage remains poorly understood. We hypothesized that pulmonary cellular redox imbalance and mitochondrial abnormalities contribute to diabetic lung injury. To test this hypothesis, we induced diabetes in rats by streptozotocin and measured redox imbalance parameters including aldose reductase activity, poly ADP ribose polymerase (PARP) activation, NAD+ and NADPH contents along with mitochondrial functional parameters represented by the enzymatic activities of complexes I to IV. Results indicate that aldose reductase activity was elevated and PARP was upregulated in diabetic lung, while the contents of both NAD+ and NADPH were decreased in diabetic lung, demonstrating an excess NADH-linked redox imbalance problem in diabetic lung. Consequently, the enzymatic activities of complexes I to IV were all elevated in diabetic lung mitochondria due to an NADH oversupply. We also found that the enzymatic activities of dihydrolipoamide dehydrogenase (DLDH) and mitochondrial sirtuin 3 (Sirt3), both of which are inducible enzymes and are NAD+-dependent, were impaired in diabetic lung, and such an impairment was due to a decreased level of protein expression for both DLDH and Sirt3. For DLDH functional impairment in diabetic lung, protein acetylation also appeared to play a role as DLDH acetylation was increased. Additionally, we found that an increased complex I activity in diabetic pulmonary mitochondria was partly due to hyperglycemia-induced upregulation of nicotinamide N-methyltransferase (NNMT) and a concomitant increase in the expression of NDUFS3, a complex I subunit that is responsible for complex I assembly. The overall outcome of this NADH-driven redox imbalance and aberrant mitochondrial enzyme functions were a decreased ATP content, an increased NAD(P)H dehydrogenase, quinone 1 (NQO1) activity, and an elevated hydrogen peroxide concentration that reflects an aggravated oxidative stress. These findings demonstrate that diabetic lung exhibits NADH/NAD+-linked redox imbalance and abnormal mitochondrial function that likely contribute to energy deficiency and oxidative damage involved in diabetic lung injury.
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    HbA1c vs FPG and 2-Hour OGTT Glucose in Identifying Dysglycemia in Youth
    (2016-03-23) de la Torre, Alejandro; Hamilton, Luke; Wilson, Don; Huynh, Ngan
    INTRODUCTION In recent years, there has been an increased incidence of pre‑diabetes and type 2 diabetes mellitus in youth 10 years of age and older.1 Dysglycemia has been shown to be a continuous risk factor for cardiovascular disease and thus offers a compelling reason for evidence-based screening and management.2 Current ADA guidelines for the diagnosis and management of pre-diabetes in youth are based upon extrapolation from adult studies and may not be valid in the pediatric population.1, 3 EXPERIMENTAL METHODS To evaluate the utility of HbA1c in identifying dysglycemia in youth, results of the HbA1c, fasting plasma glucose (FPG), and 2-h oral glucose tolerance test (OGTT) were collected retrospectively from a multiethnic cohort of 390 youth seen in a preventive cardiology clinic from 2012 to 2015. Results of the HbA1c were compared to the FPG and 2-h glucose following a standard OGTT. RESULTS Table 1. Comparison between HbA1c and FPG values Table 2. Comparison between HbA1c and OGTT 2-h glucose values Of the patients with a HbA1c DISCUSSION HbA1c is frequently used to identify dysglycemia in at‑risk youth. Although it is a convenient screening tool, the results may be discordant with other measures of dysglycemia. Results from the 2005‑2010 Yale Pathophysiology of Type 2 Diabetes in Obese Youth Study indicate that the optimal A1c threshold for identifying T2DM was 5.8% and that the best predictor of 2-h glucose at a 2-year follow-up was the combination of the subject’s baseline A1c and 2‑h glucose.4 A cross-sectional study compared results of OGTT and HbA1c to measurement of glycemia via continuous glucose monitoring. The OGTT and HbA1c each predicted different patterns of dysglycemia, with the former providing a greater correlation with peak glucose and variability and the latter providing a greater correlation with average and overnight glucose values.5 CONCLUSION Diagnostic tests for pre-diabetes and diabetes in youth are often discrepant. It would appear that HbA1c is a convenient but imperfect screening tool in youth. The cutoff for the different categories of glycemia may need to be modified, and the HbA1c may need to be paired with the OGTT to increase the sensitivity of pre-diabetes screening in at-risk youth. More studies are needed to evaluate diagnostic markers of dysglycemia and effective management of pre-diabetes in this vulnerable population.
