RESUMEN
OBJECTIVE: In IDDM, the development of microalbuminuria, which is associated with an elevation in blood pressure within the normal range, is a risk factor for future cardiovascular disease. Vascular stiffness might be one of the factors involved because it increases systolic blood pressure and the workload of the heart. RESEARCH DESIGN AND METHODS: We investigated carotid artery stiffness with a noninvasive ultrasound method in 24 microalbuminuric and 53 normoalbuminuric IDDM patients and in 54 healthy control subjects. RESULTS: The distensibility coefficient, a measure of intrinsic vascular wall elasticity, was decreased in microalbuminuric IDDM (21.6 x 10(-3)/kPa) as compared with normoalbuminuric IDDM (24.8 x 10(-3)/kPa) and control subjects (25.9 x 10(-3)/kPa; P = 0.02). This result was based on a higher blood pressure in microalbuminuric patients. After correction for the difference in blood pressure, the distensibility coefficients were similar in the three groups. In the two diabetic patient groups taken together, age, blood pressure, female sex, diabetes duration, and cigarette smoking were determinants of a decreased distensibility. CONCLUSIONS: Blood pressure is a major determinant of increased arterial stiffness in microalbuminuric IDDM patients. Increased arterial stiffness may contribute to the accelerated progression of complications if concomitant hypertension exists.
Asunto(s)
Albuminuria , Arterias Carótidas/fisiopatología , Diabetes Mellitus Tipo 1/fisiopatología , Adolescente , Adulto , Anciano , Análisis de Varianza , Presión Sanguínea , Arterias Carótidas/diagnóstico por imagen , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Elasticidad , Femenino , Hemoglobina Glucada/análisis , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/diagnóstico por imagen , Músculo Liso Vascular/fisiopatología , Fumar , Triglicéridos/sangre , UltrasonografíaRESUMEN
We investigated 24-hour ambulatory blood pressure and arterial distensibility, a marker of biophysical vessel wall properties, in 32 normoalbuminuric type I diabetic patients and 32 healthy control subjects on diets containing 50 mmol and 200 mmol sodium per day. The increase in daytime diastolic blood pressure from 50 to 200 mmol sodium was significantly higher in the diabetic patients than in the control subjects (2.3+/-4.9 versus 0.2+/-3.7 mm Hg, P<.05). On a high sodium regimen, femoral artery distensibility was decreased in the diabetic patients compared with the control subjects (19.2+/-7.6 versus 24.1+/-9.3 10[-3]/kPa, P<.05). Angiotensin-converting enzyme inhibition in the diabetic patients on a high sodium diet decreased daytime diastolic blood pressure and increased femoral artery distensibility. The blood pressure decrease in response to angiotensin-converting enzyme inhibition correlated significantly with the blood pressure increase to sodium (for 24-hour systolic and diastolic blood pressure, r=.72, P<.001 and r=.76, P<.001). In addition, we found that in the diabetic patients on a high sodium diet, the renal blood flow response to exogenous angiotensin II was not bimodally distributed, as is the case in essential hypertension, in which a subgroup of the patients are characterized by sodium sensitivity of the blood pressure and an abnormal renal blood flow response to exogenous angiotensin II ("nonmodulator phenotype"). These results show that blood pressure in insulindependent diabetes mellitus is sodium sensitive, but that this is not related to the nonmodulator phenotype, and suggest that in IDDM a relatively high sodium intake may be a factor that predisposes to the development of diabetic vascular disease.
Asunto(s)
Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 1/fisiopatología , Dieta Hiposódica , Arteria Femoral/fisiopatología , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Adaptabilidad , Diástole , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Valores de Referencia , Circulación Renal/fisiologíaRESUMEN
Arterial distensibility is a marker of functional and structural vessel wall properties. A decreased distensibility is an important risk factor for cardiovascular disease. In insulin-dependent diabetes mellitus of short duration, arterial stiffness has been reported to be increased, decreased or the same as in healthy control subjects. The influence of acute hyperglycaemia on arterial stiffness is unclear and might be one of the factors responsible for the divergent results which have been observed. We investigated arterial distensibility locally in the carotid artery during hyper- and normoglycaemia using a glucose clamp technique. Eleven healthy normotensive men underwent both a hyperglycaemic and a euglycaemic clamp on separate days. Before and after 2 h of clamping, arterial diameter (D) and change in arterial diameter during the heart cycle (dD) were measured with a non-invasive vessel wall movement detector system. Blood pressure (BP), pulse pressure (dP) and heart rate (HR) were recorded with a semi-automated device. Distensibility coefficients (DC), reflecting the intrinsic vascular wall elasticity, and compliance coefficients (CC), reflecting the buffering capacity of the vessel, were calculated from D, dD and dP. (DC = 2*dD/ D*dP, CC = pi*dD*D/2*dP). There were no significant differences between the hyperglycaemic and the euglycaemic clamp for D, DC and CC. These results suggest that an acute systemic hyperglycaemia is not responsible for changes in diameter, distensibility and compliance of the carotid artery.
