2011 ada posters 478-1260 - diabetes · 2011. 6. 28. · a134 for author disclosure information,...

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COMPLICATIONS—HYPOGLYCEMIA


[See also: Presidents Poster 379-PP, page A105.]

Guided Audio Tour: Hypoglycemia, Glucose Variability, and Vascular Effects (Posters 478-P to 485-P), see page 15.

& 478-PThe Effect of Glucose Variability on the Rate of Hypoglycemia EventsYONGMING QU, SCOTT JACOBER, QIANYI ZHANG, LINDA WOLKA, J. HANS DEVRIES, Indianapolis, IN, Amsterdam, The Netherlands

The goal of diabetes treatment is to control blood glucose (BG) while limiting hypoglycemia. It has been hypothesized that high glucose variability (GV) leads to more frequent hypoglycemia. Our aim was to evaluate the effect of GV on the rate of hypoglycemia.

This post-hoc analysis included T2D patient data from three 24-week insulin trials including patients on twice-daily (BID) insulin lispro mixtures (n=805), daily (QD) insulin glargine (GL, n=1,019), insulin lispro protamine suspension (ILPS, n=353) (QD or BID), and insulin detemir (DE, n=166) (QD or BID), all with continuation of prestudy oral antihyperglycemic medications. At baseline, mean (±SD) age was 56.9±9.7 years, duration of diabetes was 9.5±6.1 years, A1C was 8.9±1.1%, and 51.9% were male. We studied the relationship between hypoglycemia rate (between 12 and 24 weeks) and the following 12 variables regarding intra-day and inter-day GV and mean BG: daily mean BG, fasting BG (FBG), A1C, standard deviation (SD) and coeffi cient of variation (CV) of intra-day BG, intra-day minimum BG, intra-day difference between minimum and maximum BG, average inter-day SD and CV, Mean Amplitude of Glycemic Excursions (MAGE), Mean Absolute Glucose change (MAG), and Average Daily Risk Range (ADRR), all derived from 7-point self-monitored BG profi les taken at 24 weeks. A Generalized Boosted Model (GBM) was used to evaluate the relative importance of these variables and select variables with p-value

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For author disclosure information, see page 785. & Guided Audio Tour poster ADA-Funded Research

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& 481-PEffects of Hypoglycemia on Endothelial Function and Athero throm-botic Balance in Type 2 Diabetes (T2DM)NINO GOGITIDZE JOY, MAIA MIKELADZE, MAKA S. HEDRINGTON, LISA YOUNK, LINDSAY PULLIAM, IAN DAVIS, DONNA B. TATE, STEPHEN N. DAVIS, Baltimore, MD

Recent randomized clinical trials have reported an association between hypoglycemia and cardiovascular adverse events. The physiologic mecha-nisms responsible for these fi ndings have not been extensively studied. Therefore, the aim of this study was to test the hypothesis that 2 hrs of moderate hypoglycemia acutely impairs vascular biologic mechanisms in T2DM.

Eleven T2DM (2M/9F) (45±4 yrs, BMI 38±3kg/m2, HbA1c 8±1%) participated in single 2 day studies. Day 1 consisted of a 2 hour hyperinsulinemic/euglycemic (eugly) clamp (89±1mg/dL) and day 2 a 2hr hyperinsulinemic/hypoglycemic (hypo) clamp (58±0.3mg/dL). Insulin levels during clamps were similar (126±2μU/mL). Two D doppler ultrasound was used to determine endothelial function.

End of clamp (fi nal 30 minutes) responses of ICAM-1, VCAM-1, P-Selectin, PAI-1 (Plasminogen activator inhibitor 1) and VEGF (Vascular endothelial growth factor) were all increased (p

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Ach receptor mediated adrenal Cat release rate. These results suggest that recurrent Hypo could impair intrinsic adrenal medullary Epi release in addition to blunting central stimulation of sympathetic outfl ow.

& 485-PHypothalamic S-nitrosylation Contributes to the Impairment of the Counter-Regulatory Response Following Recurrent HypoglycemiaXAVIER FIORAMONTI, ADAM DEAK, SRINIDHI DESHPANDE, CORINNE LELOUP, LUC PENICAUD, ANNIE BEUVE, VANESSA ROUTH, Newark, NJ, Dijon, France

Intensive insulin therapy improves diabetic complications but increases hypoglycemia risk. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. The CRR requires ventromedial hypothalamus (VMH) nitric oxide (NO) production. However, when NO is produced in the presence of reactive oxygen species (ROS) protein S-nitrosylation occurs and desensitizes NO signaling. Hypoglycemia increases VMH ROS levels (149 ± 22%, n=7). We hypothesize that during hypoglycemia, ROS increases VMH S-nitrosylation and impairs the CRR. In support of this, we found that 3 consecutive daily episodes of RH increase VMH S-nitrosylation. We then determined whether decreased ROS production prevents the impaired CRR after RH by treating rats with the antioxidant N-acetyl cysteine (NAC) in their drinking water (5 g/l) for 9 days before and during RH. After RH, glucose levels fell further and glucagon production was inhibited in response to insulin-hypoglycemia (glucose nadir RH: 39.3 ± 1.1 mg/dl; controls: 53.5 ± 1.8 mg/dl - glucagon nadir RH: 115 ± 13 ng/l; control: 244 ± 25 ng/l; n=13; p0.05). Thus, NAC pretreatment prevented the impaired CRR. NAC pre-treatment also prevented increased VMH S-nitrosylation after RH. Finally, we performed a hyperinsulinemic/hypoglycemic after third ventricular injection of the nitrosylating agent S-nitro-L-cysteine (CSNO, 0.5 mM, 5μl, 0.5 μl/min). The glucose infusion rate necessary to maintain the hypoglycemic plateau during the last 30 minutes of the clamp was higher in CSNO injected animals (control: 9.21 ± 0.5 mg/kg/min vs CSNO: 11.02 ± 0.4 mg/kg/min; p

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489-PEvidence That Islet Sympathetic Nerves (ISN) and Islet Beta Cells Are Destroyed Via Different Mechanisms in Type 1 Diabetes (T1D)QI MEI, DARYL HACKNEY, HO CHANG, KARIN BORNFELDT, GERALD J. TABORSKY, JR., Seattle, WA

Activation of ISN and suppression of islet beta cells both contribute to the glucagon response to insulin-induced hypoglycemia. In autoimmune T1D, most ISN and islet beta cells are lost, coincident with an early, marked impairment of this glucagon response. To better understand the cause of this glucagon impairment, we sought to determine if the mechanism underlying ISN loss is different from that causing beta cell loss. We used a transgenic mouse model of T1D in which a viral glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) is driven by the rat insulin promoter (RIP); therefore this viral GP is expressed solely in islet beta cells.

Systemic LCMV injection caused a marked loss of both islet beta cells (glucose = 523 ± 40 mg/dl) and ISN (no LCMV = 104 ±17 µm2 /islet vs LCMV = 19 ± 4 µm2 /islet; Δ = -82%; p < 0.002; both n=3). This beta cell loss is caused by GP-specifi c T-lymphocytes. Since ISN do not express this viral GP, the loss of ISN must be due to a different mechanism.

It is known that binding of brain derived neurotrophic factor (BDNF) to the p75 neurotrophin receptor (p75NTR) prunes redundant sympathetic axons during target innervation. Since activated B lymphocytes release BDNF and since they invade the T1D islet, we hypothesized that, in T1D, the p75NTR on ISN is activated and causes the loss of ISN.

To test this hypothesis we crossed p75NTR knockout mice with RIP-GP mice and then injected them with LCMV. ISN area (62 ± µm2/islet; n=3) was 3-fold greater in mice lacking p75NTR than in controls (19 ± 4 µm2/islet; n=3; p0.2 nmol/L (range 0.12-1.96) in all but 1 subject (17yrs, T1D 49 wks duration), whereas only 11 (55%) subjects had retained plasma glucagon responses to hypoglycemia. Moreover, the change in plasma glucagon levels with hypoglycemia did not correlate with the peak c-peptide (Figure) or the incremental c-peptide AUC (Spearman rho=0.0, 95%CI= (-0.44, +0.44)) during the MMTT or with the time from diagnosis (Spearman rho=+0.10(-0.36, +0.52)). These data demonstrate that many youth with T1D lose their ability to mount plasma glucagon responses to hypoglycemia during the fi rst year of diabetes. In addition, although the sample size is small, these preliminary observations do not support the hypothesis that the loss of glucagon responses to hypoglycemia is closely linked to loss of residual β-cell function.

491-PMultiple Daily Insulin (MDI) and Continuous Subcutaneous Insulin Infusion (CSII) Are Associated with Lower Risk of Death among Patients Reporting Severe HypoglycemiaROZALINA GRUBINA, NILAY D. SHAH, HOLLY K. VAN HOUTEN, ROBERT A. WERMERS, STEVEN A. SMITH, Rochester, MN

Most patients with diabetes ultimately require insulin therapy, yet this causes signifi cant anxiety, particularly among patients with history of severe hypoglycemia (SH). The ADA recommends modifying treatment goals and regimens if SH occurs. Multiple daily insulin (MDI) and continuous subcutaneous insulin infusion (CSII) improve glycemic control and lower risk of microvascular complications, but are associated with higher risk of SH. Whether patients with history of SH should avoid MDI-CSII is unknown.

All patients (n=1130) seen in a specialty diabetes clinic between August 2005 and July 2006 were questioned by their healthcare providers (n=31) about presence of SH during the preceding 6 months. Surviving patients were reassessed by postal survey in quarter 1 of 2010, querying their glycemic control: oral agent(s), provider-prescribed insulin (PPI), bolus/basal/sliding scale MDI or CSII, and/or non-insulin injectables. Information about non-surviving patients was obtained from the medical record. Demographics were compared using the two sample t-test, and risk of death is expressed as risk ratio [RR; 95% confi dence interval).

At enrollment, 79 of 1130 patients (7%) reported SH; of these, 62 (78.5%) were alive at time of reassessment. Of the 79 patients, 4 (5%) used oral agent(s), 16 (20%) PPI, 32 (41%) MDI-CSII, and 1 (3%) non-insulin injectables. Survivors were younger than those who had died (54 ± 16 vs. 66 ± 13 years; p=0.01), but there was no difference in duration of diabetes (26 ± 13 vs. 23 ± 12 years; p=0.29). While baseline HbA1c was identical in those using and not using MDI-CSII (7.7 ± 4.0 vs. 7.6 ± 2%), MDI-CSII was associated with 20% lower risk of death (RR 0.2; 0.09-0.5). The follow-up survey was completed by 32 survivors (52%) and 12 (38%) reported continued SH. There was no difference in mode of diabetes management compared to those without SH.

