RESUMO
The actions of recombinant human insulin-like growth factor-I (rhIGF-I) and insulin were compared in 21 healthy young (24 +/- 1 yr) and 14 healthy middle-aged (48 +/- 2 yr) subjects during 3-h paired euglycemic clamp studies using one of three doses (rhIGF-I 0.2, 0.4, and 0.8 micrograms/kg.min and insulin 0.2, 0.4, and 0.8 mU/kg.min, doses chosen to produce equivalent increases in glucose uptake). In younger subjects, rhIGF-I infusions suppressed insulin by 19-33%, C-peptide by 47-59% and glucagon by 33-47% (all, P < 0.02). The suppression of C-peptide was less pronounced with insulin than with rhIGF-I (P < 0.007). The metabolic responses to rhIGF-I and insulin were remarkably similar: not only did both hormones increase glucose uptake and oxidation in a nearly identical fashion, but they also produced similar suppression of glucose production, free fatty acid levels, and fat oxidation rates. In contrast, rhIGF-I had a more pronounced amino acid-lowering effect than did insulin (P < 0.004). In middle-aged subjects, basal IGF-I levels were 44% lower (P < 0.0001) whereas basal insulin and C-peptide were 20-25% higher than in younger subjects. Age did not alter the response to rhIGF-I. However, insulin-induced stimulation of glucose uptake was blunted in older subjects (P = 0.05). Our data suggest that absolute IGF-I and relative insulin deficiency contribute to adverse metabolic changes seen in middle age.
Assuntos
Fator de Crescimento Insulin-Like I/farmacologia , Insulina/farmacologia , Adulto , Fatores Etários , Idoso , Peptídeo C/sangue , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/sangue , Glucagon/sangue , Glucose/metabolismo , Humanos , Pessoa de Meia-Idade , Proteínas Recombinantes/farmacologiaRESUMO
To evaluate the effects of childhood and poorly controlled insulin-dependent diabetes mellitus (IDDM) on counterregulatory hormone and symptomatic responses to hypoglycemia, we studied 16 nondiabetic children (13 +/- 2 yr), 19 nondiabetic adults (26 +/- 3 yr), and 13 children with IDDM (14 +/- 2 yr, HbA, 15.1 +/- 3.3%) during a gradual reduction in plasma glucose with the glucose-clamp technique. Plasma glucose was reduced from approximately 5 to approximately 2.8 mM over 240 min with serial assessment of counterregulatory hormone levels and symptom awareness. The plasma glucose level that triggered a sustained rise in plasma epinephrine was consistently higher in nondiabetic children than in adults (3.9 +/- 0.06 vs. 3.2 +/- 0.06 mM, P less than 0.001). Poorly controlled IDDM further elevated the glucose threshold for epinephrine release to normoglycemic levels (4.9 +/- 0.2 mM, P less than 0.001 vs. both control groups). Age and IDDM also produced an upward shift in the glucose level at which growth hormone release and symptom awareness were initiated. In contrast to the effect on glucose thresholds, maximal epinephrine responses and symptom scores were increased only by age and not IDDM (2-fold higher in children). We conclude that childhood and poor diabetes control independently contribute to an upward shift in glucose thresholds for counterregulatory hormone release and symptom awareness during mild hypoglycemia. Normoglycemic counterregulation may interfere with efforts to control diabetes in young patients.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Hipoglicemia/fisiopatologia , Adolescente , Adulto , Fatores Etários , Diabetes Mellitus Tipo 1/fisiopatologia , Epinefrina/sangue , Epinefrina/metabolismo , Glucagon/sangue , Técnica Clamp de Glucose , Hemoglobinas Glicadas/análise , Hormônio do Crescimento/sangue , Humanos , Hidrocortisona/sangue , Hipoglicemia/sangue , Sistemas de Infusão de Insulina , Valores de ReferênciaRESUMO
To evaluate the impact of mild hypoglycemia on CNS function in healthy adults, we measured brain stem auditory evoked potentials and P300 potentials (elicited by cognitive processing of auditory stimuli) during hypoglycemic or euglycemic insulin clamps (80 mU.m-2.min-1). In the hypoglycemic clamp study (n = 8), plasma glucose was allowed to fall from 4.6 to 3 mM in hourly approximately 0.5-mM steps and subsequently returned to euglycemic baseline levels. In the euglycemic clamp study (n = 8), plasma glucose was maintained at baseline levels throughout. Neither brain stem nor P300 responses changed during the euglycemic control study; symptoms and counterregulatory hormones were also unaffected. During the hypoglycemia study, epinephrine and growth hormone rose once plasma glucose reached 3.4 +/- 0.1 mM. Brain stem and P300 potentials remained unchanged until the 3-mM glucose step, when neurophysiological changes suddenly developed in conjunction with reported symptoms. At this glucose level, the wave V component of the brain stem potential was selectively altered in 7 of 8 subjects. Furthermore, P300 latency significantly increased, and amplitude diminished. Changes in both brain stem and cortical (P300) responses reversed when euglycemia was restored. We conclude that modest reductions in plasma glucose (to 3 mM) produce marked alterations in both brain stem and cortical responses to auditory stimuli. These changes in neural function appear at the same time as symptoms and follow rather than precede the rise in counterregulatory hormones during hypoglycemia. Our data suggest that the adverse effects of mild hypoglycemia on brain function are not limited to higher centers but also involve the brain stem.