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    Plasma Water T2 as a Biomarker for Early Insulin Resistance Syndrome
    (2016-03-23) Robinson, Michelle; Deodhar, Sneha; Patel, Vipul; Cistola, David; Mishra, Ina
    Insulin resistance is defined as a blunted response to insulin by tissues. It is thought to be the body's response to energy imbalance and is exacerbated by over-nutrition, physical inactivity, obesity and/or genetic factors. Early-stage insulin resistance does not occur in isolation, but is part of a broader syndrome that includes four main components: (1) compensatory hyperinsulinemia, (2) dyslipidemia, (3) subclinical inflammation with shifts in plasma protein levels, and (4) subclinical acid-base abnormalities. Individuals with insulin resistance are at higher risk for developing type 2 diabetes. Yet, insulin resistance is often undetected by the tests used to diagnose and screen for type 2 diabetes, namely fasting serum glucose and hemoglobin A1c. There is an unmet need for practical screening tools for early insulin resistance syndrome in order to preserve pancreatic function and prevent type 2 diabetes. Since water hydrogen bonds to virtually every protein and lipoprotein particle in the blood, we hypothesized that the mobility of water in plasma is sensitive to the subclinical shifts in proteins and lipoproteins that occur in early insulin resistance syndrome. Water mobility can be measured as plasma water T2 using a simple benchtop implementation of nuclear magnetic resonance. To test this hypothesis, we conducted an observational cross-sectional study of 51 asymptomatic, non-diabetic human subjects, ages 24-80, and quantified the association of plasma water T2 values with over 100 established metabolic biomarkers and diagnostic tests. Plasma water T2 exhibited bivariate correlations with markers of each of the four components of the insulin resistance syndrome. Multiple regression models revealed independent associations of plasma water T2 with fasting insulin levels, total serum protein concentration or viscosity, white blood cell or neutrophil count, and total cholesterol. Analysis using receiver operator characteristic curves demonstrated that plasma water T2 can diagnose insulin resistance (as defined by the McAuley Index) with a sensitivity of 86%. By comparison, the sensitivities of fasting glucose and hemoglobin A1c were 14 and 47%, respectively. This discovery provides a foundation for developing a new diagnostic test for early insulin resistance syndrome and a practical screening tool for the early identification of individuals at risk for type 2 diabetes.
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    Analysis of Comorbid Depression and Diabetes among Males 30 – 50 Years of Age
    (2016-03-23) Hartos, Jessica; Cheremateng, Yaa
    Introduction: Depression and diabetes are among the most prevalent chronic diseases in the United States and are common comorbid conditions. The purpose of this study was to assess whether diabetes is a risk factor for depression in a representative sample of males ages 30-50. Methods: This cross sectional analysis used 2013 data from the Behavioral Risk Factor Surveillance System for Mississippi males ages 30-50, N=712. Chi-square analyses and multiple linear regression were used to determine the association between diabetes and depression. Results: Significant relations between diabetes and depression were observed at the bivariate level (p=.02, 95% CI= 1.06, 4.23); however, the relationship was insignificant after controlling for number of chronic health problems, physical activity level, weight, tobacco use, alcohol use, educational level, marital status, age, and ethnicity/race. The relations between number of chronic health problems and depression were significant at the multivariate level. Conclusions: Overall, depression and diabetes were not related in this age group. However, number of chronic health problems was significant for this age group, and thus having multiple comorbidities such as diabetes seems to be a key factor impacting depression risk for males 30-50. Consequently, clinicians should be cognizant of the relationship between comorbidities and depression and provide screening to patients with multiple comorbidities in addition to resources or referrals as necessary.