In this cohort of ambulatory patients reporting SH, MDI-CSII was asso ciated with lower risk of death. While further research is needed to understand this relationship, MDI and CSII appear to be reasonable treatment options in patients with SH.

492-PPrediction and Prevention of Inpatient HypoglycemiaSTEPHEN SCHAFERS, MICHAEL ELLIOTT, RICHARD REICHLEY, JULIE SILVERSTEIN, JANET MCGILL, GARRY S. TOBIN, St. Louis, MO

Inpatient hypoglycemia is associated with serious morbidity and may cause death. Hypoglycemia has been reported in up to 20% of hospitalized diabetic patients. Severe hypoglycemia (SH, glucose < 40 mg/dl) is the most common medication error “never event” based on Medicare guidelines. This study was undertaken to identify risk factors for SH, to apply that knowledge to the development of a prediction algorithm, and to institute a prevention program at a tertiary medical center. We analyzed all SH events for patient characteristics, medication prescribing and administration errors, and other predisposing factors for 6 months in 2009. One-hundred seventy-two adjudicated patients with SH events were then used as a validated population to develop a computer generated algorithm to predict SH. This algorithm was tested on a subsequent population of inpatients found to have any glucose

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levels of hypoglycemia < 60 mg/dl (N=955) and < 40mg/dl (N=232). Chi-square analyses and t-tests were run to identify bi-variate associations. Signifi cant variables were entered into a partition analysis to identify interactions. Logistic regression was performed to calculate parameters related to the odds of hypoglycemia below each cut point. ROC curve analysis was used to determine sensitivity and specifi city at various cut points. The cut points that resulted in 50% sensitivity for each hypoglycemia level were determined. These were tested against the adjudicated patients with SH. Variables related to blood glucose < 60mg/dl were basal, prandial, and adjustment scale insulin dose, weight, creatinine clearance, and sulfonylurea use. The AUC value for this equation was 0.692 and the Nagelkerke r-square was 0.134. The 50% sensitivity cut point correctly identifi ed 70% of the adjudicated patients. The same analysis for < 40mg/dl gave an AUC value of 0.697 and the Nagelkerke r-square was 0.095. The 50% sensitivity cut point correctly identifi ed 55% of the adjudicated cases. This algorithm will be used to develop an alert system aimed at predicting and preventing serious hypoglycemia at our institution.

493-PPredictors of Outpatient Visits for Hypoglycemia in Type 2 Diabetes Patients on Oral Antidiabetic AgentsJASON C. SIMEONE, BRIAN J. QUILLIAM, Kingston, RI

To identify predictors of hypoglycemia-related emergency department (ED) and outpatient visits in enrollees with Type 2 diabetes.

We used the 2004-2008 MarketScan® database to conduct a nested case-control analysis. Enrollees included in the cohort were ≥18 years of age with type 2 diabetes, and were taking an oral antidiabetic agent at cohort entry. We required > 12 months of continuous enrollment in a non-capitated plan and excluded persons with type 1 or gestational diabetes. A total of 11,375 cases and 68,247 controls were selected and 6:1 matched using incidence density sampling. We used a conditional logistic regression model to estimate adjusted odds ratios (AORs) and corresponding 95% confi dence intervals for potential predictors.

Cases were more likely than controls to have diabetic complications and other comorbid conditions, and to be utilizing more antidiabetic or other medications prior to the index date. Males had lower odds of hypoglycemia (AOR: 0.83; 95% CI: 0.80-0.87). Enrollees aged 50-59 had the lowest odds of hypoglycemia, compared to enrollees aged 18-29 (AOR: 0.49; 95% CI: 0.40-0.61). Enrollees in the Northeast (relative to South) had the lowest odds of hypoglycemia (AOR: 0.85; 95% CI: 0.78-0.93). Presence of a macrovascular (AOR: 1.78; 95% CI: 1.68-1.89) or a microvascular complication (AOR: 2.80; 95% CI: 2.64-2.97) increased the odds of hypoglycemia. With no antidiabetic drug therapy as the referent, insulin monotherapy was associated with the highest odds of hypoglycemia (AOR: 2.28; 95% CI: 2.01-2.59). Monotherapy with sulfonylureas (AOR: 1.16; 95% CI: 1.06-1.26) or meglitinides (AOR: 1.40; 95% CI: 1.02-1.93) had increased odds of hypoglycemia. Metformin monotherapy (AOR: 0.77; 95% CI: 0.72-0.83) and thiazolidinedione monotherapy (AOR: 0.87; 95% CI: 0.78-0.96) had lower odds of hypoglycemia. DPP-4 and alpha-glucosidase inhibitors were not predictive.

Medications should be carefully chosen for patients at high risk of hypoglycemia, particularly those with micro- or macrovascular complications or those taking insulin, meglitinides, or sulfonylureas.

Supported by: Takeda Pharmaceuticals, Inc.

494-PRecovery from Hypoglycemia in Healthy Subjects Is Preserved Despite Glucagon Receptor Blockade by MK-0893MATTHEW D. TROYER, MARCUS HOMPESCH, BARNALI PRAMANIK, WEI ZHENG, KHIN WIN, STEPHANIE DUNBAR, SUSIE LI, MARCELLA RUDDY, JOHN AMATRUDA, KEITH KAUFMAN, JOHN WAGNER, S. AUBREY STOCH, Whitehouse Station, NJ, Chula Vista, CA

Glucagon receptor antagonists (GRAs) are drug candidates that may improve glycemic control in Type 2 diabetes (T2DM) but may also delay recovery from hypoglycemia. To better understand this risk, we studied the effect of MK-0893, a potent, competitive GRA, on recovery from hypoglycemia in healthy subjects.

This was a double-blind, placebo-controlled, crossover glucose clamp study in 13 healthy males 18-37 years old. MK-0893 doses were chosen to provide clinically effi cacious levels of functional glucagon receptor blockade. Subjects were randomized to a sequence of 2 of 3 treatments: single-dose placebo, 200-mg (∼60% blockade) or 1000-mg MK-0893 (∼90% blockade), separated by a 3-week washout. After each treatment, a hypoglycemic clamp was initiated and blood glucose was maintained at 50 mg/dL (2.8 mmol/L) for 30 minutes (min). Upon discontinuation of the clamp, recovery

time to blood glucose ≥70 mg/dL (3.9 mmol/L) was measured as the primary endpoint. Recovery to ≥65 mg/dL (3.6 mmol/L) and counterregulatory hormone levels were also assessed.

The mean increases in recovery time to 70 mg/dL [90% CI] for the 200-mg and 1000-mg doses were 12.2 min [-1.9, 26.3] and 25.1 min [11.0, 39.3] compared to placebo. Mean recovery times [range] to 70 mg/dL by treatment were 33.3 [23-46], 45.0 [29-79], and 59.1 [37-78] min for placebo, 200-mg and 1000-mg MK-0893, respectively. Mean recovery times [range] to 65 mg/dL were 29.6 [18-43], 38.9 [24-74], and 51.6 [33-67] min, respectively. Glucagon levels were increased by MK-0893 prior to clamp initiation, and both glucagon and epinephrine levels increased substantially during hypoglycemia. MK-0893 treatment was generally well tolerated.

These data indicate that MK-0893 slows recovery from hypoglycemia in normal subjects in a dose-dependent fashion, but the 200-mg dose (∼60% blockade) produced little delay despite glucose-lowering effi cacy demonstrated at that level of functional receptor blockade in a separate study in patients with T2DM (ADA abstract submitted). These results suggest that competitive GRAs may not delay recovery from hypoglycemia to a clinically important degree at doses that can improve glycemic control.

495-PRecovery from Hypoglycemic Clamp in Type 2 Diabetes (T2DM) Patients during β-Adrenergic Blockade Plus Glucagon Receptor Blockade with MK-0893MATTHEW D. TROYER, MARCUS HOMPESCH, THOMAS JAX, BARNALI PRA-MANIK, FANG LIU, LINDA MORROW, KHIN WIN, TOM REYNDERS, CHENGCHENG LIU, SAMUEL ENGEL, TIM HEISE, ELSA MALIWAT, WILLIAM S. DENNEY, DAVID E. KELLEY, JOHN A. WAGNER, S. AUBREY STOCH, Whitehouse Station, NJ, San Diego, CA, Neuss, Germany, Chula Vista, CA, Brussels, Belgium

Glucagon receptor antagonists (GRAs) are drug candidates that may improve glycemic control in T2DM, but GRAs may also delay recovery from hypoglycemia, particularly with concomitant β2-receptor blockade. We previously studied the effect of monotherapy with MK-0893, a potent, competitive GRA, and observed a modest delay in recovery from hypoglycemia in healthy subjects. To better understand the effect of β-adrenergic blockade combined with a GRA in T2DM patients, we examined the effect of combining the β1/β2-blocker propranolol with a dose of MK-0893 that provides near-maximal glucagon receptor blockade.

In this randomized, double-blind study, 22 patients (age 41-59 years, 16 male, washed off oral antihyperglycemic therapy) were titrated onto a stable dose of oral propranolol (80 mg t.i.d.). Patients then received a single dose of 1000-mg MK-0893 or placebo in a 2-period crossover and underwent a hypoglycemic clamp in each period with blood glucose = 50 mg/dL (2.8 mmol/L) for 30 minutes. After discontinuation of each clamp, recovery time to blood glucose levels ≥65 mg/dL (3.6 mmol/L) was assessed as the primary endpoint. Mean recovery time [95% CI] was delayed with MK-0893 + propranolol vs. placebo + propranolol treatment to 103 [88, 118] vs. 71 [55, 88] minutes. The estimated mean difference [90% CI] in recovery time between the two treatments was 32 [15, 49] minutes and did not meet the prespecifi ed clinical importance boundary of 60 minutes (p = .005). MK-0893 treatment was associated with signifi cantly increased plasma glucagon and cortisol during recovery. Geometric mean ratios (MK-0893 + propranolol/ placebo + propranolol) [95% CI] for hormone AUC0-180min were: glucagon, 3.76 [1.52, 9.27]; cortisol, 1.86 [1.07, 3.25]; epinephrine, 1.34 [0.53, 3.40]; growth hormone, 1.93 [0.88, 4.27].

These results indicate that a high dose, competitive GRA plus β-blockade delays recovery from hypoglycemia, but may delay recovery less than in prior studies in which glucagon secretion was inhibited. Recovery may have been facilitated by a compensatory counterregulatory hormone response, including larger increases in glucagon levels.

