Left ventricular mass in patients with type 2 diabetes is independently associated with central but not peripheral pulse pressure

An increase in left ventricular mass (LVM) occurs in the presence of type 2 diabetes, apparently independent of hypertension (1), but the determinants of this process are unknown. Brachial blood pressure is not representative of that at the ascending aorta (2) because the pressure wave is amplified from central to peripheral arteries. Central blood pressure is probably more clinically important since local pulsatile pressure determines adverse arterial and myocardial remodeling (3,4). Thus, an inaccurate assessment of the contribution of arterial blood pressure to LVM may occur if only brachial blood pressure is taken into consideration. In this study we sought the contribution of central blood pressure (and other interactive factors known to affect wave reflection, e.g., glycemic control and total arterial compliance) to LVM in patients with type 2 diabetes.

Determinants of exercise capacity in patients with type 2 diabetes

OBJECTIVE - Type 2 diabetes is associated with reduced exercise capacity, but the cause of this association is unclear. We sought the associations of impaired exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS - Subclinical left ventricular (LV) dysfunction was sought from myocardial strain rate and the basal segmental diastolic velocity (Em) of each wall in 170 patients with type 2 diabetes (aged 56 +/- 10 years, 91 men), good quality echocardiographic images, and negative exercise echocardiograms. The same measurements were made in 56 control subjects (aged 53 +/- 10 years, 29 men). Exercise capacity was calculated in metabolic equivalents, and heart rate recovery (HRR) was measured as the heart rate difference between peak and 1 min after exercise. In subjects with type 2 diabetes, exercise capacity was correlated with clinical, therapeutic, biochemical, and echocardiographic variables, and significant independent associations were sought using a multiple linear regression model. RESULTS - Exercise capacity, strain rate, Em, and HRR were significantly reduced in type 2 diabetes. Exercise capacity was associated with age (r- = -0.37, P < 0.001), male sex (r = 0.26, P = 0.001), BMI (r = -0.19, P = 0.012), HbA(1c) (AlC; r = -0.22, P = 0.009), Em (r = 0.43, P < 0.001), HRR (r = 0.42, P < 0.001), diabetes duration (r = -0.18, P = 0.021), and hypertension history (r = -0.28, P < 0.001). Age (P < 0.001), male sex (P = 0.007), BMI (P = 0.001), Em (P = 0.032), HRR (P = 0.013), and AlC (P = 0.0007) were independent predictors of exercise capacity. CONCLUSIONS - Reduced exercise capacity in patients with type 2 diabetes is associated with diabetes control, subclinical LV dysfunction, and impaired HRR.

Diastolic dysfunction is a manifestation of ventricular-vascular interaction in patients with type 2 diabetes mellitus

Vascular disease is accelerated in patients with Type 2 diabetes mellitus (T2DM). Since the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on left ventricular (LV) morphology and function in patients with T2DM. Conventional echocardiography and tissue Doppler imaging were performed in 172 T2DM patients (95 men; aged 55±11y) with preserved ejection fraction (62±5%). Patients were stratified into groups based on LV geometric pattern (normal [n = 79], concentric remodeling [n = 33], concentric hypertrophy [n = 29], eccentric hypertrophy [n = 31]). Total arterial compliance (TAC) was recorded by simultaneous radial tonometry and aortic outflow pulsed wave Doppler. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences between the LV geometric groups in demographic or clinical parameters. The concentric hypertrophy group had significantly increased carotid artery diameter (6.0±0.7mm versus 6.5±0.7mm; p < 0.05) and stiffness (1912±1203 dynes/cm2mm versus 2976±2695 dynes/cm2mm×10−6; p < 0.05) compared to those with normal geometry. However, TAC did not differ between groups. LV diastolic function, as determined by the ratio of diastolic mitral inflow velocity to mitral annulus tissue velocity (E/E_), was significantly associated with carotid artery relative wall thickness and intima media thickness (p < 0.05). Moreover, E/E_ was independently predicted by carotid artery relative wall thickness (β = 22.9; p = 0.007). We conclude that structural characteristics of the carotid artery are associated with abnormal LV structure and function in patients with T2DM. The LV functional irregularities may be a downstream consequence of amplified pressure wave reflections effecting sub-optimal ventricular-vascular interaction.