Assuntos
Tronco Encefálico/fisiopatologia , Córtex Cerebral/fisiopatologia , Potenciais Evocados/fisiologia , Hipoglicemia/fisiopatologia , Adulto , Glicemia/análise , Eletrofisiologia , Epinefrina/sangue , Feminino , Glucagon/sangue , Hormônio do Crescimento/sangue , Humanos , Hidrocortisona/sangue , MasculinoRESUMO
OBJECTIVE: To examine whether pork and human insulin induce different counterregulatory responses to hypoglycemia. RESEARCH DESIGN AND METHODS: The responses to a mild hypoglycemic stimulus were determined in 35 healthy young adults with the glucose-clamp technique to ensure standardization of glucose and insulin levels. Either pork (n = 15) or human (n = 20) regular insulin was infused (0.8 mU.kg-1.min-1) to lower plasma glucose from 4.7 +/- 0.07 to 3.3 +/- 0.04 mM (both groups) over approximately 40 min. Plasma glucose was maintained at that level (with variable rate glucose infusion) for an additional 60 min. RESULTS: Steady-state insulin levels were similar in both groups (316 +/- 50 vs. 280 +/- 29 pM, pork vs. human). Before insulin administration, basal counterregulatory hormone levels were indistinguishable. Most importantly, after plasma glucose was lowered, hormonal responses were nearly identical. No significant differences in peak values of epinephrine (1769 +/- 404 vs. 1775 +/- 311 pM, pork vs. human), norepinephrine (1.64 +/- 0.23 vs. 1.87 +/- 0.20 nM, pork vs. human), glucagon (163 +/- 29 vs. 175 +/- 20 ng/L, pork vs. human), growth hormone (14 +/- 3 vs. 17 +/- 3 micrograms/L, pork vs. human), or cortisol (543 +/- 83 vs. 458 +/- 28 nM, pork vs. human) occurred. CONCLUSIONS: Our data suggest that pork and human insulin produce a comparable and robust hormonal response in healthy adults under conditions of controlled hypoglycemia.
Assuntos
Hormônios/sangue , Hipoglicemia/fisiopatologia , Insulina/farmacologia , Adulto , Animais , Epinefrina/sangue , Retroalimentação , Feminino , Glucagon/sangue , Técnica Clamp de Glucose , Hormônio do Crescimento/sangue , Hormônios/metabolismo , Humanos , Hidrocortisona/sangue , Infusões Intravenosas , Insulina/administração & dosagem , Masculino , Norepinefrina/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Especificidade da Espécie , SuínosRESUMO
To assess the effects of GH treatment on carbohydrate and protein metabolism, we studied eight patients with short stature before and after the commencement of GH treatment. The hyperglycemic clamp procedure was employed to produce a hyperglycemic stimulus of 50 mg/dL above fasting levels for 120 min. These patients were then treated with 0.3 mg/kg. week GH for 6 months, after which they were restudied. Patients were compared to eight healthy control children matched for age, sex, and Tanner stage. Fasting plasma glucose did not change significantly, but fasting plasma insulin levels were higher after GH therapy (P < 0.005). Despite identical glucose increments during the glucose clamp procedure, both first, and second phase insulin responses were markedly greater after instituting GH treatment. Even in the face of higher mean plasma insulin levels after GH treatment, the rate of insulin-stimulated glucose metabolism did not differ during the last 60 min of both studies. Hence, the rate of insulin-stimulated glucose metabolism/mean plasma insulin ratio (an index of insulin sensitivity) was sharply reduced after GH treatment (P < 0.01). During the clamp, the fall in circulating branched chain amino acid levels was significantly greater after GH therapy (P < 0.02). We conclude that glucose-stimulated insulin responses are increased in short children treated with GH and that such hyperinsulinemic responses compensate for reductions in insulin sensitivity. The compensatory hyperinsulinemic responses induced by GH therapy may serve a beneficial role by augmenting insulin's anabolic effects on protein metabolism.
