RESUMEN
We present a detailed study of the excited state properties of 5-benzyluracil (5BU) in the gas phase and in implicit solvent using different electronic structure approaches ranging from time-dependent density functional theory in the linear response regime (LR-TDDFT) to a set of different wave-function-based methods for excited states, namely perturbed coupled cluster (CC2), algebraic diagrammatic construction method to second order (ADC(2)), and perturbed configuration interaction (CIS(D)). 5BU has been used to investigate DNA base-amino acid interactions. In particular, it served as a model of protein-DNA photoinduced cross-linking. While LR-TDDFT is computationally the most efficient first-principles approach for static and dynamic simulations of this bichromophoric system, its accuracy is difficult to assess due to the presence of excited states with charge transfer character. In this work, the performance of different exchange correlation functionals is compared against accurate benchmarks obtained either from high level wave-function-based methods or directly from experimental absorption spectra. Our investigation shows that accurate results for the excitation energies can be obtained using the hybrid meta-GGA functional M06. In view of dynamical studies of the relaxation of 5BU after photoexcitation, we also show that the PBE functional, while failing in the Franck-Condon region, provides qualitatively good results for the characterisation of a possible photocyclization path.
RESUMEN
A new application of continuous indirect calorimetry is described for measuring the disposal of a glucose load. In a group of 10 normal subjects, 3 h after a 100 g oral glucose load, 20 g glucose was oxidized at basal rate, 19 g in response to the load and 63 g stored, while a decrease of 2 g was observed in the glucose space (GS). In a group of four type I, insulin-dependent diabetics, both glucose oxidation (9 g at the basal rate and 4 g in response to the load) and glucose storage (9 g) were markedly decreased, with the remainder either being lost in the urine (36 g) or remaining in the glucose space (42 g). In a group of eight nonobese type II, non-insulin-dependent diabetics, glucose oxidation both in the basal rate and in response to the load was slightly decreased (13 and 14 g, respectively) and glucose storage decreased to 40 g. These results suggest that, in type I diabetics, complete insulin deficiency seriously impairs two major mechanisms regulating glucose homeostasis, i.e., glucose storage and oxidation, while, in type II diabetics, the remaining insulin secretion attentuates these disturbances.
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus/metabolismo , Glucosa/metabolismo , Adolescente , Adulto , Anciano , Calorimetría , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Valores de ReferenciaRESUMEN
Increased lipid oxidation is generally observed in subjects with obesity and diabetes and has been suggested to be responsible for the insulin resistance associated with these conditions. We measured, by continuous indirect calorimetry, lipid and glucose oxidation and nonoxidative glucose disposal in 82 obese subjects during a 100-g oral glucose tolerance test (OGTT) and in 26 during a euglycemic insulin (40 mU.min-1.m-2) clamp. The obese subjects were subdivided into those with normal glucose tolerance (group A), those with impaired glucose tolerance (group B), and those with overt diabetes (group C). Forty-five healthy nonobese subjects were subdivided into a young and an older control group, which were age-matched to the nondiabetic obese (groups A and B) and diabetic obese (group C) subjects, respectively. In the postabsorptive state, as well as in response to insulin stimulation (both OGTT and insulin clamp), lipid oxidation was significantly increased in all three obese groups in comparison with either young or older controls. Basal glucose oxidation was significantly decreased in obese nondiabetic and obese glucose--intolerant subjects (groups A and B) compared with age-matched controls. During the OGTT and during the insulin clamp, insulin-stimulated glucose oxidation was decreased in all three obese groups. In contrast, nonoxidative glucose disposal was markedly inhibited in nondiabetic and diabetic obese patients during the euglycemic insulin clamp but not during the OGTT. After glucose ingestion, nonoxidative glucose uptake was normal in nondiabetic obese and glucose-intolerant obese subjects and decreased in diabetic obese subjects. Statistical analysis revealed that lipid and glucose oxidation were strongly and inversely related in the basal state, during euglycemic insulin clamp, and during OGTT. The negative correlation between lipid oxidation and nonoxidative glucose uptake, although significant, was much weaker. Fasting and post-OGTT hyperglycemia were the strongest (negative) correlates of nonoxidative glucose disposal in both single and multiple regression models. We conclude that 1) reduced glucose oxidation and reduced nonoxidative glucose disposal partake of the insulin resistance of nondiabetic obese and diabetic obese individuals; 2) hyperglycemia provides a compensatory mechanism for the defect in nonoxidative glucose disposal in nondiabetic obese subjects; however, this compensation is characteristically lost when overt diabetes ensues; and 3) increased lipid oxidation may contribute, in part, to the defects in glucose oxidation and nonoxidative glucose uptake in obesity.