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496-PReduced Rates of Severe Hypoglycemia in Children and Adolescents with Type 1 Diabetes over the Decade 2000-2009SUSAN M. O’CONNELL, MATTHEW N. COOPER, MAX K. BULSARA, ELIZABETH A. DAVIS, TIMOTHY W. JONES, Perth, Australia, Fremantle, Australia

We have previously reported increased rates of hypoglycemia associated with improved glycemic control in a large population-based sample of children with T1D, however therapeutic improvements may have altered hypoglycemia incidence. In this study, rates of severe hypoglycemia (SH) (an event leading to loss of consciousness or seizure) in a population based sample of childhood onset T1D were examined and clinical associations of these events investigated.

Data were extracted from the Western Australia Childhood Diabetes Database. Clinical data, including hypoglycaemia history is prospectively recorded at each 3 monthly visit. Data from 1,683 patients with T1D from 2000-2009 inclusive (age at diagnosis 10.5 ± 4.2 years [mean ± SD], range 1–18) were analysed. Rates of SH were investigated with respect to A1c, treatment type, duration of diabetes, age and gender using interaction terms fi tted within a negative binomial regression model.

In total 7,378 patient-years of data and 780 severe events were recorded. The rate of SH/100 patient years in 2000 was 14.3, peaking at 17.3 in 2001. From 2004 there was a sharp decline, with the lowest rate of 5.8 in 2006. There was a negligible decline in HbA1c levels of 0.07% per year (p = 0.03). Using multivariate analysis optimal recommended A1c (

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COMPLICATIONS—MACROVASCULAR—ATHEROSCLEROTIC CARDIOVASCULAR DISEASE AND HUMAN DIABETES

500-PSelf Report of Severe Hypoglycemia Is Associated with Increased Risk of Death in Diabetic PatientsROZALINA GRUBINA, NILAY D. SHAH, HOLLY K. VAN HOUTEN, ROBERT A. WERMERS, STEVEN A. SMITH, Rochester, MN

Hypoglycemia is a cause of signifi cant morbidity in patients with diabetes mellitus. Recent post-hoc analyses of the ACCORD and ADVANCE trials have found a potential correlation between documented hypoglycemia and increased risk of microvascular and macrovascular complications, and mortality. Whether self-report of hypoglycemia among ambulatory patients is associated with increased mortality, however, is unknown.

All patients seen in a specialty diabetes clinic between August 2005 and July 2006 were questioned about the frequency of mild or severe hypoglycemia over the preceding 6 months. A total of 1130 patients with established diabetes mellitus were seen by 31 providers, including physicians, midlevel providers, nurse educators, and dieticians. Mild hypoglycemia was defi ned as presence of symptoms (dizziness, blurry vision, confusion, and sweating) that could be managed without external assistance, while severe hypoglycemia required assistance from others. Patients’ clinical status was reassessed in November 2010, after mean 5 years of follow-up. Demographics were compared using the two sample t-test, and risk of death is expressed as odds ratio (OR, 95% Confi dence Interval).

At enrollment, 641 of 1130 (57%) patients reported ≥ 1 episode of hypoglycemia, and 79 (7%) reported severe hypoglycemia. Those with severe hypoglycemia were more likely to have longer duration of diabetes (26 ± 12 years vs. 16 ± 12 years; p

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& 504-PToll-Like Receptor 4 (TLR4) and Vascular Infl ammation Following Weight Loss in Patients with Metabolic SyndromePADMA SATHYANARAYANA, SADEKA SHAHANI, VADIM SHERMAN, SOMA-SEKHAR KONDURU, MANDEEP BAJAJ, Houston, TX

Toll-like receptor 4 (TLR4) expression is increased in obesity and type 2 diabetes and TLR4 may be a mediator of vascular infl ammation and insulin resistance. We examined the effect of weight loss on mononuclear cell TLR4 protein and vascular infl ammation following bariatric surgery in morbidly obese non-diabetic humans with metabolic syndrome. Six subjects (age=38±4 y, BMI=48.5±4.9 kg/m2, body weight=135.1±13.8 Kg) underwent a 75 gram Oral Glucose Tolerance Test (OGTT) and peripheral blood mononuclear cell isolation before and 6 months after bariatric surgery. Following bariatric surgery, body weight (delta= 35.0 kg, p< 0.05), fasting plasma glucose (104±5 to 84±2 mg/dL, P

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Table 1. Intervention versus conventional treatmentPulse wave velocity (m/s) 95% CI p-value

Model 1 -0.44 (-0.86 ;-0.01) 0.05Model 2 -0.43 (-0.79 ;-0.06) 0.02

Model 1: adjusted for clustering (general practice), mean blood pressure and heart rate at time of measurementModel 2: model 1 + adjustment for age and sex

& 508-PTumor Necrosis Factor alpha and Interleukin-10 Genetic Poly morph-isms and Susceptibility to Peripheral Artery Diseases Asso ciated with Type 2 Diabetes Mellitus and Hypertension in Brazilian PatientsETHEL SPICHLER, DAYSE SILVA, ELIZEU FAGUNDES DE CARVALHO, ROMULO VIANNA, MARILIA PANICO, ELAINE TAVARES, JOSE ADLER PEREIRA, RENATA ADLER PEREIRA, ANNE SPICHLER, DAVID SPICHLER, Rio de Janeiro, Brazil, San Diego, CA

Polymorphisms of Tumor Necrosis Factor alpha (TNF-α) and Interleukine-10 (IL-10) cytokines may have critical functional effects, contributing to the magnitude of innate immune response toward Peripheral Artery Diseases (PAD) in association with Diabetes Mellitus (DM) and Hypertension. To determine whether single nucleotide polymorphisms G308A, G238A and G863T of TNF-α and G1082A, C819T and C592T of IL-10 have an association with PAD in patients with DM and Hypertension. Mutation detection and genotyping of both cytokines were performed on DNA from 102 patients with PAD aging ≥ 30 years and with Ankle-Brachial Index ≤ 0.9 and population controls. This model was analyzed for demographic and clinical variables. Whole gene sequencing of TNF-α and IL-10 coding regions were carried out using regular PCR and specifi c primers. Statistical analysis was conducted using SPSS, ABIGeneScan and Genotyper software, and signifi cance level was < 0.05.

PAD patients enrolled and controls showed: age (mean 70.9 ±10.2 years), and 59.1% female.(

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routine risk prediction (c statistic with or without SMI 0.788 [0.720-0.855] and 0.705 [0.616-0.794]; Hosmer-Lemeshow χ2 5.13, p=0.643 and 1.34, p=0.932, respectively).

To conclude, SMI and silent CAD are predictive for cardiovascular events in type 2 diabetic patients independently of routine assessment, especially represented by PCOAD, macroproteinuria and more intensive treatment after year 2000.

& 512-PEvaluation of Clinical Predictors of Vulnerable Coronary Plaque Detected by CT Angiography in Asymptomatic Patients with Type 2 Diabetes (T2DM)KAZUYA FUJIHARA, HIROAKI SUZUKI, AKIRA SATO, YORIKO HEIANZA, SATORU KO DAMA, KAZUMI SAITO, KAZUTO KOBAYASI, AKIMITSU TAKAHASHI, SHIGERU YA TOU, NOBUHIRO YAMADA, HIROHITO SONE, HITOSHI SHIMANO, Mito, Japan, Tsukuba, Japan

This study aimed to elucidate the clinical predictors of vulnerable coronary plaque by 64-slice CTA in asymptomatic patients with T2DM.

From April 2009 to November 2010, 73 Japanese T2DM patients who had a maximum carotid intima-media thickness (IMT) ≥1.1 mm, electrocardiogram (ECG) abnormality, or positive exercise ECG test results underwent 64-slice CTA. Luminal narrowing of ≥50% on CTA was defi ned as indicating CAD. Vulnerable coronary plaque was considered present in patients with CAD with positive vessel remodeling and low-attenuation plaque (25 yrs with chest discomfort or shortness of breath who were evaluated at an urban emergency department (130 pts) or the cardiac cath lab (25 pts) for possible AMI. The fi rst digital 12-lead ECG for each patient, obtained within 30 min of presentation, was evaluated by 2 blinded expert cardiologists. The same fi le was then analyzed by the CA for quantitative 3D ECG analysis. In each

case, the ECG was classifi ed as either likely AMI or likely non-AMI by the cardiologists or the CA. “Gold standard” was the fi nal clinical diagnosis. Statistical analysis was McNemar’s test with continuity correction.

Results: The 155 DM2 patients were 50% male, mean age 56.8 ± 12.0 yrs; 44 pts had a fi nal clinical diagnosis of AMI (17 ST elevation MI [STEMI], 27 non-ST elevation MI [NSTEMI]) and 111 had no AMI. Diagnostic results in Table:

Conclusions: Relative to standard 12L ECG read by cardiologists, CA showed signifi cant gains in sensitivity for ACS diagnosis in DM2 patients, without loss in specifi city. Sensitivity gains were particularly high in patients exhibiting NSTEMI, the most common form of AMI in DM2. Quantitative 3D analysis of ECGs in DM2 patients with suspected AMI may improve diagnostic accuracy relative to the standard 12-lead ECG.

& 514-PSurvival Following Acute Myocardial Infarction in South Asians and White Europeans in the UKNITIN N. GHOLAP, RAJ L. MEHTA, MELANIE J. DAVIES, IAIN SQUIRE, KAMLESH KHUNTI, Leicester, United Kingdom

Some UK studies have reported higher case-fatality rates following acute myocardial infarction (AMI) in British South Asian (SA) driven mainly by higher rates of diabetes mellitus (DM) compared to white European (WE) patients. Following AMI, both antecedent DM and admission hyperglycaemia regardless of DM predicts adverse outcomes. We compared survival rates post AMI in relation to abnormal glucose metabolism in SAs and WEs drawn from a multi-ethnic UK population.

We conducted a retrospective cohort study of 4111 (SAs 18%) consecutive patients with AMI admitted between October 2002 and September 2008. Cox regression models were constructed to identify determinants of 30-days and 1-year mortality, entering ethnicity, random admission blood glucose and antecedent DM individually and together along with other relevant variables.

SAs were younger (62.0 vs. 67.3 years, p < 0.05) and more likely to have hypertension (55.2% vs. 49.4%, p = 0.004) or DM (39.7% vs. 16.1%, p < 0.05) at presentation compared to WEs. Thirty day and 1-year mortality were 10.0% and 15.2% in SAs compared to respectively 9.9 % and 16.7 % in WEs. On multivariate analysis (including antecedent DM but excluding admission blood glucose) the association of SA ethnicity with mortality was signifi cant (HR 1.48, CI 1.03, 2.13). However on inclusion of admission blood glucose in the model, this association of ethnicity with mortality became non-signifi cant (HR 1.31, CI 0.86, 1.99). Conversely each unit (mom/L) increase in admission blood glucose was associated with 7% increase in mortality (HR 1.07, CI 1.04, 1.10), after adjusting for all covariates. Furthermore exclusion of ethnicity and antecedent DM from the model did not alter the predictive value of admission blood glucose (HR 1.08, CI 1.05, 1.10). Similar associations were observed for one year mortality.