Assuntos
Adaptação Fisiológica/fisiologia , Estatura , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Hiperinsulinismo/induzido quimicamente , Resistência à Insulina/fisiologia , Adolescente , Aminoácidos de Cadeia Ramificada/sangue , Peptídeo C/sangue , Criança , Feminino , Técnica Clamp de Glucose , Hormônio do Crescimento Humano/deficiência , Humanos , Hiperinsulinismo/sangue , Insulina/sangue , MasculinoRESUMO
A male infant with perineal hypospadias and a small phallus bound in chordee is described. Biochemical investigation at age 9 months after hCG stimulation revealed a testosterone to dihydrotestosterone (DHT) ratio of 40, a markedly elevated value suggestive of deficient steroid 5 alpha-reductase activity. The diagnosis of 5 alpha-reductase deficiency was confirmed by elevated urinary 5 beta/5 alpha-steroid metabolite ratios and demonstration of defective 5 alpha-reductase activity in cultured fibroblasts from the patient's scrotum and foreskin. Application of DHT cream to the patient's abdomen raised circulating levels of DHT to the adult male range. Two courses of DHT given nightly for 3 and 4 months resulted in phallic enlargement. Surgical release of the chordee and hypospadias repair have resulted in normal male appearance of the genitalia. This case illustrates the heterogeneity of the 5 alpha-reductase deficiency phenotype.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Di-Hidrotestosterona/sangue , Hipospadia/metabolismo , Testosterona/sangue , Adulto , Androstenodiona/sangue , Biópsia , Gonadotropina Coriônica , Desidroepiandrosterona/sangue , Feminino , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Hormônio Foliculoestimulante/sangue , Grécia/etnologia , Humanos , Hipospadia/enzimologia , Lactente , Cariotipagem , Hormônio Luteinizante/sangue , Masculino , Fenótipo , Receptores Androgênicos/metabolismo , Valores de Referência , Pele/enzimologia , Pele/metabolismo , Estados UnidosRESUMO
Counterregulation and awareness of hypoglycemia begins at lower plasma glucose levels in insulin-dependent diabetes mellitus (IDDM) subjects given intensive insulin treatment. To determine whether these changes are associated with an alteration in the susceptibility of the brain to mild hypoglycemia, we compared central nervous system responses to hypoglycemia in 8 intensively treated (hemoglobin A1, 8.3 +/- 0.2%; normal, <8%) and 11 conventionally treated IDDM patients (hemoglobin A1, 14.6 +/- 1.3%) with those in 10 healthy subjects. Plasma glucose was lowered from approximately 4.6 mmol/L in 0.5-0.6 steps using the clamp technique. Glucose levels triggering hormonal responses and perception of hypoglycemic symptoms were significantly lower in intensively treated patients compared to their poorly controlled counterparts (P < 0.05), and hormonal responses were suppressed compared to those in healthy controls. Similarly directed changes occurred in the level of circulating glucose required to alter cortical evoked potentials during hypoglycemia. A greater reduction in plasma glucose was required to alter P300 event-related potentials in the intensively treated patients (2.2 mmol/L) compared to those in the conventionally treated and nondiabetic groups (approximately 3.5 and approximately 3.0 mmol/L, respectively). We conclude that intensively treated IDDM patients are resistant to changes in cortical evoked potentials induced by mild hypoglycemia. This may explain why intensively treated IDDM counterregulate and experience hypoglycemic symptoms at a lower glucose level than conventionally treated patients.
