Centella asiatica and lipoic acid, or a combination thereof, inhibit monocyte adhesion to endothelial cells from umbilical cords of gestational diabetic women.

BACKGROUND AND AIMS: Diabetes mellitus is associated with inflammatory endothelial activation and increased vascular leukocyte adhesion molecule expression, both playing a prominent role in the development of vascular complications. Centella asiatica (CA) and Lipoic Acid (LA) have shown anti-inflammatory and anti-oxidant properties in a variety of experimental models; however, their action on human umbilical vein endothelial cells (HUVECs), chronically exposed to hyperglycemia and pro-inflammatory environment during pregnancy, is still unknown. METHODS AND RESULTS: In HUVECs from umbilical cords of gestational diabetic (GD) or healthy (C) women, both CA and LA affected tumor necrosis factor-α (TNF-α)-induced inflammation, being associated with a significant decrease in vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression (western blot) and exposure (flow cytometry), as well as monocyte-HUVECs interaction (adhesion assay). Notably, this was associated with a significant reduction of an index of nitro-oxidative stress, such as the intracellular peroxynitrite levels (fluorescence detection by cytometric analysis), Mitogen-Activated Protein kinase (p44/42 MAPK) expression/phosphorylation levels and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB p65) cytoplasm-nucleus translocation (flow cytometry). Overall our results indicate that both CA and LA used separately, and even better when combined, are effective to reduce the inflammatory response in TNF-α-treated HUVECs. Notably, this was more significant in GD than in C-HUVECs and also evident at baseline. CONCLUSION: In conclusion, our in vitro study demonstrates that both CA and LA, or a combination thereof, are able to mitigate the potentially dangerous effects on the endothelium of chronic exposure to hyperglycemia in vivo.

Features of endothelial dysfunction in umbilical cord vessels of women with gestational diabetes.

BACKGROUND AND AIMS: Gestational diabetes (GDM) is associated with increased oxidative stress and overexpression of inflammatory cytokines, both of which might lead to endothelial dysfunction and vascular disease. As such, GDM could be viewed as a sort of 'short lived' metabolic syndrome. As umbilical cord vessels represent a suitable model for the study of vascular alterations brought about by GDM, the aim of the present work was to characterize the phenotype of human umbilical vein endothelial cells (HUVECs) chronically exposed to hyperglycaemia and to a pro-inflammatory environment during pregnancy so as to identify molecular modifications of cellular homoeostasis eventually impacting on endothelial dysfunction. METHODS AND RESULT: Tissue specimens and HUVECs were obtained from umbilical cords of GDMand control women. As compared to controls, GD-HUVEC exhibited enhanced monocyte adhesion and vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1(ICAM-1) expression and exposure on plasma membrane after tumour necrosis factor-alpha(TNF-α) stimulation (Western blot, flow cytometer). As compared to control cells, GD-HUVEC in basal conditions exhibited enhanced monocyte adhesion, nitric oxide synthase (NOS) expression and activity (eNOS Real-Time polymerase chain reaction, Western Blot for eNOS total protein and monomers/dimers ratio, conversion of [3H]-L-arginine in [3H]-L-citrulline), increased O(-)(2)egeneration together with increased NT levels (immunofluorescence) and reduced NO bioavailability(guanosine 3',5'-monophosphate (cGMP) production, EIA). Furthermore, immunohistochemistry revealed increased eNOS and NT immunoreactivity in GD umbilical cords. CONCLUSION: Endothelial cells exposed in vivo even transiently to hyperglycaemia, oxidative stress and inflammation exhibit durable pro-atherogenic modifications.

Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus?

Thiazolidinediones have been introduced in the treatment of type 2 diabetes mellitus (T2DM) since the late 1990s. Although troglitazone was withdrawn from the market a few years later due to liver toxicity, both rosiglitazone and pioglitazone gained widespread use for T2DM treatment. In 2010, however, due to increased risk of cardiovascular events associated with its use, the European Medicines Agency recommended suspension of rosiglitazone use and the Food and Drug Administration severely restricted its use. Thus pioglitazone is the only thiazolidinedione still significantly employed for treating T2DM and it is the only molecule of this class still listed in the American Diabetes Association-European Association for the Study of Diabetes 2012 Position Statement. However, as for the other thiazolidinediones, use of pioglitazone is itself limited by several side effects, some of them potentially dangerous. This, together with the development of novel therapeutic strategies approved in the last couple of years, has made it questionable whether or not thiazolidinediones (namely pioglitazone) should still be used in the treatment of T2DM. This article will attempt to formulate an answer to this question by critically reviewing the available data on the numerous advantages and the potentially worrying shortcomings of pioglitazone treatment in T2DM.

Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus.