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Ácidos Grasos no Esterificados/sangre , Resistencia a la Insulina , Metabolismo de los Lípidos , Obesidad/fisiopatología , Adulto , Glucemia/análisis , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Valores de ReferenciaRESUMEN
Knowing the relationship between obesity and diabetes, the purpose of our work was to study the alterations in lipid metabolism as measured by continuous indirect calorimetry in the course of a 100-g oral glucose-tolerance test in groups of obese patients without and with diabetes, respectively. Seventy-nine obese patients participated in the study. They were divided into four groups according to the degree of carbohydrate intolerance: group A, normal glucose tolerance; group B, impaired glucose tolerance; group C, diabetes with hyperinsulinemic response to the load; group D, diabetes with impaired insulin response. All four groups of patients presented an increase in lipid oxidation, both in the fasting state and during the three-hour glucose tolerance test, when compared to the control group. The lipid oxidation rate was roughly parallel to plasma free fatty acid (FFA) levels. The contribution of lipids to energy expenditure was higher in obese as compared to control subjects. These observations suggest that the larger part taken by lipids in the energy metabolism of both nondiabetic and diabetic obese humans is a consequence of their increased fat stores and that the resulting decrease in carbohydrate metabolism may lead, as a late consequence, to alterations in glucose tolerance. The latter may result in delayed glucose storage and oxidation in the obese patient.
Asunto(s)
Diabetes Mellitus/metabolismo , Metabolismo de los Lípidos , Obesidad , Adulto , Factores de Edad , Calorimetría , Metabolismo Energético , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
Twenty insulin-dependent diabetic patients with signs of background retinopathy were given Buflomedil 600 mg/day orally or placebo in a randomized double-blind trial for a 6-month period. A larger number of patients had their retinal condition deteriorating in the placebo group and this finding is an indication for pursuing investigations on a larger scale in this direction.
Asunto(s)
Retinopatía Diabética/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Vasodilatadores/uso terapéutico , Retinopatía Diabética/patología , Método Doble Ciego , Evaluación de Medicamentos , Angiografía con Fluoresceína , Humanos , Persona de Mediana Edad , Distribución AleatoriaRESUMEN
Above 70 years of age, it is no more necessary to be obsessed by the prevention of late complications in introducing an intensive treatment. A symptomatic one, particularly with insulin is more appropriate. Before treating diabetics it is necessary to search symptomatically for aggravating factors like the use of thiazide or intercurrent diseases.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Dieta para Diabéticos , HumanosAsunto(s)
Regulación de la Temperatura Corporal/efectos de los fármacos , Diabetes Mellitus/fisiopatología , Glucosa/farmacología , Obesidad , Adulto , Glucemia/análisis , Diabetes Mellitus/sangre , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos no Esterificados/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana EdadAsunto(s)
Metabolismo de los Hidratos de Carbono , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo de los Lípidos , Adulto , Factores de Edad , Anciano , Glucemia/metabolismo , Calorimetría Indirecta , Ácidos Grasos no Esterificados/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
In six patients with chemical diabetes, insulin resistance was assessed by the steady-state plasma glucose (SSPG) level during a constant infusion of epinephrine, propranolol, glucose and insulin. During the infusion, the patients had elevated SSPG levels (174 +/- 20 mg/100 ml), compared with six control subjects (96 +/- 3 mg/100 ml, p less than 0.005), demonstrating increased insulin resistance. However, during the infusion, the rate of carbohydrate oxidation was similar in both groups. These results suggest that when insulinemia is controlled, the plasma glucose concentration in chemical diabetics during glucose infusion reaches hyperglycemic levels allowing normalisation of carbohydrate oxidation. Hyperglycemia can thus be considered to be a regulatory mechanism favouring glucose uptake and oxidation in patients with chemical diabetes.