Assuntos
Adaptação Fisiológica , Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Glucose/deficiência , Insulina/uso terapêutico , Adolescente , Adulto , Conscientização , Glicemia/análise , Córtex Cerebral/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Eletrofisiologia , Potenciais Evocados , Feminino , Técnica Clamp de Glucose , Hormônios/sangue , Humanos , Masculino , Valores de ReferênciaRESUMO
The difference between 1H nuclear magnetic resonance (NMR) spectra obtained from the human brain during euglycemia and during hyperglycemia is depicted as well-resolved glucose peaks. The time course of these brain glucose changes during a rapid increase in plasma glucose was measured in four healthy subjects, aged 18-22 years, in five studies. Results demonstrated a significant lag in the rise of glucose with respect to plasma glucose. The fit of the integrated symmetric Michaelis-Menten model to the time course of relative glucose signals yielded an estimated plasma glucose concentration for half maximal transport, Kt, of 4.8 +/- 2.4 mM (mean +/- SD), a maximal transport rate, Tmax, of 0.80 +/- 0.45 micromol g-1 min-1, and a cerebral metabolic glucose consumption rate (CMR)glc of 0.32 +/- 0.16 micromol g-1 min-1. Assuming cerebral glucose concentration to be 1.0 micromol/g at euglycemia as measured by 13CMR, the fit of the same model to the time course of brain glucose concentrations resulted in Kt = 3.9 +/- 0.82 mM, Tmax = 1.16 +/- 0.29 micromol g-1 min-1, and CMRglc = 0.35 +/- 0.10 micromol g-1 min-1. In both cases, the resulting time course equaled that predicted from the determination of the steady-state glucose concentration by 13C NMR spectroscopy within the experimental scatter. The agreement between the two methods of determining transport kinetics suggests that glucose is distributed throughout the entire aqueous phase of the human brain, implying substantial intracellular concentration.
Assuntos
Encéfalo/metabolismo , Glucose/metabolismo , Adolescente , Adulto , Transporte Biológico , Glicemia/metabolismo , Barreira Hematoencefálica , Espaço Extracelular/metabolismo , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Modelos Biológicos , Concentração Osmolar , Prótons , Fatores de Tempo , Distribuição TecidualRESUMO
Idiopathic growth hormone deficiency is a disorder that is not clearly understood. We therefore evaluated the MR scans of 35 patients with idiopathic growth hormone deficiency in an attempt to define more clearly the abnormalities of the hypothalamohypophyseal axis, determine the frequency of these abnormalities, and determine whether a relationship exists between the MR findings and the patient's clinical history and endocrine function. Patients with MR abnormalities fell into two groups; those with an ectopic neurohypophysis (15 patients, or 43%), which consisted of a neurohypophysis near the median eminence, absence of the infundibulum, and absence of the normal posterior pituitary bright spot; and those with a small anterior pituitary gland (15 patients, or 43%), which was an isolated finding in five patients and associated with an ectopic neurohypophysis in 10 patients. Examination of endocrine function identified two groups of patients: those with multiple hormone deficiencies and those with isolated growth hormone deficiency. An ectopic neurohypophysis was present in 87% of the first group and 10% of the second group. The anterior pituitary dysfunction in those with an ectopic neurohypophysis was thought to be related to the absent infundibulum, which normally houses the portal system. Our MR findings demonstrated that over 40% of patients with idiopathic growth hormone deficiency have an ectopic neurohypophysis and absence of the infundibulum. We believe that the growth hormone deficiency in these patients is related to the absent infundibulum.
Assuntos
Neoplasias do Ventrículo Cerebral/diagnóstico , Coristoma/diagnóstico , Transtornos do Crescimento/etiologia , Hormônio do Crescimento/deficiência , Sistema Hipotálamo-Hipofisário/anormalidades , Imageamento por Ressonância Magnética , Adeno-Hipófise/anormalidades , Neuro-Hipófise , Adolescente , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Eminência MedianaAssuntos
Peptídeo C/sangue , Glucagon/sangue , Fator de Crescimento Insulin-Like I/farmacologia , Adulto , Animais , Conscientização , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Glucose/metabolismo , Técnica Clamp de Glucose , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipoglicemia/fisiopatologia , Insulina/sangue , Insulina/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Norepinefrina/sangue , Ratos , Proteínas Recombinantes/farmacologiaRESUMO
An almost 3-year-old boy was evaluated for pubic hair and unilateral testicular enlargement 1 week after resection of an astrocytoma of the posterior fossa. Rather than the expected diagnosis of central precocity due to increased intracranial pressure, a diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) with testicular adrenal rest cells was made. The differential diagnosis, laboratory evaluation, and currently accepted medical management of congenital adrenal hyperplasia are described.
