RESUMEN
AIMS: Insulin resistance and a parental history of diabetes mellitus are independently associated with endothelial dysfunction. Oxidative stress has a pivotal role in the pathophysiology of vascular injury. Metformin, in addition to its glucose-lowering properties, has vasculoprotective effects. We investigated whether metformin has beneficial effects on the nutritive skin capillary circulation and deceases oxidative stress in a group at high risk for Type 2 diabetes mellitus (T2DM) and cardiovascular disease. METHODS: Thirty normoglycaemic subjects with the metabolic syndrome (MS),who had first-degree relatives with T2DM, participated. The mean age was 39.1 +/- 8.4 years and body mass index (BMI) 35.7 +/- 4.8 kg/m2 (mean +/- SD). SUBJECTS: were randomized 1 : 1 to receive placebo (n=14) or metformin (n=16; 1700 mg/day) in a double-blind study. At baseline and post treatment, blood and urine samples were collected for biochemical and 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) analysis, respectively. Microcirculation was assessed by nailfold videocapillaroscopy, analysing afferent (AF), efferent (EF) and apical (AP) diameters of capillary loops, functional capillary density (FCD), red blood cell velocity at rest (RBCV), after 1 min arterial occlusion (RBCVmax) and time (TRBCVmax)taken to reach it. RESULTS: Groups did not differ significantly in anthropometric, clinical, laboratory or microvascular measurements at baseline. In the metformin group, weight,BMI, systolic blood pressure and fasting plasma glucose fell, and lipid profile and microcirculatory parameters FCD, AF, EF, AP, RBCVmaxand TRBCVmax improved (all P<0.01). No relationship between clinico-laboratory parameters and microvascular reactivity was observed, except for changes in total and low density lipoprotein-cholesterol and RBCVmax* 8-epi-PGF2alpha did not change significantly in either group. CONCLUSIONS: Metformin improved skin capillary reactivity in normoglycaemic MS subjects independently of significant changes in 8-epi-PGF2alpha levels.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Síndrome Metabólico/complicaciones , Metformina/uso terapéutico , Adulto , Capilares , Método Doble Ciego , Femenino , Humanos , Masculino , Microcirculación/fisiología , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Factores de Riesgo , Piel/irrigación sanguíneaRESUMEN
Advanced glycation endproducts (AGEs) may enhance vascular permeability in diabetic subjects. To test this hypothesis, AGEs were prepared in the presence of albumin (AGE-Alb). Control albumin (Alb) and AGE-Alb were then labeled with FITC (fluoresceinisothiocyanate) and injected i.v. into anesthetized hamsters at a dose of 7 mg/100 g B.W. Normal hamsters were given FITC-Alb or FITC-AGE-Alb and FITC-dextran. Vascular permeability changes were measured by direct intravital microscopy of the hamster cheek pouch preparations in fluorescent light and recorded as number of sites (=leaks) with extravasation of FITC-labeled albumin in postcapillary venules. No changes were seen during 1 hour after i.v. injection of FITC-Alb or FITC-AGE-Alb. Repeated local application of histamine 5 x 10(6) M or bradykinin 5 x 10(7) M to the cheek pouch for 5 min with 30-min intervals induced reversible increases in vascular permeability in all hamsters. Maximal number of leaks/cm2 before and at 30 and 60 min after FITC-Alb-injection and histamine application was 257 +/- 6 (SEM), 243 +/- 6 and 231 +/- 6 leaks/cm2 in the FITC-Alb-group and 258 + 6 (SEM), 302 +/- 12 and 316 +/- 11 leaks/cm2 in the FITCAGE-Alb-group, respectively, (P < 0.05 at 30 and 60 min). Similar results were seen with bradykinin. Our conclusions showed that i.v.-injected AGEs augmented the histamine- and bradykinin-induced increase in vascular permeability by 34% and 46%.
