Acute Effects of Metformin and Vildagliptin after a Lipid-Rich Meal on Postprandial Microvascular Reactivity in Patients with Type 2 Diabetes and Obesity: A Randomized Trial.

BACKGROUND: Type 2 diabetes mellitus and obesity are both related to endothelial dysfunction. Postprandial lipemia is a cardiovascular risk. Notably, it is known that a high-fat diet may elicit microvascular dysfunction, even in healthy subjects. Since anti-diabetic drugs have different mechanisms of action and also distinct vascular benefits, we aimed to compare the results of two anti-diabetic drugs after the intake of a lipid-rich meal on microcirculation in patients with type 2 diabetes and obesity. In parallel, we also investigated the metabolic profile, oxidative stress, inflammation, plasma viscosity, and some gastrointestinal peptides. SUBJECTS/METHODS: We included 38 drug-naïve patients, all women aged between 19 and 50 years, with BMI ≥ 30 kg/m2. We performed endothelial measurements and collected samples before (fasting) and after the intake of a lipid-rich meal at 30, 60, 120, and 180 min. Patients were randomized to metformin or vildagliptin, given orally just before the meal. Endothelial function was assessed by videocapillaroscopy and laser-Doppler flowmetry to investigate microvascular reactivity. Besides, we also investigated plasma viscosity, inflammatory and oxidative stress biomarkers, gastrointestinal peptides, and metabolic profile in all time points. RESULTS: No differences at baseline were noted between groups. Vildagliptin increased glucagon-like peptide-1 compared to metformin. Paired comparisons showed that, during the postprandial period, vildagliptin significantly changed levels of insulin and glucagon-like peptide-1, and also the dipeptidyl peptidase-4 activity, while metformin had effects on plasma glucose solely. Metformin use during the test meal promoted an increase in functional capillary density, while vildagliptin kept non-nutritive microvascular blood flow and vasomotion unchanged. CONCLUSIONS: After the intake of a lipid-rich meal, the use of vildagliptin preserved postprandial non-nutritive microflow and vasomotion, while metformin increased capillary recruitment, suggesting protective and different mechanisms of action on microcirculation.

30-days effects of vildagliptin on vascular function, plasma viscosity, inflammation, oxidative stress, and intestinal peptides on drug-naïve women with diabetes and obesity: a randomized head-to-head metformin-controlled study.

BACKGROUND: Obesity is the main risk factor for diabetes and excessive visceral fat triggers low-grade inflammatory process, mediated by activation and release of cytokines and high flow of free fatty acids that contribute to insulin resistance, increased oxidative stress, and impaired endothelial function. Metformin and vildagliptin have known vasculoprotective actions, but the value of these drugs on drug-naïve diabetic patients during 30 days use warrants investigation. Our purpose was to observe their effects on endothelial function, oxidative stress, inflammatory biomarkers, and plasma viscosity. METHODS: 38 women with obesity and type 2 diabetes drug-naïve, aged between 19 and 50 years, BMI ≥ 30 kg/m2, were recruited and subjected to measurements of endothelial function, nutritive skin microvascular reactivity, plasma viscosity, inflammatory and oxidative stress biomarkers at baseline and randomized 1:1 to ingest metformin (850 mg twice/day) or vildagliptin (50 mg twice/day) during 30 days, and then, re-evaluated. RESULTS: No differences between groups were noticed at baseline. After treatment, vildagliptin promoted an improvement on endothelial-dependent and -independent vasodilatations, at arteriole level, while metformin resulted in improved nutritive microvascular reactivity, at the capillary level. Intragroup analysis showed that vildagliptin reduced insulin, C-peptide and oxidized LDL, and increased adiponectin and glucagon-like peptide-1 while metformin reduced weight, plasma glucose, total cholesterol, HDL-c, LDL-c, and dipeptidyl peptidase-4 activity, with an unexpected increase on tumor necrosis factor-α. No significant difference in plasma viscosity was noted. CONCLUSIONS: In the vascular beds investigated, both drugs used for only 30 days improved endothelial function, through distinct, and possibly, complementary mechanisms on drug-naïve diabetic women.Trial Registration ClinicalTrials.gov: NCT01827280.

Short-term effects of low-dose estradiol on endothelial function and blood viscosity in nondiabetic postmenopausal overweight women: a double-blind, placebo-controlled study.

