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Objective: Our goal is to measure real-world effects of at-risk driver physiology on safety-critical tasks like driving by monitoring driver behavior and physiology in real-time. Drivers with type ...

Background: Thromboxane A2 (TxA2), a lipid mediator plays a critical role in cardiovascular disease and chronic inflammatory disorders. TxA2 signaling is regulated by TxA2 synthase (Tbxas1), an enzyme that produces TxA2, and TxA2 receptor (Tbxa2r). Objective: To determine if Tbxa2r gene expression in adipose tissue (AT) is higher in obese insulin resistant (IR) subjects compared to overweight non-IR subjects. Methods: Insulin resistance was measured via a homeostatic model assessment of insulin resistance (HOMA-IR). Subcutaneous AT biopsies were obtained from overweight (BMI between ≥25 to 2.5) subjects. Gene expression of Tbxa2r and Tbxas1 were analyzed in tissue samples and compared between groups. Results: The mRNA levels of Tbxa2r and Tbxas1 were significantly higher in obese IR subjects compared to overweight subjects (P Conclusion: Our data suggest that TxA2 signaling is activated in AT in obesity and is associated with the development of insulin resistance in obesity. Tbxas1 and/or Tbxa2r may be a potential therapeutic target for obesity-linked metabolic diseases. Disclosure D. Alcaraz Alvarez: None. S. Viswanathan: None. T. Thangavelu: None. N. Kumar: None. K. Kelley: None. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S.

OBJECTIVE To investigate the efficacy and safety of once-daily semaglutide in comparison with once-daily liraglutide and placebo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, multicenter, double-blind trial involved patients diagnosed with type 2 diabetes with HbA1c 7.0–10.0% (53–86 mmol/mol) and treated with diet and exercise with or without metformin. Patients were randomized 2:2:1 to once-daily semaglutide, liraglutide, or placebo in one of four volume-matched doses (semaglutide 0.05, 0.1, 0.2, or 0.3 mg and liraglutide 0.3, 0.6, 1.2, or 1.8 mg, with both compared within each volume-matched dose group). Primary end point was change in HbA1c from baseline to week 26. RESULTS In total, 705 randomized patients were exposed to trial products. At week 26, a dose-dependent change in HbA1c was observed with semaglutide from −1.1% (0.05 mg) to −1.9% (0.3 mg) and with liraglutide from −0.5% (0.3 mg) to −1.3% (1.8 mg) (all P < 0.001 in favor of volume-matched semaglutide dose). Change with pooled placebo was −0.02% (P < 0.0001 vs. semaglutide). Gastrointestinal (GI) disorders were the most common adverse events (AEs) with semaglutide and liraglutide, occurring in 32.8–54.0% and 21.9–41.5% of patients, respectively. CONCLUSIONS Once-daily semaglutide at doses up to 0.3 mg/day resulted in greater reductions in HbA1c compared with liraglutide or placebo but with a higher frequency of GI AEs.

Aim: To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects. Materials and methods: Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c

Objective Endothelial cell (EC) oxidative stress can lead to vascular dysfunction which is an underlying event in the development of cardiovascular disease (CVD). The lack of a potent and bioavailable anti-oxidant enzyme is a major challenge in studies on antioxidant therapy. The objective of this study is to determine whether copper/zinc superoxide dismutase (CuZnSOD or SOD1) after nanoformulation (nanoSOD) can effectively reduce EC oxidative stress and/or vascular inflammation in obesity. Methods. Human aortic endothelial cells (HAECs) were treated with native- or nanoSOD for 6 h followed by treatment with linoleic acid (LA), a free fatty acid, for 6–24 h. To determine the in vivo relevance, the effectiveness of nanoSOD in reducing vascular cell activation was studied in a mouse model of diet-induced obesity. Results. We noted that nanoSOD was more effectively taken up by ECs than native SOD. Western blot analysis further confirmed that the intracellular accumulation of SOD1 protein was greatly increased upon nanoSOD treatment. Importantly, nanoSOD pretreatment led to a significant decrease in LA-induced oxidative stress in ECs which was associated with a marked increase in SOD enzyme activity in ECs. In vivo studies showed a significant decrease in markers of EC/vascular cell activation and/or inflammation in visceral adipose tissue (VAT), thoracic aorta, and heart collected from nanoSOD-treated mice compared to obese control mice. Interestingly, the expression of metallothionein 2, an antioxidant gene was significantly increased in nanoSOD-treated mice. Conclusion. Our data show that nanoSOD is very effective in delivering active SOD to ECs and in reducing EC oxidative stress. Our data also demonstrate that nanoSOD will be a useful tool to reduce vascular cell activation in VAT and aorta in obesity which, in turn, can protect against obesity-associated CVD, in particular, hypertension.

Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD.A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months.27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment.Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.

The objective of this study was to determine the effects of enrichment with n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the differentiation of 3T3-L1 preadipocytes. Enrichment with DHA but not EPA significantly increased the differentiation markers compared to control differentiated cells. DHA compared to EPA treatment led to a greater increase in adiponectin secretion and, conditioned media collected from DHA treated cells inhibited monocyte migration. Moreover, DHA treatment resulted in inhibition of pro-inflammatory signaling pathways. DHA treated cells predominantly accumulated DHA in phospholipids whereas EPA treatment led to accumulation of both EPA and its elongation product docosapentaenoic acid (DPA), an n-3 fatty acid. Of note, adding DPA to DHA inhibited DHA-induced differentiation. The differential effects of EPA and DHA on preadipocyte differentiation may be due, in part, to differences in their intracellular modification which could impact the type of n-3 fatty acids incorporated into the cells.

Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity.Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks.The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice.Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively.

Kidney transplantation is being performed more frequently for individuals with end stage renal disease (ESRD) due to improved survival and quality of life compared to long-term dialysis. Though rates decrease after transplant, cardiovascular disease (CVD) remains the most common cause of death after kidney transplant. New-onset diabetes after transplant (NODAT), a common complication following kidney transplantation, and pre-transplant diabetes both significantly increase the risk for CVD. Several other risk factors for CVD in kidney transplant recipients have been identified; however, optimal therapy for controlling the risk factors of CVD after kidney transplantation, including NODAT and pre-transplant diabetes, is not well defined. In the following review we will discuss the role of traditional and non-traditional risk factors in CVD after kidney transplant and the mechanisms involved therein. We will also examine the current literature regarding treatment of these risk factors for the prevention of CVD. Finally, we will review the current recommendations for pre- and post-transplant cardiovascular evaluation and management.

Diabetes is at epidemic proportions in the U.S. Patients with diabetes are at increased risk for micro- and macrovascular complications. The benefit of glycemic control in decreasing the risk for microvascular disease is well established. However, the role of glycemic control in decreasing macrovascular complications has been controversial. Several large clinical trials looking at this issue have either shown no benefit or even potential harm. The possibility of hypoglycemia as a risk factor for cardiovascular events is a topic of much debate. In this review article, we discuss the evidence for and against this hypothesis and the possible mechanisms that might be involved. Patients with diabetes have an increased risk of cardiovascular disease. The link between glycemic control and microvascular complications has been firmly established (1,2). However, the association between glycemic control and macrovascular disease is mainly obtained from epidemiological studies, and intensive glucose control has often failed to reduce macrovascular events. Intensive glucose control invariably increases the risk of hypoglycemia and sometimes the severity of hypoglycemia (2) Several epidemiological studies and smaller prospective studies have linked hypoglycemia to increased cardiovascular risk (3⇓–5). Recent large randomized trials looking at intensive glycemic control have either shown no benefit (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] and Veterans Affairs Diabetes Trial [VADT]) or increased all cause mortality (Action to Control Cardiovascular Risk in Diabetes [ACCORD]) (6). While the reason for the increased mortality is unclear and hypoglycemia has not been implicated as a cause of death, these studies have increased the debate about the degree of glycemic control required to decrease diabetes complications and the role of hypoglycemia in cardiovascular morbidity and mortality. The modern definition of hypoglycemia is plasma glucose

Objective Insulin resistance is an independent risk factor for cardiovascular disease. PPAR-gamma agonists like pioglitazone decrease insulin resistance and have been shown to reduce neointimal hyperplasia in the short-term. However long-term studies on endothelial regrowth and neointimal hyperplasia have not been done. Methods and results We used hyperinsulinemic, normoglycemic Zucker fatty rats. Rats were treated with either 10 mg/kg body wt. pioglitazone or placebo till the end of the experiment. Rats underwent carotid angioplasty at age 12–14 weeks, 1 week after treatment was begun. In one set of experiments rats were sacrificed at 6 months and neointimal hyperplasia and VEGF expression was assessed. In another set of experiments rats were sacrificed at 3 and 6 months. Endothelial regrowth was determined. The rats were all normoglycemic and hyperinsulinemic. Pioglitazone treated rats had a significantly lesser degree of neointimal hyperplasia than control rats. Treated rats also had decreased VEGF expression. Endothelial regrowth was decreased in the treated rats at 6 months. Conclusion We conclude that although pioglitazone decreases neointimal hyperplasia even at 6 months, it retards endothelial regrowth, which could predispose the denuded vessel to thrombotic events. This may be modulated by a suppression of VEGF expression.

OBJECTIVE—In some studies intensive diabetes treatment in patients with type 2 diabetes may be associated with increased cardiovascular events. It is not clear whether these events are related to hypoglycemic episodes. To determine whether episodes of hypoglycemia were more likely to be associated with cardiac ischemia than normoglycemia or hyperglycemia, we carried out a study in 21 patients with coronary artery disease (CAD) and type 2 diabetes treated with insulin who had good glycemic control. RESEARCH DESIGN AND METHODS—We carried out 72-h continuous glucose monitoring along with simultaneous cardiac Holter monitoring for ischemia. Patients also recorded symptoms of cardiac ischemia (chest pain) and symptoms of hypoglycemia. RESULTS—Satisfactory continuous glucose monitoring system recordings were obtained in 19 patients. We recorded 54 episodes of hypoglycemia (blood glucose 200 mg/dl; none symptomatic). Of the 54 episodes of hypoglycemia, 10 were associated with symptoms of chest pain, during 4 of which electrocardiographic abnormalities were documented. In contrast, only 1 episode of chest pain occurred during 59 episodes of hyperglycemia. No chest pain or electrocardiographic abnormalities occurred when the blood glucose was within the normal range. The difference between the frequency of ischemia during hypoglycemia and the frequency during both hyperglycemia and normoglycemia was statistically significant (P < 0.01). There were 50 episodes during which the blood glucose changed by >100 mg over a 60-min period, and ischemic symptoms occurred during 9 of these episodes (P < 0.01 compared with stable normoglycemia or hyperglycemia). CONCLUSIONS—Hypoglycemia is more likely to be associated with cardiac ischemia and symptoms than normoglycemia and hyperglycemia, and it is particularly common in patients who experience considerable swings in blood glucose. These data may be important in the institution of insulin treatment and attempting near-normal glycemia in patients with known CAD. Further research is needed to determine strategies to prevent ischemia associated with hypoglycemia.