Asunto(s)
Bradiquinina/farmacología , Permeabilidad Capilar/efectos de los fármacos , Productos Finales de Glicación Avanzada/farmacología , Histamina/farmacología , Albúminas , Animales , Cricetinae , Dextranos , Sinergismo Farmacológico , Fluoresceína-5-Isotiocianato/análogos & derivados , Colorantes Fluorescentes , Productos Finales de Glicación Avanzada/administración & dosificación , Masculino , Mesocricetus , Mucosa Bucal/irrigación sanguínea , Mucosa Bucal/efectos de los fármacosRESUMEN
The purpose of this study was to determine the in vivo microvascular reactivity of arterioles (mean internal diameter range: 16.0 to 106.4 microm) and venules (mean internal diameter range: 24.0 to 117.3 microm) in the hamster cheek pouch to insulin and to the mixture insulin + metformin. Experiments were performed using an intravital microscope coupled to a closed-circuit TV system and a videotape. The TV monitor display was used to obtain arteriolar and venular internal diameter measurements by an image-shearing device. The studied drugs were applied topically, added to the superfusion solution, to avoid systemic effects that would complicate the analysis of the results. In control animals (glycemia 7.7 +/- 0.4 mmol/L), application of insulin (10 to 500 microU/mL/min) evoked vasodilatation in a dose-dependent fashion in arterioles (4.9 +/- 3.2% to 50.9 +/- 6.5%, smallest and largest concentration, respectively, values expressed in percent of the initial diameter as mean +/- SE) and venules (-2.1 +/- 3.1% to 14.3 +/- 5.1%), decreased and finally abolished the spontaneous vasomotion frequency (from 9.5 +/- 0.3 cycles per minute [cpm] to 0.0 +/- 0.0 cpm) and amplitude (from 8.6 +/- 0.3 to 0.0 +/- 0.0 microm). Addition of metformin, 0.2 mg/mL/min, did not significantly change either the observed vasodilatation in arterioles and venules or the vasomotion frequency and amplitude curves. Two types of diabetic hamsters were studied: severely diabetic, induced with three intraperitoneal injections of streptozotocin, diluted in physiological saline, 50 mg/kg/dose, given in three consecutive days, and mildly diabetic, induced by a single dose of streptozotocin. All diabetic animals were studied four weeks after the onset of diabetes and no specific treatment for diabetes was given. In severely diabetic hamsters (glycemia 18.0 +/- 2.2 mmol/L), application of insulin, in the same concentration range, evoked a significantly reduced vasodilatation in arterioles as compared with control animals (5.9 +/- 1.3% to 18.9 +/- 3.5%) and did not change the vasodilatation observed in the venules (5.9 +/- 1.4% to 21.3 +/- 2.5%). In these preparations no spontaneous arteriolar vasomotion could be detected. Addition of metformin did not significantly improve the impaired vasodilatation. In mildly diabetic hamsters (glycemia 12.1 +/- 0.8 mmol/L), application of insulin, in the same concentration range, evoked vasodilatation, in a dose-dependent fashion, equivalent to the one observed in control animals, in arterioles (3.1 +/- 2.5% to 53.4 +/- 10.0%) and venules (7.1 +/- 3.0% to 29.9 +/- 4.8%) and also reduced the vasomotion frequency (from 10.1 +/- 0.3 to 0.1 +/- 0.1 cpm) and amplitude (from 9.2 +/- 0.6 to 0.2 +/- 0.2 microm). Addition of metformin tended to increase the observed arteriolar dilatation (6.6 +/- 3.0% to 67.8 +/- 5.5%), did not change the venular dilatation (6.7 +/- 4.8% to 28.0 +/- 3.3%), and tended to preserve vasomotion frequency and amplitude. These experiments show that (1) insulin has a direct dilatatory effect on arterioles and venules; (2) the vasodilatation evoked by insulin is impaired in severe diabetes, and (3) no significant abnormality could be detected on microvascular reactivity in mild diabetes. Further addition of metformin helped to maintain the spontaneous arteriolar vasomotion even during moderate vasodilatation and tended to augment the arteriolar dilatation evoked by insulin in mildly diabetic animals.