Assuntos
Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/diagnóstico , Puberdade Precoce/etiologia , Hiperplasia Suprarrenal Congênita/terapia , Astrocitoma/complicações , Astrocitoma/cirurgia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Pré-Escolar , Fossa Craniana Posterior , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
Since the development of recombinant DNA technology, there has been a rapid expansion of interest in the use of human insulin-like growth factor I (IGF-I) synthesized by recombinant DNA technology for the treatment of clinical disorders. This article reviews recent studies of the metabolic effects of recombinant human IGF-I in normal humans. These studies demonstrated that under euglycemic conditions, IGF-I had potent effects on glucose (hepatic and peripheral), lipid and amino acid metabolism that closely resemble those of insulin, despite a concomitant inhibitory effect on insulin secretion. Hypoglycemia produced by IGF-I infusions (free-fall study and glucose clamps) had a different effect on counterregulatory responses compared with insulin. The glucagon response was absent, growth hormone (GH) release was attenuated, while norepinephrine levels were increased. Suppression of glucagon release during hypoglycemia impaired glucose recovery. Paradoxically, awareness of hypoglycemia was enhanced with IGF-I, partly due to stimulation of sympathetic activity. Studies performed under hyperglycemic conditions showed that IGF-I inhibited glucose-stimulated insulin secretion, but that this inhibitory effect was partially overcome by increasing the hyperglycemic stimulus. Moreover, despite the decrease in insulin secretion, glucose disposal was accelerated by IGF-I. These observations imply that IGF-I might be effective in human diabetes. In particular, normalization of the decreased basal IGF-I levels, which are characteristic of poorly controlled patients with insulin-dependent diabetes mellitus (IDDM), in pubertal patients might lower glucagon and GH levels and improve cellular metabolism in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Fator de Crescimento Insulin-Like I/farmacologia , Adulto , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Técnica Clamp de Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Fator de Crescimento Insulin-Like I/uso terapêutico , Proteínas Recombinantes/farmacologiaRESUMO
We noted the presence of elevated levels of circulating 1,25-dihydroxyvitamin D (83 pg/ml (200 pmol/L), with low total serum calcium concentration (6.5 mg/dl (1.88 mmol/L), in an untreated adolescent boy with hypoparathyroidism. Furthermore, an inverse relationship between total serum calcium and circulating 1,25-dihydroxyvitamin D levels was evident during treatment with 1,25-dihydroxyvitamin D3. We examined this relationship with a 33-hour intravenous infusion of calcium gluconate in the absence of exogenous 1,25-dihydroxyvitamin D3 therapy. The infusion was accompanied by a gradual increase of both total serum calcium and blood ionized calcium concentrations from hypocalcemic to normocalcemic ranges, and produced a 50% reduction in circulating 1,25-dihydroxyvitamin D values, with minimal changes in circulating phosphorus, magnesium, and 25-hydroxyvitamin D values. These results suggest that calcium-dependent, parathyroid hormone-independent regulation of 1,25-dihydroxyvitamin D production may exist in human beings.