Asunto(s)
Diabetes Mellitus/sangre , Carbohidratos de la Dieta/metabolismo , Resistencia a la Insulina , Adulto , Glucemia/análisis , Epinefrina/farmacología , Femenino , Glucosa/farmacología , Humanos , Insulina/farmacología , Masculino , Oxidación-Reducción , Propranolol/farmacologíaRESUMEN
The purpose of the study was to examine the effect of short-term weight loss on glucose disposal and lipid oxidation in obese patients. Twenty-six obese patients were divided into three groups according to their degree of glucose intolerance: normal glucose tolerance = Gp I; impaired glucose tolerance without diabetes = Gp II; diabetes = Gp III. The patients submitted to an hypocaloric, high-protein diet for 8 to 45 weeks. Respiratory exchange measurements were performed by means of continuous indirect calorimetry during a 100 g, 3 h oral glucose tolerance test (OGTT) before weight loss and were repeated at the end of the weight loss period, 3 to 8 weeks after the reintroduction of a balanced isocaloric diet. Glucose tolerance, which was decreased in Gps II and III, improved after weight loss. Glucose oxidation, which was decreased in Gps II and III showed improvement after weight reduction in both Gp II (30.9 +/- 2.3 after weight loss vs 24.2 +/- 2.0 g/3 h before, P less than 0.025) and in Gp III (33.1 +/- 1.6 vs 25.8 +/- 4.1, ns). In the diabetic group (Gp III), before weight loss, a decrease in nonoxidative glucose uptake was observed, which was probably due both to a decrease in glucose storage and to the inhibition of splanchnic glucose output. After weight loss, it increased significantly from 27.7 +/- 5.2 to 56.9 +/- 2.3 g/3 h (P less than 0.001). Postabsorptive plasma insulin levels decreased in all groups following weight reduction. When exaggerated the insulin response to the glucose load fell to normal values whereas the insulin response increased in the diabetic patients in whom it was initially blunted. Lipid oxidation rates, both preload and postload, were markedly elevated before weight loss in all three groups. They were substantially reduced after weight loss. This study shows that a weight loss of 10 to 33 kg in obese patients promoted an increase in the subnormal glucose oxidation rate in Gp II as well as an improvement of the low nonoxidative glucose uptake in the diabetic group, thus improving their glucose tolerance. There was a simultaneous reduction in lipid oxidation in both groups. Furthermore, the insulin response to the glucose load, whether elevated or decreased before weight loss, tended towards normalization after weight reduction.
Asunto(s)
Peso Corporal , Complicaciones de la Diabetes , Glucosa/metabolismo , Obesidad/metabolismo , Adulto , Calorimetría Indirecta , Diabetes Mellitus/metabolismo , Ácidos Grasos no Esterificados/sangre , Humanos , Insulina/sangre , Metabolismo de los Lípidos , Persona de Mediana Edad , Obesidad/complicaciones , Oxidación-Reducción , Proteínas/metabolismoRESUMEN
Sixty-seven subjects with moderate obesity (50 +/- 3 percent above ideal body weight) were given an oral glucose tolerance test with the simultaneous measurement of rates of glucose and lipid oxidation by continuous indirect calorimetry. When the subjects were stratified into nine 5-year classes of duration of obesity, the prevalence of impaired glucose tolerance (IGT) and overt diabetes both increased with increasing duration of obesity. Both basal and post-OGTT lipid oxidation rates were, however, similar in all classes. To assess the independent influence of IGT, diabetes, age, and duration of obesity on glucose metabolism, the data were subjected to analysis of variance using a factorial design with metric covariates. Age by itself was found to be associated (P less than 0.05) with a decline in total post-OGTT glucose oxidation. Both IGT and diabetes, on the other hand, were associated with increased plasma insulin and free fatty acid (FFA) levels, both in the fasting state and following glucose ingestion (P = 0.05-P less than 0.002). Only diabetes, however, was associated with a drastic reduction in nonoxidative glucose disposal, which marked the appearance of, and strongly correlated with (r = -0.81, P less than 0.001), fasting hyperglycemia. Duration of obesity had significant metabolic consequences in its own right: a fall in the insulin response to glucose (P = 0.05) and in the rate of total glucose oxidation (P = 0.03), and a rise in post-OGTT glucose levels (P = 0.04). We conclude that: (a) increased lipid oxidation is common in obesity, but is not sufficient to explain the deterioration of glucose tolerance in long-term obesity; (b) very-long-term obesity may be associated with partial exhaustion of the beta cell, and the resultant insulinopenia may cause depressed glucose oxidation and impaired glucose tolerance, and (c) a defect in nonoxidative glucose disposal is a characteristic feature of frank diabetes at any stage of obesity.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus/sangre , Prueba de Tolerancia a la Glucosa , Obesidad , Adulto , Calorimetría Indirecta , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Indirect calorimetric studies were performed during a 100 g oral glucose tolerance test in diabetic patients with varying degrees of endocrine pancreatic dysfunction and in a control group of normal subjects. In 3 obese diabetics the study was repeated after a 3 day protein sparing modiefied fast. In diabetic patients the results show alterations of oxidation and storage of carbohydrates, related to insulin secretion deficiency on the one hand, and to overweight on the other. Endocrine pancreatic insufficiency may account directly for alterations observed in individuals with decreased or absent insulin response to glucose load, wheras metabolic factors such as adipose mass, hepatic steatosis, and peripheral insulin resistance appear to be responsible for alterations in carbohydrate oxidation and storage in subjects with relative endocrine pancreatic insufficiency, particularly obese diabetics.