Despite higher prevalence of DM in SAs, their mortality post AMI was similar to WEs. Furthermore, admission hyperglycaemia more so than antecedent DM was an important predictor of increased mortality post AMI. To improve survival, active management of admission hyperglycaemia should be considered in patients with AMI, regardless of DM or ethnicity.

Supported by: CLARHC Project

& 515-PMyocardial Metabolic Flexibility in Complicated Type 2 DiabetesJACQUELINE T. JONKER, NATHANJA TJEERDEMA, MIEKE T.J. BUS, HILDO J. LAMB, AAN V. KHARAGJITSINGH, ALBERT DE ROOS, JOHANNES A. ROMIJN, JOHANNES W.A. SMIT, Leiden, The Netherlands, Hague, The Netherlands

A very low calorie diet induces an increase in plasma levels of non-esterifi ed fatty acids (NEFA). This is associated with an increase in myocardial triglyceride (TG) content and a decrease in diastolic cardiac function in

WITHDRAWN

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healthy subjects and patients with uncomplicated type 2 diabetes mellitus (DM2). Whether this fl exibility of myocardial TG content is also present in DM2 patients with cardiovascular complications is yet unknown.

Therefore we aimed to assess whether myocardial TG accumulation and cardiac function are amendable to dietary intervention by a 3-day very low calorie (VLCD) diet in DM2 patients with cardiovascular complications.

Fourteen patients with DM2 were included (age: 57±3 years, BMI 28.9± 1.1 kg/m2, HbA1c: 7.7 ± 0.4%). Inclusion criteria were: ischemia on single photon emission computed tomography and/ or >70% occlusion at computed tomography coronary angiogram. Left ventricular (LV) function, myocardial TG content and hepatic TG content were determined using magnetic resonance (MR) imaging and proton MR spectroscopy before and after a 3-day VLCD (471 kcal/day). We calculated diastolic deceleration of the early fi lling phase (E deceleration) and the ratio between early and atrial fi lling phase (E/A ratio) as measures for LV diastolic function.

We found plasma levels of NEFA were 0.63 ± 0.08 mmol/l at baseline and increased to 1.22 ± 0.08 mmol/l after the VLCD (P

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pg/mL, p=0.0052). In conclusion, Ros improved levels of serum YKL-40 and urine albumin excretion, associated with endothelial function, and of infl ammatory markers in addition to lipid-lowering effects. These fi ndings may in part explain the stability and regression of atherosclerotic plaques induced by statins. Such evidence could suggest a new therapeutic use of statins in the prevention of development of nephropathy and vascular complications in patients with type 2 diabetes.

& 519-PSimilar Circulating Concentrations of Adhesion Molecules between Type 1 Diabetes and LADA Patients: Results from the Action LADA StudyMINH-NGUYET PHAM, MOHAMMED HAWA, MICHAEL RODEN, GUNTRAM SCHERNTHANER, PAOLO POZZILLI, RAFFELLA BUZZETTI, WERNER SCHERBAUM, JOCHEN SEISSLER, HUBERT KOLB, STEVEN HUNTER, RICHARD DAVID LESLIE, NANETTE CATHRIN SCHLOOT, ACTION LADA STUDY GROUP, Düsseldorf, Germany, London, United Kingdom, Vienna, Austria, Rome, Italy, Belfast, United Kingdom

Systemic concentrations of adhesion molecules are associated with increased cardiovascular complications. We compared patients with type 2 diabetes known to be at high risk for cardiovascular disease with patients who have type 1 diabetes or LADA (Latent Autoimmune Diabetes in Adults) and hypothesized that these immune mediators are elevated in patients with type 2 diabetes.

We analyzed serum concentrations of sE-Selectin, sICAM-1 and sVCAM-1 by multiplex beads based technology in 90 type 1 diabetes (age 45.3±10.1 yrs, F/M=28/62), 61 LADA (51.8±10.2 yrs, F/M=35/26 yrs), 465 type 2 diabetes (54.9±9.1 yrs, F/M=202/263) and 41 healthy subjects (47.2±9.4 yrs, F/M=25/16). Diabetes duration in all patients obtained from the Action LADA cohort was maximum 5 years. Multivariate regression analysis was used to compare cytokines of four groups adjusted for sex, age, BMI, blood pressure and diabetes duration.

Increased concentrations of adhesion molecules were detected in patients with type 2 diabetes (p < 0.02). Type 1 diabetes, LADA and control subjects were similar in their immune mediator levels. Signifi cantly increased levels of adhesion molecules in type 2 diabetes compared to type 1 diabetes, LADA and healthy subjects persisted in spite of adjusting for age, sex, BMI, blood pressure and diabetes duration (p < 0.04). Diastolic and systolic blood pressure were positively associated with sE-Selectin adjusted for age, sex and BMI in patients (p < 0.045). Higher BMI and increased concentrations of adhesion molecules were positively associated in all groups (p < 0.0001).

Overall, our results show that metabolic confounders affect systemic concentrations of adhesion molecules that associate with increase cardiovascular risk. However, even after adjustment for these confounders type 2 diabetes had higher concentration of these markers suggestive of a diabetes type related effect. LADA and type 1 diabetes were similar, despite their different pathogenic process leading to slower deterioration of β-cell function in LADA and faster deterioration of β-cell function in type 1 diabetes.

& 520-PFructosamine-Modifi ed Plasminogen in Diabetes Reversibly Inhibits Fibrinolysis by Reducing Plasminogen-Fibrin Interactions and Alter-ing Plasmin ActivityRAMZI A. AJJAN, TOBY GAMLEN, KRISTINA F. STANDEVEN, SALIHAH MUGHAL, KATHARINA HESS, FLADIA PHOENIX, PAUL J. THORNALLEY, M.M. ANWAR, N. RABBANI, HELEN PHILIPPOU, PETER J. GRANT, Leeds, United Kingdom, Aachen, Germany, Warwick, United Kingdom

Fibrinolysis is dependent on plasminogen/fi brin interactions and inhibition of this process is associated with atherothrombotic events in diabetes. We investigated the effects of plasminogen glycation on plasmin generation, protein activity, interaction with fi brin and fi brinolysis using plasma samples and purifi ed protein from type 1 diabetes (T1DM) subjects before and after improving glycaemic control. Plasminogen activity was measured by chromogenic, turbidimetric and conversion assays, binding to fi brin using plasmon resonance and glycation by GlyPro test/mass spectrometry (MS).

HbA1c reduction by 0.9% in 27 subjects was associated with decreased plasma clot lysis from 516±16 to 400±16 sec (p

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were independently related to an increase in LDL/HDL ratio (p

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526-P8-Hydroxy-2-Deoxyguanosine Prevents Plaque Formation in a Partial Ligated ApoE Knockout Mouse, an Acute Model of Athero-sclerosisJOO YOUNG HUH, HANJOONG JO, MYUNG-HEE CHUNG, HUNJOO HA, Seoul, Republic of Korea

Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fi brous elements in the large arteries. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) along with accumulation of extracellular matrix (ECM) are important pathogenic mechanisms in lesion development. Infl ammation and oxidative stress are known to be related in this process, but an effective therapeutic modality remains elusive. 8-Hydroxy-2-deoxyguanosine (oh8dG), which is known as a marker of oxidative stress, has been recently reported to possess anti-oxidative and anti-infl ammatory effect. In this study, we investigated the effects of oh8dG on advanced lesion development in a partial carotid ligation model, which is a newly developed and more physiologically relevant model of disturbed fl ow. Partially ligated apoE knockout mice fed with high fat diet developed an advanced lesion in 2 weeks and oh8dG treatment signifi cantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infi ltration, and ECM accumulation. Further studies performed with cultured VSMCs in vitro showed that oh8dG inhibited FBS- or PDGF-induced proliferation. Also, rat aortic ring assay showed that oh8dG dramatically decreased PDGF-induced VSMC proliferation and migration. Angiotensin II-induced increase in rac1 activity was ameliorated by oh8dG pretreatment in VSMCs. This indicates a possible involvement of rac1 in anti-infl ammatory and anti-oxidative effect of oh8dG. Our results have shown for the fi rst time that oh8dG treatment suppresses plaque formation in vivo and VSMC activation in vitro possibly through inhibition of rac1. This points to a novel mechanism of action of oh8dG to reduce oxidative stress and infl ammation, and emphasize a new therapeutic avenue to benefi t atherosclerosis.

Supported by: 800-20080663, 800-20090208; J.Y.H. supported by Brain Korea 21

527-PAccelerated Diabetic Complications in Japanese Type 1 Diabetes with Nonalcoholic Fatty Liver DiseaseCHIHIRO YONEDA, HIROYUKI MATSUURA, JUN OGINO, TAKENORI HARUKI, YOSHIFUMI SUZUKI, NAOTAKE HASHIMOTO, Yachiyo, Japan, Asahi, Japan

Nonalcoholic fatty liver disease (NAFLD) is a signifi cant health problem and there have been many reports of the association between type 2 diabetes, but the signifi cance of NAFLD in type 1 diabetes has not been fully discussed. Therefore, we studied the association of NAFLD in Japanese type 1 diabetes and attempted to clarify the phenotype of type 1 diabetes with NAFLD. The mean patient age was 56.8 and 46.8 years old with (N=15) and without NAFLD (N=42) There was a signifi cant difference in the present body mass index (BMI) (P

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530-PAsymmetric Dimethylarginine (ADMA) Does Not Affect Endothelial Function in Subjects with Alterations of Glucose RegulationDANIELA LUCCHESI, LAURA PUCCI, ROSAMARIA BRUNO, LORENZO GHIADONI, ELEONORA RUSSO, GIUSEPPE A. DANIELE, MONIA GAROFOLO, STEFANO TADDEI, ROBERTO MICCOLI, GIUSEPPE PENNO, MARKUS C. STUHLINGER, STEFANO DEL PRATO, Pisa, Italy, Innsbruck, Austria

ADMA has been related to endothelial dysfunction (ED) and athero-sclerosis. Increased ADMA has been described in type 1 and type 2 diabetic subjects with nephropathy or CVD. Studies assessing ADMA in people with uncomplicated diabetes report confl icting results. ADMA, SDMA (symmetrical dimethylarginine) and L-arginine (L-arg; HPLC), brachial artery fl ow-mediated dilation (FMD) and nitrate endothelium-independent dilation (GTN) were evaluated in 26 subjects with normal glucose tolerance (NGT), 34 with pre-diabetes (IFG or IGT, preDM) and 18 with newly diagnosed type 2 diabetes (newT2DM; OGTT). Groups were similar for gender, smoking, BMI, waist, dBP, total and LDL-C, apoA1 and apoB, fi brinogen, fasting insulin, eGFR and cystatin C. Age, fasting and post-load glucose, glucose area under the OGTT curve (AUCgluc), HbA1c (6.0±0.4, 6.5±0.6 vs 5.5±0.4%, p

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the dose, completely corrected the abnormal recovery slope of platelet COX-1 activity. We conclude that inter-individual variability in the recovery rate of platelet COX-1 activity during the aspirin dosing interval most likely refl ects abnormal megakaryopoiesis associated with T2DM while is not infl uenced by 24-hr glucose control or other glycemic indices; inadequate TX inhibition can be overcome by a twice daily regimen.