OBJECTIVE: The beneficial effects of estrogen on endothelial function depend on its integrity. This study evaluates the short-term effects of low-dose transdermal estradiol on endothelial function, insulin sensitivity, and blood viscosity in nondiabetic overweight/obese women. METHODS: Forty-four nondiabetic overweight/obese women with a history of recent menopause were randomly allocated, in a double-blind fashion, to receive transdermal estradiol (1 mg/d, n = 22) or placebo (n = 22). The following parameters were assessed: endothelial reactivity (venous occlusion plethysmography and nailfold videocapillaroscopy), plasma levels of soluble adhesion molecules, insulin sensitivity (homeostasis model assessment of insulin resistance and areas under the curve of insulin and glucose during an oral glucose tolerance test), and blood and plasma viscosity. Data were expressed as means ±â€ŠSD or medians [first to third quartiles]. RESULTS: Participants were aged 51.8 ±â€Š2.3 years with a body mass index of 31.5 ±â€Š2.5 kg/m and time since menopause was 3 [2-5] years. At baseline, no differences between the groups were observed; however, after 3 months of treatment, the following changes were observed in the estradiol group compared with the placebo group: a decrease in the forearm vascular resistance at baseline (36.37 [24.9-51.27] vs 51.3 [40.88-70.03] mm Hg/mL per min 100 mL tissue, P < 0.01) and during the postocclusive reactive hyperemia response (15.93 [11.32-22.29] vs 22.13 [16.46-29.7] mm Hg/mL per min 100 mL tissue, P < 0.01), and an increase in red blood cell velocity at rest (0.316 [0.309-0.326] vs 0.303 [0.293-0.308] mm/s, P < 0.001) and during postocclusive reactive hyperemia response (0.374 [0.353-0.376] vs 0.341 [0.333-0.355] mm/s, P < 0.001). Furthermore, blood viscosity was lower in the estradiol group than in the placebo group (3.57 ±â€Š0.12 vs 3.76 ±â€Š0.22 mPa.s; P < 0.01). CONCLUSIONS: Short-term use of low-dose transdermal estradiol in nondiabetic overweight/obese women with a history of recent menopause improved endothelial function and decreased blood viscosity compared with placebo.

Relationships between emerging cardiovascular risk factors, z-BMI, waist circumference and body adiposity index (BAI) on adolescents.

OBJECTIVE: The body adiposity index (BAI) has been recently proposed as an alternative index to body mass index (BMI) and waist circumference (WC) to evaluate adiposity in adults, with special focus on its ability to discriminate gender specificities on adiposity. Endothelial dysfunction, circulating endothelial cells (CECs), endothelin-1 and adipocytokines are all related to atherosclerosis and nowadays considered as markers of emerging cardiovascular (CV) risk. This study aimed to determine in normal weight and obese adolescents which measures of body composition (BAI and z-BMI) or distribution (WC) correlate better with emerging CV risk markers. PATIENTS: Forty adolescents were selected according to BMI: normal weight (n = 20; 7 girls/13 boys, 14·7 ± 1·4 years, 53·4 ± 6·0 kg, z-BMI 0·6 ± 0·1) and obese ones (n = 20; 13 girls/7 boys, 14·1± 1·0 years, 86·7 ± 11·5 kg, z-BMI 2·7 ± 0·4). MEASUREMENTS: Body fat and fat mass were measured by dual-energy X-ray absorptiometry (DXA). Non-nutritive skin microvascular reactivity was evaluated by laser Doppler flowmetry with iontophoretic release of vasoactive drugs. Activated CECs were assessed by flow cytometric analysis. RESULTS: In adolescents, the measurement of % fat by DXA showed high correlation with BAI (ρ = 0·75, P < 0·0001), z-BMI (r = 0·84, P < 0·0001) and WC (r = 0·83, P < 0·0001). Endothelin-1 and activated CECs did not correlate with any anthropometric measures while adipocytokines expressed variable associations among them. Endothelium-dependent vasodilation showed higher correlation with BAI (r = -0·51, P < 0·0001) compared to z-BMI (r = -0·40, P < 0·001) or WC (r = -0·45, P < 0·001), specially on females. CONCLUSIONS: BAI was associated with emerging CV risk markers in adolescents but further research is needed to evaluate its potential in clinical and epidemiological sets.

Obesity, metabolic syndrome, impaired fasting glucose, and microvascular dysfunction: a principal component analysis approach.

BACKGROUND: We aimed to evaluate the multivariate association between functional microvascular variables and clinical-laboratorial-anthropometrical measurements. METHODS: Data from 189 female subjects (34.0 ± 15.5 years, 30.5 ± 7.1 kg/m2), who were non-smokers, non-regular drug users, without a history of diabetes and/or hypertension, were analyzed by principal component analysis (PCA). PCA is a classical multivariate exploratory tool because it highlights common variation between variables allowing inferences about possible biological meaning of associations between them, without pre-establishing cause-effect relationships. In total, 15 variables were used for PCA: body mass index (BMI), waist circumference, systolic and diastolic blood pressure (BP), fasting plasma glucose, levels of total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), insulin, C-reactive protein (CRP), and functional microvascular variables measured by nailfold videocapillaroscopy. Nailfold videocapillaroscopy was used for direct visualization of nutritive capillaries, assessing functional capillary density, red blood cell velocity (RBCV) at rest and peak after 1 min of arterial occlusion (RBCV(max)), and the time taken to reach RBCV(max) (TRBCV(max)). RESULTS: A total of 35% of subjects had metabolic syndrome, 77% were overweight/obese, and 9.5% had impaired fasting glucose. PCA was able to recognize that functional microvascular variables and clinical-laboratorial-anthropometrical measurements had a similar variation. The first five principal components explained most of the intrinsic variation of the data. For example, principal component 1 was associated with BMI, waist circumference, systolic BP, diastolic BP, insulin, TG, CRP, and TRBCV(max) varying in the same way. Principal component 1 also showed a strong association among HDL-c, RBCV, and RBCV(max), but in the opposite way. Principal component 3 was associated only with microvascular variables in the same way (functional capillary density, RBCV and RBCV(max)). Fasting plasma glucose appeared to be related to principal component 4 and did not show any association with microvascular reactivity. CONCLUSIONS: In non-diabetic female subjects, a multivariate scenario of associations between classic clinical variables strictly related to obesity and metabolic syndrome suggests a significant relationship between these diseases and microvascular reactivity.