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2011 ADA Posters 1261-2041.Indd INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO 1622-P 1624-P Hyperglycemia Mediated Accelerates Aging in Vascular Endothelial Unique Cellular Responses of Adult Blood-Derived Endothelial Pro- Cells genitor Cells and Mature Endothelial Cells to High Glucose ROKHSANA MORTUZA, SHALI CHEN, BIAO FENG, SUBRATA CHAKRABARTI, EMILY KEATS, ZIA A. KHAN, London, ON, Canada London, ON, Canada, Lindon, ON, Canada Diabetes leads to dysfunction of selected organ systems, and vascular Glucose-induced endothelial cell dysfunction is a main factor causing endothelial cell (EC) dysfunction and loss is the key initiating and perpetuating tissue damage in the eye, kidney, heart and nerve in Diabetes. We step in the development of secondary diabetic complications. A number hypothesized that hyperglycemia induced oxidative stress causes an of studies have investigated the effect of diabetes on non-vasculogenic accelerated aging process and that such process is mediated through precursor cells (also known as early endothelial progenitor cells). However, a alterations of silent information regulator proteins or sirtuins(SIRTs) through comparative study investigating the effects of high levels of glucose on the epigenetic mechanisms. proliferative/vasculogenic endothelial progenitor cells (EPCs; late EPCs) and We investigated glucose induced aging and alterations of SIRTs in two mature ECs is lacking. We herein determined the response of adult blood- types of endothelial cells, human umbilical vein endothelial cells(HUVECs) derived EPCs and mature ECs to high levels glucose. and human microvascular endothelial cells(HMECs). The cells were grown Mononuclear cells (MNCs) from normal adult blood were successfully and propagated in high glucose (25 mmol, HG) and low glucose(5 mmol, NG). differentiated into ECs and characterized through our established protocol. Cells were observed daily and images taken to analyze their rate of growth Mature ECs were obtained from neonatal foreskin. Cells were then subject to and confl uency. At each passage subculture, some cells were collected 5 mmol/L or 25 mmol/L glucose and cellular activity assays were performed. for analysis of SIRTs, excision repair cross complimenting 1 and 4(ERCC1, We further investigated the mechanisms of increased oxidative stress in ERCC4) by RT-PCR. Cells from each passage were stained for senescence these EC types. activated beta galactosidase(SA-βgal), a known biomarker of cellular aging. Blood-derived EPCs were characterized by fl ow cytometry, cell staining, Morphometric analyses were performed. and RT-PCR. The progenitor phenotype was confi rmed by our recently Both types of cells grew faster in NG compared to HG. When exposed to discovered endostatin response assay. Following characterization, the HG, both cell types showed evidence of early senescence as evidenced by cells were exposed to high levels of glucose for 6 and 12 days. Our results increased SA-βgal expression. The replicative capacities of these cells were show that short term exposure (6-day) to glucose increased endothelin-1 diminished and they developed an irregular and hypertrophic phenotype. while decreasing the endothelin receptors in both EPCs and mature ECs. Interestingly, we found that HMEC cells started showing such changes after Interestingly, long-term exposure of cells to glucose (12 days) increased passage 1 in HG(compared to passage 4 in NG), whereas such changes were endothelin receptors in mature ECs but not EPCs. These results suggest seen in HUVECs at passage 4 in HG(compared to passage 7 in NG). Almost that mature ECs are more susceptible to the adverse effect of high glucose. all HMECs in HG at passage 5(compared to only 1.5% in NG) and HUVECs Our results also show high glucose-induced E-selectin expression in EPCs in HG at passage 11(compared to 61.4% in NG) showed β-gal positivity. suggesting an angiogenic phenotype which was not evident in mature ECs. Quantitative RT-PCR analyses showed this aging process was associated Lastly, our data illustrate NADPH oxidase was increased in mature ECs but with decreased SIRT 1, 2, 5 expressions in both cell lines. ERCC1, ERCC4 remained unaltered in the EPCs. mRNA expression was found to be decreased in HMEC but increased in In conclusion, our results show differential response of adult blood EPCs HUVEC in earlier passages. Such changes were prevented by treatment with and mature ECs to high levels of glucose and evidence for the therapeutic resveratrol. potential of vasculogenic EPCs. Data from this study suggests that hyperglycemia leads to accelerated Supported by: Canadian Diabetes Association and the Lawson Health Research aging in the endothelial cells. Furthermore, such aging process is mediated Institute through SIRTs, ERCC1 and 4 and varies depending on the cell type. 1623-P INTEGRATED PHYSIOLOGY—INSULIN SECRETION Transcription Factor mafB and a Functional Link to E-cadherin IN VIVO Expression in β Cell Differentiation MARIKO TSUCHIYA, KEN TSUCHIYA, KOSAKU NITTA, ATSUSHI MAEDA, Tokyo, [See also: Presidents Posters 451-PP to 