Asunto(s)
Diabetes Mellitus/metabolismo , Glucosa/metabolismo , Obesidad/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/deficienciaRESUMEN
Insulin resistance is a common feature of Type 2 (non-insulin-dependent) diabetes mellitus. This defect in insulin-mediated glucose metabolism could result from a defect in either glucose oxidation or non-oxidative glucose disposal. To examine this question, euglycaemic insulin clamp studies were performed in 16 normal weight Type 2 and 11 age-matched control subjects. In Type 2 diabetic patients the fasting plasma glucose concentration, 8.39 +/- 0.50 mmol/l, was allowed to decline (over 54 +/- 6 min) to 5.33 +/- 0.11 mmol/l before starting the insulin clamp. Total body glucose uptake was significantly decreased in Type 2 diabetic patients vs control subjects (148 +/- 15 vs 264 +/- 25 mg/min.m2, p less than 0.001). Both total glucose oxidation (59 +/- 6 vs 89 +/- 6 mg/min.m2, p less than 0.005) and non-oxidative glucose disposal (89 +/- 15 vs 179 +/- 24 mg/min.m2, p less than 0.005) were significantly reduced in the Type 2 diabetic patients. Basal glucose oxidation was also reduced in the Type 2 diabetic patients (22 +/- 3 vs 38 +/- 5 mg/min.m2, p less than 0.01). In conclusion, during the postabsorptive state and under conditions of euglycaemic hyperinsulinaemia, impairment of glucose oxidation and non-oxidative glucose disposal both contribute to the insulin resistance observed in normal weight Type 2 diabetic patients. Since lipid oxidation was normal in this group of diabetic patients, excessive non-esterified fatty acid oxidation cannot explain the defects in glucose disposal.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Ácidos Grasos no Esterificados/sangre , Femenino , Glucagón/sangre , Glucólisis , Humanos , Insulina/sangre , Sistemas de Infusión de Insulina , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Proteínas/metabolismo , Valores de ReferenciaRESUMEN
Increased fasting hepatic glucose production is present in NIDDM patients, and has been shown to be due to increased gluconeogenesis. In order to determine the contribution of the cycling between glucose and three-carbon compounds (Cori and glucose-alanine cycles) to the increased hepatic glucose production, glucose kinetics measured overnight in seven obese NIDDM patients and six lean healthy subjects with both 6.6 2H glucose and U-13C glucose were determined. At 0500 h obese NIDDM subjects showed a 40% increase in glucose appearance calculated from 6.6 2H glucose, whereas glucose appearance calculated from U-13C glucose was similar compared to lean subjects, indicating increased glucose cycling. Non-oxidative glucose disposal was also increased three-fold in NIDDM patients. Glucose cycling was increased by 111% in NIDDM patients (118 +/- 18 mumole min-1 vs. 56 +/- 11 in controls, P < 0.05) and was positively correlated with plasma glucose concentration (r = 0.831, P < 0.001) and with non-oxidative glucose disposal (r = 0.714, P < 0.01). Four NIDDM patients were studied again after 3 days of insulin therapy. Insulin restored near-normoglycaemia (7.4 +/- 0.8 mmole l-1) and normalized rates of glucose appearance and glucose cycling. It is concluded that increased glucose cycling in obese NIDDM patients accounts for a major part of the increased fasting hepatic glucose production and non-oxidative glucose disposal in obese NIDDM subjects.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus/metabolismo , Glucosa/metabolismo , Obesidad , Adulto , Anciano , Análisis de Varianza , Glucemia/análisis , Calorimetría , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Insulina/sangre , Cinética , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The use of continuous indirect calorimetry in the course of a 100 g OGTT in 10 normal subjects has shown that carbohydrate oxidation rises with the secondary fall in blood glucose, suggesting that it could result from glucose stored under the influence of insulin. The experimental increase in FFA by a neutral fat infusion in 8 normal subjects decreased this oxidation in spite of the insulin rise. In a group of 5 non-obese, non-ketotic insulin-deficient diabetics, carbohydrate oxidation was found to be normal and directly correlated with plasma glucose levels. On the other hand, in 7 obese diabetics with high plasma insulin levels carbohydrate oxidation was found to be low, suggesting that carbohydrate intolerance could result from the non-oxidation of glucose. This study shows heterogeneity of diabetes, since glucose intolerance could result from non-oxidation of glucose as well as from insufficient pancreatic secretion.