534-PDiabetes Effects on Progression of the Ankle Brachial IndexNKETI I. FORBANG, YIHUA LIAO, MARY MCDERMOTT, MICHAEL CRIQUI, La Jolla, CA, Chicago, IL

Diabetes mellitus is a risk factor for peripheral arterial disease (PAD) and medial arterial calcifi cation (MAC). The ankle brachial index (ABI) is abnormally low in PAD, but high in the presence of MAC in the leg arteries. We studied associations of diabetes mellitus with change in the ABI over time.

Over four years, 551 men and women participants with and without PAD were identifi ed from Chicago-area medical centers and followed prospectively with annual ABI measurements. Co-morbid illness was determined at baseline from medical records, patient self-report, laboratory values, and a primary care physician questionnaire. Participants who underwent lower extremity revascularization during follow-up were censored at the time of revascularization. Prevalent PAD at baseline was defi ned as ABI < .90.

Adjusting for ABI in the previous year, annual average ABI changes were -.011 (95% CI: -.02, -.002) in diabetics with PAD, -.013 (95% CI: -.02, -.007) in non-diabetics with PAD, -.001 (95% CI: -.013, .01) in diabetics without PAD, and .008 (95% CI: .001, .014) in non-diabetics without PAD. Mean (SD) ABI at baseline were .68 (.13), .67 (.14), 1.08 (.11), and 1.09 (.09) respectively. Compared to non-diabetics without PAD, annual ABI changes were signifi cantly different in diabetics with PAD and non-diabetics with PAD (p-value

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538-PEffect of Structured Blood Glucose Monitoring Versus Usual Care on Levels of hs-CRP—A Marker of Cardiovascular Risk—In Poorly Controlled Type 2 Diabetes PatientsOLIVER SCHNELL, ILDIKO AMANN-ZALAN, ZHIHONG JELSOVSKY, CHRISTOPHER PARKIN, BETTINA PETERSEN, MATTHIAS SCHWEITZER, LAWRENCE FISHER, WILLIAM POLONSKY, Munich, Germany, Mannheim, Germany, Tampa, FL, Indianapolis, IN, San Francisco, CA, San Diego, CA

Hs-CRP is a sensitive biomarker of cardiovascular (CV) risk. In the Structured Testing Program (STeP) study, the use of structured self-monitoring of blood glucose (SMBG) was recently shown to improve glycemic control in type 2 diabetes patients compared to non-specifi ed SMBG. We assessed the effect of the structured SMBG intervention on hs-CRP levels in 483 patients with non-insulin treated type 2 diabetes patients. Data for this evaluation were derived from the STeP study, a 12-month, cluster-randomized clinical trial that assessed the use of structured SMBG on glycemic control compared to usual care. Baseline characteristics were comparable among the 2 groups. In the study, Hs-CRP measurements were taken at baseline and months 3, 6, 9 and 12 during the study, using the Hitachi system (Roche Diagnostics, Rotkreuz, Switzerland). Mean (SD) baseline value: Control=6.9 (9.1) mg/L, Experimental=6.6 (14.1) mg/L. At months 3, 6, 9 and 12, experimental subjects showed signifi cantly lower mean (SE) change in hs-CRP levels (mg/L) compared to controls: -1.7(0.4) vs. -0.1(0.5), P=0.008, -0.0(0.5) vs. 0.0(0.5), P

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of diabetes medications, salsalate may be a novel therapy for patients with abnormal glucose tolerance with a neutral effect on cardiovascular risk. Further study is needed to elucidate the effects of longer-term SAL treatment on glycemia, lipids and CVD outcomes.

Supported by: The VA Clinical Sciences Research Program

542-PExenatide Effects on Cardiovascular Risk Biomarkers in Patients with Type 1 DiabetesMAY ALATTAR, REBECCA J. BROWN, KRISTINA I. ROTHER, TAMMY NGUYEN, Bethesda, MD

Exenatide (Byetta™) therapy has been shown to improve blood glucose control and cardiovascular disease (CVD) risk biomarkers in patients with type 2 diabetes (T2DM) as it induced weight loss, decreased HbA1C, total cholesterol (TC), triglycerides (TG), and LDL, and increased HDL. It also increased adiponectin (ADPN), a polypeptide with anti-infl ammatory and cardioprotective properties after prolonged therapy (12 months). An increase in ADPN may be a useful marker for decreased coronary artery disease risk.

We hypothesized that exenatide therapy in individuals with type 1 diabetes (T1DM) would result in improved CVD profi les similar to the effects seen in patients with T2DM.

14 subjects with long-standing T1DM (mean duration 20.2±11.4 years) participated in a cross-over study (6 months on and 6 months off exenatide). Plasma samples were collected at baseline, and on and off exenatide. Statistical analysis using ANOVA fi xed effect model was applied to determine changes in body weight, HbA1C, fasting and postprandial blood glucose, daily insulin requirements, plasma ADPN, TC, TG, LDL and HDL on and off exenatide.

Variable On exenatide Off exenatide P valueHbA1c (%) 6.6±0.6 6.8 ±0.6 0.3878Fasting plasma glucose (mg/dl) 142.5 ± 4.42 132.2 ± 3.45

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OGTT was performed. Insulin resistance was calculated by HOMA-IR and body composition by DEXA. CIMT was performed in a subset of our population, (WAW, n=8) and (AAW, n=12) by B mode ultrasonography.

Results: AAW were more obese (BMI- 32.8±6.5 vs 27.8±5.0 kg/m2, p= 0.007 and % body fat- 47.6±7.6 vs 42.6±8.6%, p=0.05) vs WAW. There were no differences in glucose tolerance, blood pressure or HOMA-IR. We found no differences in total cholesterol, HDL-C, LDL-C and apoB. However, we found lower triglycerides (62.2±23.4 vs 88.3±46.5mg/dl, p=0.02) and higher apoA1 (185.2±29.7 vs 159.7±46mg/dl, p=0.03) in AAW. PON1 was lower (0.97±0.35 vs 2.09±0.29ng/ml, p=0.0001) and hsCRP (3.96±3.7 vs 2.2±2.5mg/L, p=0.07) and ox-LDL (8.2±2.5 vs. 4.5±1.2U/L, p=0.0001) were signifi cantly higher in our AAW vs WAW. CIMT (0.69±0.10 vs 0.61±0.02mm, p=0.04) was signifi cantly higher in AAW than WAW. PON1 negatively correlated with CIMT in our population (r=-0.42, p=0.06). After adjusting for race, a 1 unit increase in PON1 was associated with a 0.0038mm decrease in CIMT.

Conclusion: We speculate that the higher CIMT seen in AAW can be attributed in part to the HDL dysfunction (PON1) with the resultant HDL-associated antiinfl ammatory and antioxidant properties. Further studies, with larger sample sizes are warranted to confi rm these fi ndings.

Supported by: Award # UL1RR025755, National Center for Research Resources, NIH

546-PHigh Prevalence of Atherosclerotic Plaque Detected by the Carotid and Lower Extremity Artery Ultrasonography in Hospitalized Chinese Type 2 Diabetic PatientsLIANXI LI, FANG LIU, YUQIAN BAO, WEIPING JIA, Shanghai, China

Aims: Our aim was to evaluate the prevalence of atherosclerosis detected by the carotid and lower extremity artery ultrasonography and the risk factors associated with atherosclerosis in hospitalized Chinese type 2 diabetic patients.

Methods: A number of 709 hospitalized Chinese type 2 diabetic patients were prospectively assessed.Atherosclerosis was defi ned as the presence of either carotid or lower extremity arterial atherosclerotic plaque in any of the above-mentioned artery segments. Body measurements including height, weight, waist circumference and hip circumference, resting heart rate and blood pressure, fasting and 2-h postprandial blood measures were investigated. Diabetic retinopathy was assessed by fundus photographs. Diabetic nephropathy was assessed by 24-h albumin excretion rate. Both carotid and lower extremity arterial atherosclerosis were measured by Doppler ultrasound. The prevalence of atherosclerosis was calculated, and the risk factors associated with atherosclerosis were evaluated using binary logistic regression.

Results: (1) The prevalence rate of atherosclerosis was 79.4% in hospitalized Chinese patients diagnosed with type 2 diabetes, 81.2% in male patients, and 77.6% in female patients. There was no signifi cant difference in the prevalence of atherosclerosis in patients between the sexes. (2) Atherosclerotic patients were older and had longer duration of diabetes, higher systolic blood pressure, neutrophil percentages, common carotid and lower extremity artery IMT. In addition, the prevalence of hypertension, cardiovascular and cerebrovascular diseases were higher in type 2 diabetes with atherosclerosis. (3) Atherosclerosis was signifi cantly associated with duration of diabetes, older age, systolic blood pressure, and low extremity artery IMT based on logistic regression analysis.

Conclusions: The prevalence of atherosclerosis was high in Chinese in-patients with type 2 diabetes, especially in elderly patients. Combination of carotid and lower extremity ultrasound examination resulted in a signifi cant improvement in the detection of type 2 diabetes with atherosclerosis.

547-PhsCRP Is Associated with Cardiovascular Disease Progression after TransplantMEGHAN GAULE, ELIZABETH LYDEN, FANG YU, TERICA HUDSON, JENNIFER LARSEN, Omaha, NE

Introduction: Cardiovascular disease (CVD) remains the greatest cause of death after kidney transplant (KTX) and infl ammation is one of the nontraditional risk factors associated with CVD. Methods: In recipients >6mo after KTX with a GFR>30 ml/min, we evaluated the association of highly sensitive CRP (hsCRP) with other CVD risk factors and CVD progression as analyzed by carotid intima media thickness (CIMT). Results: The study population (n=342;192 M/150 F) with mean age of 52+1y was 5.9+0.3y since KTX (0.5-33.8y). 50% had diabetes. Of this cohort, 50.3% had an elevated hsCRP (>3mg/mL), and this group was closer to transplant (p=0.0003), had a higher BMI (p0.05). However, sirolimus (61% vs. 39%; p3 mg/L. hsCRP was also signifi cantly associated with CVD progression as expressed by CIMT in a general linear regression model (p=0.01). Conclusions: In a representative KTX cohort, hsCRP is signifi cantly elevated in half, even long after KTX, and was positively correlated with CVD progression after KTX. CVD risk factors most closely associated with hsCRP were BMI, features of insulin resistance (e.g., elevated triglycerides and HOMA-IR), and type 2 or post-transplant diabetes. Whether hsCRP is also an independent CVD risk factor is yet to be determined.