Asunto(s)
Arterias Carótidas/fisiopatología , Endotelio Vascular/fisiopatología , Hiperglucemia/fisiopatología , Adaptabilidad , Humanos , Masculino , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Técnica de Clampeo de la Glucosa , Hiperglucemia/fisiopatología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Islotes Pancreáticos/efectos de los fármacos , Compuestos de Sulfonilurea/administración & dosificación , Compuestos de Sulfonilurea/uso terapéutico , Administración Oral , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Péptido C/sangre , Péptido C/efectos de los fármacos , Femenino , Glucagón/sangre , Glucagón/efectos de los fármacos , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Preparaciones Farmacéuticas/metabolismo , Proinsulina/sangre , Proinsulina/efectos de los fármacosRESUMEN
1. Pharmacological stimulation of the synthesis of nitric oxide (NO) may be important in the prevention or treatment of cardiovascular diseases. 2. There is much discussion as to whether the precursor of NO, L-arginine, is able to stimulate basal endothelial NO production. L-Arginine is known to have vasodilating effects. However, it is not clear whether L-arginine-induced vasodilatation is attributable to an increase in NO production or to other systemic effects of L-arginine. 3. To investigate further the mechanisms of the L-arginine-induced vasodilatation, we compared the responses to L-arginine with those to saline and L-lysine in healthy subjects. L-Lysine is not a substrate for NO synthesis, but shares many of L-arginine's other properties. 4. During L-arginine infusion, blood pressure decreased [systolic blood pressure from 120.2 (SD 8.8) to 117.3 (12.1) mmHg (P = 0.05); diastolic blood pressure from 65.3 (5.9) to 61.6 (7.9) mmHg (P < 0.01)], and heart rate and extracellular fluid volume increased. The total peripheral vascular resistance decreased during L-arginine infusion by 18.0 (11.4)% (P < or = 0.05 compared with baseline and compared with L-lysine infusion). These results indicate vasodilation. No changes were observed during L-lysine and saline infusion. 5. Plasma cyclic GMP (the second messenger for NO) increased during L-arginine but also during L-lysine infusion [from 5.7 (1.2) to 6.8 (1.7) nmol/l (P < 0.01), and from 5.8 (1.8) to 7.0 (2.9) nmol/l (P < 0.05) respectively]. Plasma L-citrulline (a by-product of NO synthesis from L-arginine) increased during L-arginine infusion from 30.6 (7.5) to 47.1 (9.9) mumol/l (P < 0.001), but also during L-lysine infusion from 32.7 (6.5) to 42.0 (8.3) mumol/l (P < 0.001). 6. Plasma electrolytes and atrial natriuretic peptide concentrations responded similarly to L-arginine and L-lysine infusion, indicating similar effects on osmolality, plasma volume expansion and potassium distribution. 7. In conclusion, although L-lysine infusion had effects that were similar to those of L-arginine infusion, no vasodilatation was observed. Therefore, these effects cannot account for the L-arginine-induced vasodilatation. This finding indirectly supports the hypothesis that the vasodilatation during L-arginine infusion might be mediated by an increase in NO synthesis. If so, our data suggest that the presumed markers for NO synthesis, plasma cyclic GMP and L-citrulline concentrations, do not accurately reflect this increase. Instead, the rise in plasma cyclic GMP may be related to the rise in ANP. The rise in L-citrulline may be related to competition with L-arginine for the same cell membrane transport mechanism and to stimulation of the urea cycle.
Asunto(s)
Arginina/farmacología , Lisina/farmacología , Vasodilatación/efectos de los fármacos , Adulto , Arginina/administración & dosificación , Factor Natriurético Atrial/sangre , Presión Sanguínea/efectos de los fármacos , Citrulina/sangre , GMP Cíclico/sangre , Electrólitos/sangre , Espacio Extracelular/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Lisina/administración & dosificación , Masculino , Óxido Nítrico/biosíntesis , Resistencia Vascular/efectos de los fármacosRESUMEN
Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9 +/- 9.8 years; diabetes duration, 14.9 +/- 7.9 years; glycated hemoglobin, 7.9 +/- 1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 micrograms glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10 +/- 0.52 mm) compared with C (2.89 +/- 0.55 mm, P = 5.0). FMD in IDDM patients was decreased (12.0 +/- 9.1% versus 15.7 +/- 9.5% in C, P = .046), as was GTN-induced vasodilation (14.9 +/- 8.2% versus 18.3 +/- 8.5% in C, P = .045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.