Treating type 2 diabetes through insulin resistance

Type 2 diabetes is an insidious disorder, with micro and/or macrovascular and nervous damage occurring in many patients before diagnosis. This damage is caused by hyperglycaemia and the diverse effects of insulin resistance. Obesity, in particular central obesity, is a strong pre-disposing factor for type 2 diabetes. Skeletal muscle is the main site of insulin-stimulated glucose disposal and appears to be the first organ that becomes insulin resistant in the diabetic state, with later involvement of adipose tissue and the liver. This study has investigated the use of novel agents to ameliorate insulin-resistance in skeletal muscle as a means of identifying intervention sites against insulin resistance and of improving glucose uptake and metabolism by skeletal muscle. Glucose uptake was measured in vitro by cultured L6 myocytes and isolated muscles from normal and obese diabetic ob/ob mice, using either the tritiated non-metabolised glucose analogue 2-deoxy-D-glucose or by glucose disposal. Agents studied included lipoic acid, isoferulic acid, bradykinin, lipid mobilising factor (provisionally synonymous with Zinca2 glycoprotein) and the trace elements lithium, selenium and chromium. The putative role of TNFa in insulin resistance was also investigated. Lipoic acid improved insulin-stimulated glucose uptake in normal and insulin resistance murine muscles, as well as cultured myocytes. Isoferulic acid, bradykinin and LMF also produced a transient increase in glucose uptake in cultured myocytes. Physiological concentrations of TNFa were found to cause insulin resistance in cultured, but no in excised murine muscles. The effect of the M2 metabolite of the satiety-inducing agent sibutramine on lipolysis in excised murine and human adipocytes was also investigated. M2 increased lipolysis from normal lean and obese ob/ob mouse adipocytes. Arguably the most important observation was that M2 also increased the lipolytic rate in adipocytes from catecholamine resistant obese subjects. The studies reported in this thesis indicate that a diversity of agents can improve glucose uptake and ameliorate insulin resistance. It is likely that these agents are acting via different pathways. This thesis has also shown that M2 can induce lipolysis in both rodent and human adipocytes. M2 hence has potential to directly reduce adiposity, in addition to well documented effects via the central nervous system.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes

Background - To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods - We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results - A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions - Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)

Contradiction versus Selfcontradiction in Fuzzy Logic

* This work is partially supported by CICYT (Spain) under project TIN 2005-08943-C02-001 and by UPM-CAM (Spain) under project R05/11240.

An automatic tuning strategy for local fuzzy logic ramp metering algorithm using Particle Swarm Optimization (PSO)

Freeway systems are becoming more congested each day. One contribution to freeway traffic congestion comprises platoons of on-ramp traffic merging into freeway mainlines. As a relatively low-cost countermeasure to the problem, ramp meters are being deployed in both directions of an 11-mile section of I-95 in Miami-Dade County, Florida. The local Fuzzy Logic (FL) ramp metering algorithm implemented in Seattle, Washington, has been selected for deployment. The FL ramp metering algorithm is powered by the Fuzzy Logic Controller (FLC). The FLC depends on a series of parameters that can significantly alter the behavior of the controller, thus affecting the performance of ramp meters. However, the most suitable values for these parameters are often difficult to determine, as they vary with current traffic conditions. Thus, for optimum performance, the parameter values must be fine-tuned. This research presents a new method of fine tuning the FLC parameters using Particle Swarm Optimization (PSO). PSO attempts to optimize several important parameters of the FLC. The objective function of the optimization model incorporates the METANET macroscopic traffic flow model to minimize delay time, subject to the constraints of reasonable ranges of ramp metering rates and FLC parameters. To further improve the performance, a short-term traffic forecasting module using a discrete Kalman filter was incorporated to predict the downstream freeway mainline occupancy. This helps to detect the presence of downstream bottlenecks. The CORSIM microscopic simulation model was selected as the platform to evaluate the performance of the proposed PSO tuning strategy. The ramp-metering algorithm incorporating the tuning strategy was implemented using CORSIM's run-time extension (RTE) and was tested on the aforementioned I-95 corridor. The performance of the FLC with PSO tuning was compared with the performance of the existing FLC without PSO tuning. The results show that the FLC with PSO tuning outperforms the existing FL metering, fixed-time metering, and existing conditions without metering in terms of total travel time savings, average speed, and system-wide throughput.