BACKGROUND: Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus. OBJECTIVES: To evaluate the effects of acarbose, an alpha-glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients. METHODS: Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE). RESULTS: Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) excretion rate as early as after 8 weeks and at each subsequent time point (between-group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11-dehydro-TXB(2) urinary excretion rate (beta = 0.39, P = 0.002) and MAGE the only predictor of 8-iso-PGF(2alpha) urinary excretion rate (beta = 0.42, P = 0.001). CONCLUSIONS: Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time-dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.

Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function.

UNLABELLED: Thyroid dysfunction and the presence of thyroid antibodies increase the risk of infertility and miscarriage. The aim of the present study was to assess if patients with autoimmune thyroid disease undergoing assisted reproduction technologies (ART) are afflicted by poor pregnancy and/or delivery rate and if the outcome is conditioned by pre-ART thyroid status. The study was retrospective (from January 2000 to January 2005) and was carried out at the Division of Physiopathology of Human Reproduction. Women who underwent ART were tested for TSH, free T4 (FT4), thyroid peroxidase antibodies (TPOAb) before and during pregnancy. A total of 416 euthyroid women were selected; 42 (10.1%) were TPOAb (+). Women >35 yr were excluded. The endpoints were pregnancy and delivery rates. RESULTS: no differences in pregnancy and delivery rates were observed between women with and without antibodies. In TPOAb (+), women who failed to become pregnant or miscarried displayed higher TSH values before ART (2.8 mIU/l) compared to the ones who delivered (1.6 mIU/l; p=0.032) and compared to TPOAb (-) (1.1 mIU/l; p=0.018). CONCLUSIONS: in euthyroid women undergoing ART the pregnancy and delivery rates are not affected by the presence of TPOAb. In TPOAb (+) high-normal TSH values are associated with increased risk of unsuccessful pregnancy or subsequent miscarriage. Further studies are required to ascertain possible benefits of levo-T4 (L-T4) in such patients.

The effects of irbesartan and telmisartan on metabolic parameters and blood pressure in obese, insulin resistant, hypertensive patients.

Obesity, hypertension, dyslipidemia and glucose intolerance cluster in the insulin resistance syndrome. Angiotensin II receptor blockers (ARB) are able to reduce insulin resistance. Furthermore, among ARB, telmisartan displays the property of stimulating PPARgamma. The aim of the study was to examine if and to what extent treatment with irbesartan and telmisartan induces variations in metabolic parameters in insulin resistant, hypertensive subjects. Forty-six non diabetic, obese, insulin-resistant, hypertensive patients took part in the study. They were divided into 2 groups. Group A (23) was submitted to irbesartan 150 mg/day, Group B (23) to telmisartan 80 mg/day for 6 months. Adiponectin, glucose, cholesterol, triglycerides, free fatty acids (FFA), steady-state plasma insulin and glucose (SSPG), 24-hBP were determined at the beginning and at the end of the study. Both irbesartan or telmisartan reduced blood pressure and ameliorated the insulin sensitivity, with increased adiponectin values; in Group B, the amelioration of metabolic parameters was greater than in Group A and the reduction of blood pressure was related with variation of adiponectin levels. Data obtained showed that the antihypertensive action of telmisartan and irbesartan is associated with the amelioration of the metabolic picture. The greater impact on the improvement of the metabolic profile showed by telmisartan and the inverse correlation between adiponectin levels and blood pressure may be partly due to the action as partial PPARgamma agonist displayed by telmisartan.

Practice guidelines: useful and "participative" method? Survey of Italian physicians by professional setting.

BACKGROUND: Professional setting might be a key determinant of physicians' attitudes toward practice guidelines, influencing the effect of their implementation. Because no previous surveys have specifically considered this aspect, we evaluated the perceived role and usefulness of guidelines, as well as barriers to and facilitators of their implementation, for hospital, primary care, and nonpracticing clinicians. METHODS: A 43-item self-administered questionnaire was sent to all National Health Service physicians in the province of Modena, Italy (593 primary care physicians, 1049 hospital physicians, and 149 nonpracticing clinicians), and 1199 (66.9%) responded. Opinions and attitudes were assessed using 5-point ordinal scales and an attitude measurement scale. Results were evaluated overall and by professional setting, sex, age, year of graduation, and academic background. RESULTS: Practice guidelines were generally perceived to be less useful than other sources of medical information (eg, personal experience, conferences, colleagues, articles, the Internet, and textbooks [pharmaceutical representatives were the exception]). Most physicians thought that guidelines are developed for cost-containment reasons and expressed concerns about their limited applicability to individual patients and local settings. Most respondents did not favor the involvement of health professionals other than physicians in guideline development and use and preferred nonmonetary incentives for their implementation. Answers to individual items and attitude scores varied significantly across professional settings. Primary care physicians showed, in general, the least favorable attitudes toward practice guidelines, toward nonphysicians participating in guideline development and use, and toward incentives for guideline users. CONCLUSIONS: Physicians perceived practice guidelines as externally imposed and cost-containment tools rather than as decision-supporting tools. Regularly monitoring attitudes toward practice guidelines can be helpful to evaluate potential barriers to their adoption.