Assuntos
Calcitriol/metabolismo , Cálcio/fisiologia , Hipoparatireoidismo/metabolismo , Adolescente , Cálcio/sangue , Doença Crônica , HumanosRESUMO
The metabolic effects of recombinant human insulin-like growth factor I (rhIGF-I) on glucose, amino acid, and free fatty acid (FFA) metabolism were examined in nine healthy nonobese subjects. Each received a 3-h primed continuous infusion of rhIGF-I (20 micrograms/kg bolus, 0.4 microgram.kg-1.min-1) while maintaining euglycemia using an exogenous glucose infusion. Total IGF-I levels increased from 125 +/- 11 to 444 +/- 22 ng/ml, and free IGF-I levels rose from undetectable to 73 +/- 5 ng/ml. Insulin levels fell from 95 +/- 9 to 64 +/- 8 pM, and C-peptide fell from 453 +/- 48 to 206 +/- 29 pM; circulating glucagon levels also declined from 72 +/- 9 to 42 +/- 4 pg/ml, rhIGF-I produced a two- to threefold increase in glucose uptake as measured by [3H] glucose (from 10.3 +/- 0.6 to 27.4 +/- 3 mumol.kg-1.m-1), and, despite the fall in insulin secretion, there was a marked 60-70% inhibition of hepatic glucose production. Furthermore, FFA and branched-chain amino acids declined by 40-60% (411 +/- 58 to 165 +/- 36 and 406 +/- 23 to 219 +/- 14 microM, respectively). Our data demonstrate that rhIGF-I has potent effects on glucose (hepatic and peripheral), lipid, and amino acid metabolism in normal humans. The scope of the actions of rhIGF-I closely resemble those of insulin, despite a concomitant inhibitory effect on insulin secretion.
Assuntos
Aminoácidos/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Adulto , Glicemia/análise , Humanos , Fígado/metabolismo , Masculino , Proteínas RecombinantesRESUMO
OBJECTIVE: Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children, but a physiologic mechanism has not been established. This study was performed to address this issue. DESIGN: Metabolic, hormonal, and symptomatic responses to a standard oral glucose load (1.75 gm/kg; maximum, 120 gm) were compared in 25 healthy children and 23 young adults, and the hypoglycemic clamp, together with measurements of P300 auditory evoked potentials, was used to assess whether children are more vulnerable than adults to neuroglycopenia. SETTING: Children's Clinical Research Center, Yale University School of Medicine. RESULTS: Baseline and oral glucose-stimulated plasma glucose and insulin levels were similar in both groups, including the nadir glucose level 3 to 5 hours after oral administration of glucose (3.4 +/- 0.1 mmol/L (61 +/- 1.8 mg/dl) in children and 3.5 +/- 0.1 mmol/L (63 +/- 1.8 mg/dl) in adults). The late glucose decrease stimulated a rise in plasma epinephrine levels that was twofold higher in children than in adults (2260 +/- 289 vs 1031 +/- 147 pmol/L (407 +/- 52 vs 186 +/- 26 pg/ml), p < 0.01) and a significant increase in hypoglycemic symptom scores in children (p < 0.01), but not in adults. During control experiments, in which six of the healthy children ingested a sugar-free drink, there were no significant changes in plasma glucose levels, hormone concentrations, or hypoglycemic symptom scores. During the hypoglycemic clamp, P300 potentials did not change in any of eight adult subjects until the plasma glucose concentration was lowered to 3.0 mmol/L (54 mg/dl), whereas similar changes in P300 potentials were observed in six of seven children at glucose levels 3.6 to 4.2 mmol/L (65 to 75 mg/dl). CONCLUSION: Enhanced adrenomedullary responses to modest reductions in plasma glucose concentration and increased susceptibility to neuroglycopenia may be important contributing factors to adverse behavioral and cognitive effects after sugar ingestion in healthy children.
Assuntos
Medula Suprarrenal/efeitos dos fármacos , Encefalopatias/etiologia , Carboidratos da Dieta/efeitos adversos , Hipoglicemia/etiologia , Adolescente , Medula Suprarrenal/fisiopatologia , Adulto , Glicemia/análise , Encefalopatias/sangue , Encefalopatias/fisiopatologia , Criança , Doença Crônica , Suscetibilidade a Doenças , Potenciais Evocados Auditivos/efeitos dos fármacos , Feminino , Teste de Tolerância a Glucose , Humanos , Hipoglicemia/sangue , Hipoglicemia/fisiopatologia , Insulina/sangue , Masculino , Valores de Referência , Fatores de TempoRESUMO
Cerebral metabolism of D[1-13C]glucose was studied with localized 13C NMR spectroscopy during intravenous infusion of enriched [1-13C]glucose in four healthy subjects. The use of three-dimensional localization resulted in the complete elimination of triacylglycerol resonance that originated in scalp and subcutaneous fat. The sensitivity and resolution were sufficient to allow 4 min of time-resolved observation of label incorporation into the C3 and C4 resonances of glutamate and C4 of glutamine, as well as C3 of aspartate with lower time resolution. [4-13C]Glutamate labeled rapidly reaching close to maximum labeling at 60 min. The label flow into [3-13C]glutamate clearly lagged behind that of [4-13C]-glutamate and peaked at t = 110-140 min. Multiplets due to homonuclear 13C-13C coupling between the C3 and C4 peaks of the glutamate molecule were observed in vivo. Isotopomer analysis of spectra acquired between 120 and 180 min yielded a 13C isotopic fraction at C4 glutamate of 27 +/- 2% (n = 4), which was slightly less than one-half the enrichment of the C1 position of plasma glucose (63 +/- 1%), p < 0.05. By comparison with an external standard the total amount of [4-13C]glutamate was directly quantified to be 2.4 +/- 0.1 mumol/ml-brain. Together with the isotopomer data this gave a calculated brain glutamate concentration of 9.1 +/- 0.7 mumol/ml, which agrees with previous estimates of total brain glutamate concentrations. The agreement suggests that essentially all of the brain glutamate is derived from glucose in health human brain.