Hypertension, poor glycemic control, and microalbuminuria in Cuban Americans with type 2 diabetes

Purpose: To investigate to what degree the presence of hypertension (HTN) and poor glycemic control (GC) influences the likelihood of having microalbuminuria (MAU) among Cuban Americans with type 2 diabetes (T2D).Methods: A cross-sectional study conducted in Cuban Americans (n = 179) with T2D. Participants were recruited from a randomly generated mailing list purchased from KnowledgeBase Marketing, Inc. Blood pressure (BP) was measured twice and averaged using an adult size cuff. Glycosylated hemoglobin (A1c) levels were measured from whole blood samples with the Roche Tina-quant method. First morning urine samples were collected from each participant to determine MAU by a semiquantitative assay (ImmunoDip).Results: MAU was present in 26% of Cuban Americans with T2D. A significantly higher percentage of subjects with MA had HTN (P = 0.038) and elevated A1C (P = 0.002) than those with normoalbuminuria. Logistic regression analysis showed that after controlling for covariates, subjects with poor GC were 6.76 times more likely to have MAU if they had hypertension compared with those without hypertension (P = 0.004; 95% confidence interval [CI]: 1.83, 23.05). Conclusion: The clinical significance of these findings emphasizes the early detection of MAU in this Hispanic subgroup combined with BP and good GC, which are fundamentals in preventing and treating diabetes complications and improving individuals’ renal and cardiovascular outcomes.

Glycated hemoglobin, body weight and blood pressure in type 2 diabetes patients initiating dapagliflozin treatment in primary care:a retrospective study

Introduction - The present study aimed to describe characteristics of patients with type 2 diabetes (T2D) in UK primary care initiated on dapagliflozin, post-dapagliflozin changes in glycated hemoglobin (HbA1c), body weight and blood pressure, and reasons for adding dapagliflozin to insulin. Methods - Retrospective study of patients with T2D in the Clinical Practice Research Datalink with first prescription for dapagliflozin. Patients were included in the study if they: (1) had a first prescription for dapagliflozin between November 2012 and September 2014; (2) had a Read code for T2D; (3) were registered with a practice for at least 6 months before starting dapagliflozin; and (4) remained registered for at least 3 months after initiation. A questionnaire ascertained reason(s) for adding dapagliflozin to insulin. Results - Dapagliflozin was most often used as triple therapy (27.7%), dual therapy with metformin (25.1%) or added to insulin (19.2%). Median therapy duration was 329 days [95% confidence interval (CI) 302–361]. Poor glycemic control was the reason for dapagliflozin initiation for 93.1% of insulin-treated patients. Avoiding increases in weight/body mass index and insulin resistance were the commonest reasons for selecting dapagliflozin versus intensifying insulin. HbA1c declined by mean of 9.7 mmol/mol (95% CI 8.5–10.9) (0.89%) 14–90 days after starting dapagliflozin, 10.2 mmol/mol (95% CI 8.9–11.5) (0.93%) after 91–180 days and 12.6 mmol/mol (95% CI 11.0–14.3) (1.16%) beyond 180 days. Weight declined by mean of 2.6 kg (95% CI 2.3–2.9) after 14–90 days, 4.3 kg (95% CI 3.8–4.7) after 91–180 days and 4.6 kg (95% CI 4.0–5.2) beyond 180 days. In patients with measurements between 14 and 90 days after starting dapagliflozin, systolic and diastolic blood pressure decreased by means of 4.5 (95% CI −5.8 to −3.2) and 2.0 (95% CI −2.9 to −1.2) mmHg, respectively from baseline. Similar reductions in systolic and diastolic blood pressure were observed after 91–180 days and when follow-up extended beyond 180 days. Results were consistent across subgroups. Conclusion - HbA1c, body weight and blood pressure were reduced after initiation of dapagliflozin in patients with T2D in UK primary care and the changes were consistent with randomized clinical trials.