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    Effect of Body Mass Index and Menopausal Status on Lipid Levels in African American Women
    (2016-03-23) Mecwan, Neil; Dodgen, Leilani; Eke, Ikechukwu; Mandapati, Surendra; Kitzman-Ulrich, Heather; Killion, Jordan
    Background: Lipid levels are negatively impacted by menopause. Total cholesterol (TC), low density lipoproteins (LDL), and triglyceride levels have been shown to increase due to menopause, increasing risk of cardiovascular disease (CVD). Limited research indicates this relationship may be independent of weight status. This study aims to examine lipid levels (TC, LDL-C, fasting glucose) by menopausal and weight status (Body Mass Index [BMI] [greater than] 25) in African American (AA) women to better understand this relationship. Methods: Lipid profile, BMI, and menopausal status were obtained from AA women enrolled in a NIH-funded study, Better Me Within, to evaluate a faith-based diabetes prevention program. This study included overweight and obese AA women with an absence of hysterectomy. Lipid profile (TC, LDL-C, fasting glucose) was obtained after a 12-hour fast via finger stick (Alere Cholestech LDX Analyzer). BMI was calculated with objectively collected height and weight data, and menopausal status through self-report. Results: 56 AA female participants with a mean age of 46.7 (SD=12.4) years were included. LDL, TC, and fasting glucose were all significantly higher in postmenopausal as compared to premenopausal women (all p values Conclusion: In this study of AA women, TC, LDL, and fasting glucose were higher for postmenopausal women compared to premenopausal, and in obese postmenopausal women compared to obese premenopausal women. This study indicates greater levels of BMI worsen the effect of menopausal status on lipid levels. Future research is needed to evaluate the relationship between excess weight, menopause, and lipid levels in larger samples, particularly since AA women are at higher risk for chronic conditions including diabetes and CVD.
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    The Association between Child Health Status and Family Functioning with Risk for Type 2 Diabetes among 10-14 Year Olds
    (2016-03-23) Fulda, Kimberly; Franks, Susan; Fernando, Shane; Habiba, Nusrath; Chen, Peng
    The Association between Child Health Status and Family Functioning with Risk for Type 2 Diabetes among 10-14 Year Olds Authors: Peng Chen – School of Public Health; Kimberly G Fulda, DrPH, Department of Family Medicine, Texas College of Osteopathic Medicine; Susan Franks, PhD, Department of Family Medicine, Texas College of Osteopathic Medicine; Shane Fernando, PhD, Department of Pediatrics, Texas College of Osteopathic Medicine; Nusrath Habiba, MD, Department of Pediatrics, Texas College of Osteopathic Medicine IRB # 2012-151 Abstract Introduction: Obesity is a risk factor for type 2 diabetes (DM2), and family environment stressors can increase risk of obesity among children and adolescents. Family factors such as parental divorce, cohabitation, and remarried family relationships are among these stressors. For example, living in a single-parent family is positively associated with BMI and greater risk of obesity. Poor family functioning has also been linked to overweight and obesity in children. Research, however, has not assessed associations between these stressors and risk for DM2. The purpose of this study was to assess whether child health status and family functioning are associated with being high risk for DM2 among Mexican American children aged 10-14 years. Methods: This cross-sectional study included 298 children and a parent/caregiver. High risk for DM2 was determined by having ≥ 3 of these 5 risk factors: first or second degree relative with DM2, BMI ≥ 95th percentile, blood pressure ≥ 95th percentile, elevated glucose, positive for Acanthosis Nigricans. Logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs) for the association between child’s health status and family functioning with being high risk for DM2. Multiple regression controlled for child factors (age, ethnicity, gender), parent/legal guardian’s factors (marital status, health status, relationship to child), and household factors (primary language spoken in the household and highest household education). Results: Of 298 children, 91 (31%) were high risk for DM2. Parents rated the child’s health as poor/fair/good for 105 (35%) of child participants. Children with poor/fair/good health status were over 5 times (OR: 5.37; 95% CI: 2.84-10.14) more likely to be high risk for DM2 compared to children with very good/excellent health status. None of the family functioning predictors (sharing ideas about things that matter, relationship to child, making decisions together, and coping with demands of parenting) were significantly associated with being high risk for DM2. Conclusions: Our research shows that a parent’s assessment of their child’s health predicts risk for DM2. This may be important for clinical visits, such as well child visits, or for programs aimed at reducing DM2 in children. While our research did not demonstrate an association between family functioning and risk for DM2, these factors should be explored further with questions obtained from validated measures.