Supported by: NIH R01 34-5226-2002 (Clinicaltrials.gov: NCT00374595)

548-PHyperglycemia after Coronary Artery Bypass Grafting and Its Effects on Hospital OutcomesDAOUD DAOUD, SUSAN BAIMBRIDGE, CHARLES BAIMBRIDGE, GLENN R. CUNNINGHAM, Houston, TX

We investigated the relationship between postoperative hyperglycemia and outcomes (OCs) in patients who underwent isolated coronary artery bypass grafting (CABG).

We conducted a retrospective study of 1504 consecutive patients who had isolated CABG at St Luke’s Episcopal Hospital between 1/1/07 and 12/31/09. Patients were stratifi ed into 5 groups based on their preoperative risk of mortality (MR), using the Society of Thoracic Surgeons’ criteria. Average glucose levels for the fi rst 2 days after surgery (ave.2d.g) were determined and correlated with relevant OCs: ICU time (ICUT), post-op length of stay (LOS), ventilation time (VT) and overall complications (Comp). The ave.2d.g values within each group were divided into 4 quartiles (QTs). Continuous OCs were considered cases if values were greater than the median. Logistic regression analysis was used to determine if the OCs were related to glycemic control.

The number of patients in each MR group 1 through 5 (low to high) was 761, 344, 139, 80 and 180, respectively. Consistent and signifi cant correlations between OCs and glycemic control were confi ned to Group 1. The Mean±SD glucose levels for each QT were 131.7±7.3, 147.3±4.0, 163±5.6 and 199.1±25.7 mg/dL. Glycemic control was not correlated with red blood cell transfusion, septicemia, deep sternal wound infection or mortality.

Table 1. Odds Ratios (ORs) for OCs vs. 2 Day Average Glucose Levels

Outcome median 2nd vs. 1st QTOR (95% CI)

p value

3rd vs. 1st QTOR (95% CI)

p value

4th vs. 1st QTOR (95% CI)

p value

+10 mg/dL IncreaseOR (95% CI)

p valueICUT(hours)

32.63 1.31 (0.87-1.96)0.19

1.63 (1.09-2.46)0.02 1.86 (1.23-2.79) 0.003 1.07 (1.02-1.13)0.007

LOS (days)

7 1.36 (0.85-2.17)0.20

1.70 (1.07-2.69)0.02 2.39 (1.52-3.78)0.001 1.09 (1.04-1.15)0.001

VT (hours)

8.87 1.81 (1.20-2.72)0.004 1.72 (1.14-2.59)0.01 2.32 (1.53-3.50)0.001 1.09 (1.03-1.15)0.002

CompN(%)

280¹(36.8)

1.74 (1.13-2.67)0.01

1.63 (1.06-2.52)0.03 1.82 (1.18-2.80) 0.006 1.06 (1.01-1.12) 0.03

¹Number of cases (%)

Hyperglycemia in the fi rst two days after CABG appears to affect adversely multiple postoperative outcomes.

Supported by: Internal funds

549-PHyperhomocysteinemia Exacerbated Hyperglycemia-Induced Endo-thelial Dysfunction by Modulation of Cyclooxygenase-Calpain SignalingZHONGJIAN CHENG, XIAOHUA JIANG, STANISLAV SIDOROV, PU FANG, MEGHAN PANSURIA, ROSARIO SCALIA, DOMENICO PRATICO, WILLIAM DURANTE, XIAOFENG YANG, HONG WANG, Philadelphia, PA, Columbia, MO

Accumulative evidence indicates that elevated plasma homocysteine (Hcy) level is a stronger risk factor of cardiovascular diseases in diabetes. We examined the effect of hyperhomocysteinemia (HHcy) on endothelial

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function in hyperglycemic mice. Moderate HHcy and severe HHcy (plasma Hcy: 30 and 256 μM, respectively) was developed by feeding a high methionine diet (2%) for 8 weeks in 8-week old male cystathionine beta-synthase (CBS+/+ and CBS-/+) mice. Hyperglycemia (HG) was generated by streptozotocin (40 mg/kg for 5 consecutive days, i.p.) started at the time of dietary intervention. Severe HHcy impaired endothelium-dependent vascular relaxation to acetylcholine (ACh) in the absence and presence of HG in CBS-/+ mice (98% to 77% and 83% to 63%, respectively). Endothelium-independent vascular relaxation to sodium nitroprusside was not changed by HHcy. Vascular relaxation to ACh was completely abolished by L-NAME (nitric oxide (NO) synthase inhibitor) and normalized by indomethacin (cyclooxygenase (COX) inhibitor) in all mouse groups. COX-1 inhibitor SC560 and COX-2 inhibitors celecoxib or NS398 improved vascular relaxation to ACh in HHcy-HG mice. Calpain inhibitory therapy using a calpain inhibitor MDL28170 (1 mg/kg for 2 weeks, i.p.) completely rescued severe HHcy-impaired vascular relaxation to ACh both in the absence and presence of HG. Furthermore, preincubation with calpain inhibitors (MDL28170, ALLM and calpeptin) normalized vascular response to ACh in HHcy-HG mice. Calpain activity was increased in cultured mouse primary aortic endothelial cells from HHcy and HHcy-hyperglycemic mice (125% and 261%, respectively). Finally, L-Hcy (500 µM, 48h) increased calpain activity in cultured human aortic endothelial cells (HAECs) and that is potentiated by D-glucose (44 mM, 273% and 743%, respectively). SC560 and celecoxib markedly reversed HHcy-induced calpain activation in HAECs, suggesting that activation of calpain is secondary from activation of COX by HHcy and/or HG. Conclusions: HHcy exacerbates HG-induced endothelial dysfunction (ED). Modulation of COX-calpain signaling may play a critical role in HHcy-induced ED in diabetes.

550-PInfl uence of Cigarette Smoking on QTc Interval Duration in Patients with Type 2 Diabetes MellitusPETROS THOMAKOS, STAVROS LIATIS, STAVROULA KALOPITA, IOANNIS VLAHO-DIMITRIS, CHRYSSOULA STATHI, NICHOLAS KATSILAMBROS, KONSTANTINOS MAKRILAKIS, Athens, Greece

Prolongation of the QT interval corrected for heart rate (QTc) is associated with a lowered ventricular fi brillation threshold and an increased incidence of sudden cardiac death. Both type 2 diabetes (T2D) and cigarette smoking are well identifi ed risk factors for cardiovascular disease. The mechanism by which smoking may lead to cardiovascular events in T2D patients has not been adequately investigated.

Aim of the present study was to assess the relationship between smoking and QTc interval (measured by continuous ECG monitoring) in T2D patients.

A total of 72 T2D patients (36 chronic smokers, 36 non-smokers), age- and sex-matched, on oral antidiabetic agents, underwent continuous 24-hour ECG Holter monitoring. QTc interval during the day and night was separately analyzed.

Smokers (21 men/15 women) and non-smokers (20 men/16 women) were not different regarding age [mean±SD]: [54.9±9.0 vs. 56.7±8.2 years (p=0.362)], diabetes duration [5.5±4.6 vs. 5.3±4.3 years (p=0.83)], HbA1c [7.3±1.2 vs. 6.9±0.9% (p=0.09)] and systolic blood pressure [125.1±14.5 vs. 128.2±15.4 mmHg (p=0.38)], but smokers had a lower BMI [29.8±5.1 vs. 32.6±5.2 kg/m2 (p=0.02)].

Smokers showed increased QTc duration during the 24 hours [439.25±26.95 vs. 425.91±23.28 ms (p=0.03)] as well as during day [439.14±24.31 vs. 427.86±24 ms (p=0.053)] and night period [440.91±32.3 vs. 426.55±25.34 ms (p=0.046)]. After adjusting for BMI and HbA1c (using linear regression analysis), smoking was independently and signifi cantly associated with increased QTc during the 24 hours (standardized β=0.27, p=0.03), as well as during the day (β=0.25, p=0.046) and night period (β=0.27, p=0.037).

Cigarette smoking is associated with prolongation of the QTc interval in T2D patients and this effect may be implicated with an increased cardiovascular risk in this population.

551-PInfl uence of Diastole Duration on Subendocardial Myocardial Via-bility and Role of Cardiac Autonomic Dysfunction in Type 2 Diabetic and Obese PatientsQINDA CHEN, YAHYA JABER, HUBERT DABIRE, SABRINA CHIHEB, ISABELA BANU, MINH TUAN NGUYEN, EMMANUEL COSSON, PAUL VALENSI, Shanghai, China, Bondy, France, Maisons-Alfort, France

Cardiac autonomic dysfunction (CAD) characterized by reduced vagal activity and relative sympathetic overdrive might shorten diastole duration (DD) and thus impair coronary perfusion. The aim was to study the relation between DD and subendocardial myocardial viability (SEVR) and the infl uence of CAD in patients with type 2 diabetes (T2D) or obesity.

We included 607 T2D (58.5±10.8 yrs) and 185 non diabetic obese patients (40.5±13.5 yrs, BMI 39.1±6.4 kg/m2), all free of cardiac history. Using applanation tonometry (SphygmoCor®), we measured heart rate (HR), DD, aortic and radial blood pressures and stiffness (amplifi cation index AIx) and pulse wave velocity. The percentage of DD (DD% = (DD/duration of heart period) x100) and SEVR (areas under diastolic/systolic aortic pressure curves) were calculated.

CAD was assessed in 482 of the patients (349 T2Ds and 133obeses) using standard tests (deep-breathing, lying-to-standing, Valsalva) which mostly depend on vagal control. CAD was found in 237 T2Ds, and among the obese patients, CAD was absent in 74 (G0), moderate (G1: 1 abnormal test) in 43, and confi rmed or severe (G2: 2 or 3 abnormal tests) in 16 patients.