452-PP, page A125.] Japan It is essential to clarify the mechanism by which endocrine cells including β-cells differentiate or transform during development or regeneration in Guided Audio Tour: Insulin Secretion—In Vivo Physiology (Posters 1625-P the pancreas. First, we identifi ed a few cells in the ductal epithelium of to 1634-P), see page 13. the pancreas of newborn that stained positive for insulin and mafB and & 1625-P negative for E-cadherin, whereas almost all the surrounding duct cells Short-Term Administration of the Atypical Antipsychotic Olanzapine stained positive for E-cadherin, suggesting that there may be cross-talk Induces Meal-Specifi c Impairments in Glucose and Lipid Metabolism, between mafB and E-cadherin. The purpose of the present study was to Independent of Weight Gain or Psychiatric Disease elucidate the consequences of E-cadherin and mafB expression in relation KAREN L. TEFF, MICHAEL R. RICKELS, JOANNE GRUDZIAK, KARL RICKELS, Phila- to induction of ductal epithelial cell (β-cell progenitor) differentiation into delphia, PA endocrine cells by mafB. We used the technique to intravenously inject The atypical antipsychotics are associated with an increased incidence mice and transfect cultured cells with synthetic mafB-siRNA and analyzed of diabetes. The mechanisms underlying these metabolic defects are not the resulting alterations in gene and protein expression level by real-time understood, although it has been speculated that the initiating pathophysiology PCR or immunohistochemistry. To observe the precise mechanism of this is weight gain, secondary to centrally-mediated increases in appetite. Our process, we suppressed mafB gene expression to 40% of the control level objectives were to determine if olanzapine administration impairs insulin in AsPc1 cells, a cell line derived from a pancreatic carcinoma in which sensitivity and post-prandial responses to the physiologically-relevant stimulus maf expression has been confi rmed by real-time PCR. Suppression of mafB of a meal, independent of weight gain or psychiatric disease. Healthy male 2 Obesity expression by siRNA in AsPC1 cells resulted in upregulation of mRNA (1.4 subjects (BMI=69.8+2.6 Kg/m ) were admitted into the CTRC for 12-days. POSTERS fold) and immunostaining intensity (1.4 fold) of E-cadherin. Expression of Activity was maintained for each subject at a level matched to their free α-catenin (1.2 fold), which is indispensable for cadherin-catenin-complex- living levels. On Days 1 and 3 in a randomized order, subjects underwent a 600 Integrated Physiology/ mediated cell adhesion, was also increased, and β-catenin was increased kcal mixed nutrient meal challenge (n=10) and a euglycemic, hyperinsulinemic by 3.5 fold and GSK3 was slightly suppressed (0.8 fold), suggesting that clamp (7/10 subjects). The meal was labeled with [1-13C] glucose to monitor mafB may regulate ductal epithelial progenitor differentiation by expression 2 glucose appearance and 6,6-[ H2]-glucose was infused to measure glucose of the cadherin-catenin complex in the WNT signaling pathway. In the in disposal and endogenous glucose production during both the meal challenge vivo study mafB-siRNA treatment in the mouse pancreas resulted in similar and the clamp. Subjects were then administered olanzapine (5 mg/d, Days 4-5; changes. Moreover, mafB suppression downregulated expression of γ-actin 10 mg/d, Days 6-12). On Days 10 and 12, the metabolic tests were repeated. by the results of microarray profi ling. Taken together, the fi ndings in this Weight remained stable throughout the study (69.8+2.6,pre:70.1+2.9 Kg/ study suggested that mafB, whose expression is modifi ed by other mafs or m2, post-olanzapine) and no increase in food intake was found. Olanzapine other genes, even in stress or metabolic conditions in the mature pancreas increased post-prandial glucose (area under the curve: pre, 4363+1981 vs may regulate the E-cadherin-catenin complex in the WNT signaling pathway, post, 6579+1838, P<0.02), insulin (6824+4162 vs 13676+6739, P<0.001) and resulting in cell adherence and endocrine cell differentiation. triglyceride (1962+3995 vs. 4200+3938, P<0.01) concentrations. Small but For author disclosure information, see page 785. & Guided Audio Tour poster ADA-Funded Research A442 INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO signifi cant decreases in glucose disposal were found during the meal and the clamp (P<0.01) but no ef fects were obser ved on endogenous glucose production. These data demonstrate that short-term administration of olanzapine to normal subjects induces meal specifi c impairments in post-prandial glucose 1627-P and lipid metabolism, independent of weight gain or psychiatric disease. Hyperglycemic Clamp EvaluationWITHDRAWN of First and Second Phase Insulin The metabolic dysregulation likely contributes to the increased incidence of Secretion in Type 2 Diabetic Patients with BMI 24 - 34 Kg/m2 Submitted metabolic disease in patients treated with this and similar medications. to the Ileal interposition Associated with Sleeve Gastrectomy Supported by: NIH DK084383 (KLT).
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