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    Does Physical Health Differ by Physical Activity in Diabetic Middle-aged Males?
    (2016-03-23) Hartos, Jessica PhD; Meadows, Ashley; Fejer, Hayes; Hamala, Amanda; Lamon, Abby; Kane, John PA-C
    Introduction: The purpose of the study was to assess the relationship between physical activity and physical health in diabetic middle aged males. Method: This cross sectional analysis used 2013 BRFSS data from South Carolina, West Virginia, Tennessee, Alabama, and Mississippi in multiple linear regression analysis. Results: The results indicated that middle aged males reported higher days of physical health for all levels of physical activity after controlling for alcohol use, tobacco use, educational level, employment status, weight, age, and race/ethnicity. Conclusion: Providers should assess levels of physical activity in their middle aged diabetic male patients and, if needed, provide patient education for the importance of physical activity for their physical health.
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    GLP-1 and its implications for neuroprotection in diabetes-associated neurodegenerative diseases
    (2016-03-23) Printz, Richard PhD; Niswender, Kevin MD PhD; Ha, Christopher
    Background: There is growing evidence linking type 2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer’s disease (AD). The incretin hormone glucagon-like peptide 1 (GLP-1), utilized for its insulinotropic properties in the treatment of T2D, is also synthesized in the CNS as a neuropeptide and has been demonstrated to have neuroprotective effects. We studied the effects of GLP-1 on insulin signaling in astrocytes, the only type of brain cells that store glycogen, which is utilized in learning and memory. Hypothesis: Our hypothesis was that GLP-1 would act on astrocytes and mimic insulin action at baseline conditions. In the presence of insulin, we expected GLP-1 to enhance insulin action, exhibiting a mechanism by which astrocytic glycogen storage could ultimately be augmented. Methods: We first treated astrocytes with GLP-1 and used a cAMP assay to determine if there was a functional GLP-1 receptor (GLP-1R) on the astrocytes. We then treated astrocytes with insulin alone, insulin and GLP-1 added 18 hours prior, insulin and GLP-1 added 30 minutes prior, and GLP-1 alone and determined expression of pAKT and pGSK-3B with Western Blot analysis. Results: Astrocytes appear to express a functional GLP-1R, suggesting the possibility that previously studied neuroprotective effects of GLP-1 occur via an astrocytic mechanism. GLP-1 was shown to mimic astrocytic insulin signaling at baseline conditions and enhance the phosphorylation of both AKT and GSK-3B when astrocytes are treated acutely at 30 min. as well as at 18 hours. GLP-1’s effects on insulin signaling suggest it can ultimately increase glycogen synthesis. The enhancement of insulin signaling by GLP-1 is most apparent at 10nM insulin, inducing a near maximal response. Summary: Our results suggest GLP-1 may have a role in attenuating insulin resistance and decreased glycogen storage, providing a mechanism by which GLP-1 analogs can offer neuroprotection to patients with diabetes-associated neurodegenerative disease such as Alzheimer’s.