In T2D and obese patients, DD% correlated negatively with HR (r=-0.826 and r=-0.638, p

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553-PPeripheral Endothelial Function and Silent Coronary Artery Disease in Type 2 Diabetic PatientsMINH TUAN NGUYEN, ISABELLE PHAM, ALAIN NITENBERG, PAUL VALENSI, EMMANUEL COSSON, Bondy, France

Endothelial dysfunction is early involved in atherosclerosis. The aim of the study was to assess if peripheral endothelial dysfunction was associated with silent myocardial ischemia (SMI) and the presence of occult signifi cant coronary artery disease (CAD) in type 2 diabetic patients (T2D) (NCT00685984).

The humeral diameter was measured by ultrasound examination before and one minute after ischemic hyperaemia. Endothelium-dependent fl ow-mediated dilation (FMD: change in diameter in %) was calculated in 30 control subjects ≤ 40 years (19 males, body mass index (BMI) 22±2 kg/m², 25±6 years), 30 overweighed or obese subjects without diabetes (3 males, BMI 34±4 kg/m², 40±13 years) and 116 asymptomatic patients with T2D for 15±7 years (70 males, BMI 31±5 kg/m², 62±8 years). All the T2D patients had additional risk factors and fulfi lled the criteria of the French Alfediam-SFC guidelines for SMI screening. They were prospectively screened for SMI defi ned as an abnormal stress myocardial scintigraphy and/or stress echo-cardiography. A coronary angiography was performed in those with SMI.

FMD was 4.5±3.3; 4.6±6.8 and 1.2±3.9% in control, overweighed or obese subjects and T2D patients (p

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556-PRelation between Aorta Stiffness and Advanced Diastolic Function Indices in Patients with Diabetes Mellitus Type 1—Assessment with MRI and Speckle Tracking Strain AnalysisLINDA D. VAN SCHINKEL, DOMINIQUE AUGER, SASKIA G.C. VAN ELDEREN, NINA AJMONE, VICTORIA DELGADO, ARNOLD C.T.A. NG, JOHANNES W.A. SMIT, JEROEN J. BAX, ALBERT DE ROOS, JOS J.M. WESTENBERG, Leiden, The Netherlands

Increased pulse wave velocity (PWV) is a marker for aortic stiffness and is associated with cardiovascular disease. PWV can be accurately assessed with MRI. Whether an increased MRI PWV translates in early diastolic dysfunction in patients with diabetes mellitus type 1(DM1) remains unexplored. The purpose of this study is to evaluate the correlation between PWV and advanced diastolic function parameters in patients with DM1.

Normal PWV age-relation was determined in 25 healthy volunteers, age 18-65 years with a 1.5T MRI scanner and is represented by the formula: PWV=A×AGE+B, with A±SE=0.03±0.01m/s/year and B±SE=3.70±0.46m/s. Next, PWV was assessed in 41 DM1 patients. Subjects were divided into 3 groups. Group 1 (normal PWV) consisted of patients with normal PWV values up to 1×SE, group 2 (moderately increased PWV) had values up to 2×SE and group 3 (high PWV) had a PWV>2×SE. Then patients underwent echocardiography for assessment of conventional diastolic function indices (e.g. isovolumic relaxation time (IVRT), transmitral early (E) and atrial (A) peak fi lling velocities, E/A-ratio). Tissue Doppler imaging was performed to determine mean mitral annulus velocity (E’). Moreover, longitudinal speckle tracking strain analysis was performed to derive advanced diastolic indices [peak transmitral E-wave to strain rate during the isovolumic relaxation period (SRIVR)] and left atria l(LA) systolic strain. Next the peak E/SRIVR ratio was calculated.

Of 41 DM1 patients (age 50±9years), 19 were in group 1 (PWV 5.72±0.78m/s), 9 in group 2 (PWV 6.37±0.58m/s) and 13 in group 3 (PWV 9.87±2.06m/s). After correction for age, gender and mean arterial pressure, aortic PWV was signifi cantly correlated with SRIVR (p=0.000,β=-0.71), E/SRIVR (p=0.002,β=0.61) and LA strain (p=0.014,β=-0.47).

In patients with DM1, increased PWV is correlated with advanced indices for diastolic dysfunction. Increased MRI PWV may therefore be a marker of early left ventricular diastolic dysfunction.

Supported by: The Netherlands Heart Foundation (Project UL 2009-4548)

557-PScreening Method for Asymptomatic Coronary Heart Disease in Japanese Subjects with Type 2 DiabetesYUKIKO KAWASAKI, YOSHIYUKI HAMAMOTO, SACHIKO HONJO, KANAKO MORI, HIROKI IKEDA, YOSHIHARU WADA, KAZUHIRO NOMURA, YORIHIRO IWASAKI, HIROYUKI KOSHIYAMA, Osaka, Japan

We investigated the usefulness of screening methods using the treadmill tolerance test (TTT) as the fi rst line test or the risk-guided approach including the 1998 ADA guideline for the detection of asymptomatic coronary heart disease (CHD) in Japanese patients with type 2 diabetes. Subjects included consecutive inpatients with type 2 diabetes (n= 481). They were checked with electrocardiogram (ECG) at rest and TTT, and those with abnormal TTT fi ndings were investigated with stress myocardial perfusion scintigraphy (MPS), and those with abnormal MPS fi ndings were examined with coronary angiography (CAG). The number of patients who met the criteria of ADA guideline, or those of patients with cardiac autonomic neuropathy (CAN) or maximal carotid artery intima-media thickness (max IMT) of ≥1.1mm were examined. CAN was defi ned as the coeffi cients of variation of R-R intervals of ECG less than 2%. A total of 69 had positive TTT, among whom, a total of 22 had positive MPS. A total of 14 subjects received CAG, and eight of them (only 1.7% of the total subject) were fi nally indicated to have CHD. The patients who met the criteria of ADA were 53.6% of TTT-positive patients, 45.5% of MPS-positive patients, and 62.5% of CAG-positive patients, respectively. The patients with CAN and/or increased max IMT were 46.0/75.4%, 55.0/77.3% and 57.1/87.5% of patients with positive TTT, MPS and CAG, respectively.

The unexpectedly low rate of asymptomatic CHD in our screening suggested that considerable subjects with asymptomatic CHD had escaped the present screening method; in fact, among those with negative results, three patients developed CHD during the follow-up. Furthermore, it was suggested that the risk-guided approach with the ADA guideline or that incorporating CAN and/or increased max IMT with risk factors would have overlooked some subjects with CHD, even those who could be detected in the present screening.

These results suggest that neither the screening methods using TTT as the fi rst line test nor the risk-guided approach including the ADA guideline

are suffi ciently adequate for detecting asymptomatic CHD in Japanese subjects with type 2 diabetes.

558-PSDF-1β Protects Cardiac Cells from Palmitate-Induced Nitrosative Stress-Mediated ER Stress and Cell Death through Activation of AMPK-Mediated IL-6 ExcretionYUGUANG ZHAO, YI TAN, WEI LI, LU CAI, Changchun, China, Louisville, KY

Elevated saturated free fatty acids including palmitate (Pal) often occur in the patients with obesity and diabetes, and are also primary trigger for cardiac cell death, but its mechanisms remain largely unknown. Stromal cell-derived factor-1beta (SDF-1β) was cardiac protective, but whether it also protects the heart from lipotoxicity remains unknown. Using H9c2 cardiac cell line, we studied the apoptotic effect of Pal and its possible protection by SDF-1β. Exposure of H9c2 cells to Pal at 62.5 nM for 16 h causes a signifi cant apoptotic effect (DNA fragmentation and cleaved caspase-3). Pal also induced signifi cant increases in 3-nitrotyrosine at 3 – 6 h and endoplasmic reticulum (ER) stress [GRP78, CHOP and caspase-12] at 6 – 9 h after treatment. Inhibition of NADPH oxidase (NOX)-activation or scavenging superoxide and peroxynitrite with their specifi c inhibitors abolished Pal-induced ER stress and cell death. Inhibition of ER stress with 4PBA and TUDCA prevents cell death. It suggests that Pal-induced cell death is mediated by ER stress-associated cell death pathway activated by NOX-activation associated nitrosative stress. Pretreatment with SDF-1β abolishes Pal-induced nitrosative damage, ER stress and cell death, and induces AMPK-mediated IL-6 production. AMPK activator signifi cantly prevents Pal-induced cardiac apoptosis and increases IL-6 while AMPK inhibito abolishes SDF-1β’s cardiac protection. Direct addition of recombinant human IL-6 to cell cultures offers a signifi cant prevent of Pal-induced ER-stress and cell death. These results suggest that cardiac apoptotic effect of Pal is mediated by NOX activation-triggered nitrosative damage and ER stress cell death pathway. SDF-1β prevents Pal apoptotic effect via activating AMPK-mediated IL-6. The fi nding that SDF-1β protects cardiac cell death from fatty acid opens a new road for the research on cardiac protection by SDF-1β that provides cardiac protection independent of stem cell mobilization. ADA-Funded Research

559-PSecretory Products from Epicardial Adipose Tissue from Patients with Type 2 Diabetes Affect MiRNA Expression in CardiomyocytesMARCEL BLUMENSATT, SABRINA GREULICH, DANIELLA HERZFELD, BUJAR MAXHERA, ARTUR LICHTENBERG, JUERGEN ECKEL, MARGRIET OUWENS, Düsseldorf, Germany

Epicardial adipose tissue (EAT) is a visceral fat depot around the heart, which is not separated by a fascia. Therefore, factors secreted from EAT can directly affect the function of the myocardium. We have recently found that the secretory profi le of EAT is altered in patients with type 2 diabetes (T2D). Furthermore, conditioned media (CM) generated from EAT from patients with T2D (CM-EAT-T2D) induce cardiomyocyte dysfunction as illustrated by the induction of insulin resistance and reductions in sarcomere shortening and cytosolic Ca2+-fl uxes. Here, we examined whether the detrimental effects induced by CM-EAT can be ascribed to alterations in miRNA expression in cardiomyocytes. Therefore, primary adult rat cardiomyocytes were incubated with CM generated from EAT-biopsies collected from patients without (ND) and with T2D undergoing open heart surgery. Alterations in expression levels of 343 rat miRNA species (miRBase V13.0) were quantifi ed by real-time PCR. Adult rat cardiomyocytes were found to express 164 miRNA species. Of these, let7c and the miRNA-143/145 cluster were selectively up-regulated by CM-EAT-T2D compared to CM-EAT-ND. In addition, miRNA-26a, miRNA-26b, miRNA-425, miRNA-191 and miRNA-218 were signifi cantly down-regulated by CM-EAT-T2D versus CM-EAT-ND.