Assuntos
Aminoácidos/biossíntese , Encéfalo/metabolismo , Glucose/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Adulto , Ácido Aspártico/biossíntese , Glicemia/metabolismo , Isótopos de Carbono , Feminino , Ácido Glutâmico/biossíntese , Humanos , Marcação por Isótopo/métodos , Masculino , Valores de Referência , Fatores de TempoRESUMO
Glucose is the main fuel for energy metabolism in the normal human brain. It is generally assumed that glucose transport into the brain is not rate-limiting for metabolism. Since brain glucose concentrations cannot be determined directly by radiotracer techniques, we used 13C NMR spectroscopy after infusing enriched D-[1-13C]glucose to measure brain glucose concentrations at euglycemia and at hyperglycemia (range, 4.5-12.1 mM) in six healthy children (13-16 years old). Brain glucose concentrations averaged 1.0 +/- 0.1 mumol/ml at euglycemia (4.7 +/- 0.3 mM plasma) and 1.8-2.7 mumol/ml at hyperglycemia (7.3-12.1 mM plasma). Michaelis-Menten parameters of transport were calculated to be Kt = 6.2 +/- 1.7 mM and Tmax = 1.2 +/- 0.1 mumol/g.min from the relationship between plasma and brain glucose concentrations. The brain glucose concentrations and transport constants are consistent with transport not being rate-limiting for resting brain metabolism at plasma levels greater than 3 mM.
Assuntos
Química Encefálica , Glucose/análise , Espectroscopia de Ressonância Magnética/métodos , Adolescente , Transporte Biológico , Encéfalo/metabolismo , Glucose/metabolismo , HumanosRESUMO
To determine whether the insulin resistance in patients with Turner syndrome, which may be exaggerated by treatment with human growth hormone, leads to excessive insulin secretion, we applied the hyperglycemic glucose-clamp technique to produce a standard hyperglycemic stimulus (6.9 mmol/L, or 125 mg/dl, greater than fasting plasma glucose level for 120 minutes) in seven patients with Turner syndrome and in seven healthy children. These studies were repeated in the patients after 6 to 12 months of therapy with growth hormone. Fasting plasma levels of insulin were comparable in control subjects and patients before therapy but increased significantly in the patients after 6 to 12 months of treatment with growth hormone. Despite identical glucose increments in the two groups during the glucose-clamp procedure, both first- and second-phase insulin responses were significantly greater in the patients than in the control subjects. Moreover, the hyperinsulinemic responses to glucose were markedly exaggerated in the patients after their treatment with growth hormone, reaching values (first phase 474 +/- 100 pmol and second phase 826 +/- 100 pmol; p less than 0.02 vs pretreatment values) that were almost threefold greater than those in control subjects (p less than 0.001). Nevertheless, the rate of insulin-stimulated glucose metabolism during the last 60 minutes of the clamp procedure was similar in all three groups of studies. Glycosylated hemoglobin, total cholesterol level, and blood pressure remained normal in patients after therapy with growth hormone. We conclude that glucose-stimulated insulin response is increased in patients with Turner syndrome and that these alterations are further exaggerated by treatment with growth hormone. These hyperinsulinemic responses appear to compensate for reductions in insulin sensitivity.