Levels of these miRNA species were not affected by CM from subcutaneous and pericardial adipose tissue from the same patients. Predicted target genes for these miRNAs include the key regulator of myocardial Ca2+-metabolism, SERCA2a, which is downregulated by CM-EAT-T2D in cardiomyocytes. In line with this, preliminary validation experiments suggest that silencing of let7c increases the abundance of SERCA2a. Collectively, these data suggest that alterations in miRNA expression in cardiomyocytes induced by factors secreted from epicardial adipose tissue could contribute to the pathogenesis of diabetes-related heart disease.

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560-PSoluble CD36 (sCD36) in Maturity Onset Diabetes of the Young (MODY) SubjectsMA P. KYITHAR, SIOBHAN BACON, AASE HANDBERG, MARIA M. BYRNE, Dublin, Ireland, Aarhus, Denmark

MODY subjects are lean, insulin sensitive and usually have normal lipid profi le. Other than the long duration of hyperglycemia, MODY patients have minimal additional cardiovascular risk factors. However, studies have shown that hepatocyte nuclear factor (HNF) 1A-MODY subjects have an increased risk of cardiovascular morbidity. CD36, a transmembrane glycoprotein, has been associated with infl ammation, atherosclerosis and platelet activation, and increased plasma sCD36 levels have been correlated with plaque instability. This study evaluated sCD36 levels in different forms of MODY and to compare this to type 2 diabetes (T2DM) & HNF1A-mutation negative controls with normal glucose tolerance (NGT).

Plasma sCD36 levels were measured by ELISA in 32 HNF1A-, 11 glucokinase (GCK)-, 9 HNF4A-MODY, 19 T2DM & 10 NGT subjects. HbA1c, fasting insulin & C-peptide, oral glucose insulin sensitivity index (OGIS) & area-under the curve (AUC) insulin were measured from 2-hour 75-g oral glucose tolerance test. Subjects were BMI-matched. sCD36 levels (mean ± standard error of means) in HNF1A subjects were signifi cantly lower compared to NGT controls (0.71±0.07 vs. 1.15±0.16 arbitrary units,P=0.02). No signifi cant difference was seen in sCD36 levels among HNF1A, GCK & HNF4A subjects. sCD36 levels in MODY groups did not differ when compared with BMI-matched T2DM subjects. In GCK-MODY, a signifi cant inverse correlation was seen between sCD36 and HbA1c (r=-0.63,P=0.04) & OGIS (r=-0.82,P=0.004). A positive correlation was found between sCD36 & fasting insulin in NGT subjects (r= 0.75,P=0.02). sCD36 levels did not correlate with age, diabetes duration, BMI, fasting insulin & C-peptide, OGIS & AUC insulin in HNF1A, HNF4A and T2DM subjects.

Our data suggest that HNF1A mutations may play a role in regulation of sCD36 levels and sCD36 may be a measure of insulin sensitivity in GCK-MODY subjects.

561-PSpontaneous Platelet Aggregation Evaluated by Laser Light Scatter in Patients with Type 2 Diabetes: Effects of Short-Term Improved Glycemic Control and AdiponectinKENJI HARA, YOSHIMASA ASO, KYOKO OMORI, TOMOKO TERASAWA, RIKA NARUSE, KOHOZO TAKEBAYASHI, TOSHIHIKO INUKAI, Koshigaya, Japan

Spontaneous platelet aggregation (SPA) is enhanced in patients with type 2 diabetes. Adiponectin may inhibit platelet aggregation. The aims of the present study were to identify factors associated with in vitro SPA measured by a laser light scattering method, and to investigate the effects of short-term glycemic control and adiponectin on SPA. We investigated SPA in 20 healthy control subjects and 82 patients with type 2 diabetes. Next, we evaluated changes of SPA and serum high molecular weight (HMW) adiponectin after 2 weeks of improved glycemic control in 20 hospitalized diabetic patients. Using washed platelets from 10 subjects, in vitro SPA was measured over 15 min in the absence or presence of recombinant adiponectin (20μg/ml). SPA was defi ned as formation of small aggregates (SA) under constant stirring in the absence of any agonists. SPA was increased in diabetic patients compared with control subjects. In diabetic patients, SPA was positively correlated with plasma fi brinogen, fasting plasma glucose, glycated albumin, and high-sensitivity C-reactive protein. Step-wise multivariate analysis showed plasma fi brinogen to be the strongest independent determinant of SPA. SPA decreased signifi cantly after 2 weeks of glycemic control in diabetic patients. There was a signifi cant negative correlation between changes of SPA and those of HMW adiponectin during treatment. The in vitro study showed that adiponectin inhibited the spontaneous aggregation of washed platelets. In conclusion, hyperfi brinogenemia and hyperglycemia are independently associated with SPA in patients with type 2 diabetes.

SPA is reduced after even short-term improvement of glycemic control and adiponectin inhibits directly SPA.

562-PThe Effects of the Metabolic Syndrome on Early Subclinical Diastolic Dysfunction Is Primarily Driven by the Inclusion in the Defi nition of HyperglycemiaALOIS SALLER, PAOLA BIGOLIN, MARINO BRUSEGHIN, MARCO ARBOIT, ISABELLA BARZON, Padua, Italy, Padova, Italy

The purpose of this study was to evaluate the presumed importance of hyperglycaemia (HG) as the basic mechanism underlying early subclinical diastolic dysfunction (DD) by recent more sensitive transthoracic echocardiographic (TTE) techniques in patients (pts) with Metabolic Syndrome (MeS). MeS ATPIII criteria were assessed in 154 adults with normal systolic left ventricular (LV) function. As controls served 45 subjects which presented less than 2 risk factor components except impaired fasting glucose (CS-IFG) and 22 type II diabetes pts without criteria for MeS (DM-MeS). TTE was used to assess LV structure (LV mass) and DD: by colour M-mode TTE and fl ow propagation velocity (pv) in order to calculate E/pv ratio and colour-guide pulsed wave tissue Doppler from the apex to calculate E/E’ ratio. All patients had normal global systolic function (ejection fraction 67.4±6%, mean±S.D.; 51-69%, min-max). 114 pts (84%) presented left ventricular hypertrophy (LVH) and 45 pts (31%) had DD. Logistic regression analysis model showed that only HG was signifi cantly associated with both DD parameters (E/E’ 4.7 O.R. 95% CI. (0.99-22.14), p=0.05; E/pv 13.2 O.R. 95% CI. (1.6-109.2), p=0.017). Subgroup analysis: The prevalence of LV DD derived by E/E’ and E/pv in the MeS group with IFG ranged from 34.4%-41.3%, in MeS without IFG from 10%-5.3%, in CS-IFG from 6.7%-4.4% and DM-MeS from 22%-22.7 (p

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564-PThe Relationship of Serum Infl ammatory Factors, Insulin Resistance and Sub-Clinical Vascular Disease in Type 2 Diabetic PatientsXIAO-ZHEN JIANG, QUAN JIANG, XIAO-HUI ZHAO, YU-FENG ZOU, Shanghai, China

Object: Chronic low-grade infl ammation in subjects with type 2 diabetes is associated with health complications including insulin resistance and cardiovascular diseases. However,there were little study about the relationship of serum infl ammatory factors and sub-clinical vascular disease or insulin resistance. We investigated the association of serum C-reactive protei(CRP), interleukin-6(IL-6), adiponectin (APN), leptin (LEP), tumor necrosis factor-α (TNF-α), matrix metallo -proteinases(MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), insulin resistance and sub-clinical vascular disease in type 2 diabetic patients in this study. Methods: Serum levels of CRP, IL-6, APN, LEP, TNF-α, MMP-9 and TIMP-1 of 199 T2DM patients without clinical macroangiopathy were tested. We measured their carotid intima-media thickness (IMT) by ultrasound, and calculated HOMA-IR of each patient. If the IMT was greater than 0.9mm, the patients were assigned to sub-clinical vascular disease group (group A), the rest were in non-clinical vascular disease group (group B). Results: CRP (3.19±1.33 vs 2.55±1.05), IL-6 (3.5±0.93 vs 2.79±0. 72), MMP-9 (72.01±17.91 vs 54.83±17.20), TIMP-1 (63.09±8.11 vs 43.38±7.78), LEP (0.85±0.44 vs 0.62±0.36) and HOMA-IR (6.78±2.98 vs 4.93±2.93) were higher but APN (8.83±3.99 vs 9.79±4.47) was lower in group A than in group B (P0.05) between two groups. In group A, APN was negatively correlated to HOMA-IR and IMT (P

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COMPLICATIONS—MACROVASCULAR—CELLULAR MECHANISMS OF ATHEROGENESIS IN DIABETES

568-PVascular Smooth Muscle Dysfunction Is Differently Associated with Vascular Complications and Risk Factors from Endothelial Dys-function in Type 2 Diabetic PatientsNAOYA KAWANO, MASANORI EMOTO, YUKO YAMAZAKI, HIROMI URATA, SHOKO TSUCHIKURA, KOKA MOTOYAMA, TOMOAKI MORIOKA, KATSUHITO MORI, SHINYA FUKUMOTO, TETSUO SHOJI, YASUHISA OKUNO, YOSHIKI NISHIZAWA, MASAAKI INABA, Osaka, Japan

Atherosclerosis and arteriosclerosis are mainly caused by dysfunction of components of artery, vascular endothelial cell, smooth muscle cell, and extracellular matrix. Endothelial dysfunction is well established as a predictive surrogate marker of cardiovascular event. But, little is known regarding clinical implications of vascular smooth muscle dysfunction on cardiovascular disease and microangiopathy. In the present study, we aimed to clarify the association of arterial function with micro-/macroangiopathy and conventional cardiovascular risk factors in 190 type 2 diabetic patients (T2DM: age, 64±11 (SD) years old; duration of diabetes, 12±10 years). Flow-mediated dilatation (FMD) as an endothelial function and nitoroglycerin-mediated dilatation (NMD) as vascular smooth muscle function were assessed by a novel ultrasound equipment, UNEXEF18G (Unex Co. Ltd., Japan).

In all T2DM, FMD was 6.7±3.9%, ranging from 0.7 to 19.2%, and NMD 13.1±6.6%, 0.5 to 28.9%. There were no signifi cant differences in FMD between in T2DM with and without micro- or macroangiopathy. However, NMD in T2DM with micro- and macroangiopathy was signifi cantly lower than those without both anigopathy.

Although both FMD and NMD were lower in accordance with the progression of CKD stage (FMD, stage1 9.4±5.0, stage2 6.6±3.7, stage3 6.3±3.4, stage4/5 5.3±3.9, p=0.005; NMD, stage1 17.9±6.2, stage2 14.1±6.5, stage3 11.3±6.1, stage4/5 7.8±3.2, p

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2011 ada posters 478-1260 - diabetes · 2011. 6. 28. · a134 for author disclosure information,...

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