RESUMO
PURPOSE: An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index. METHODS: We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55). RESULTS: IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04). CONCLUSIONS: Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies.
Assuntos
Agonistas de Dopamina , Fator de Crescimento Insulin-Like I , Neoplasias Hipofisárias , Prolactinoma , Humanos , Prolactinoma/tratamento farmacológico , Prolactinoma/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/análise , Feminino , Masculino , Adulto , Estudos Retrospectivos , Agonistas de Dopamina/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/sangue , Pessoa de Meia-Idade , Cabergolina/uso terapêutico , Peso Corporal/efeitos dos fármacos , Seguimentos , Prolactina/sangue , Índice de Massa Corporal , PrognósticoRESUMO
Concurrent with the epidemic of childhood obesity, an unprecedented increase in the prevalence of several adiposity-related complications in this age group has emerged. In particular, type 2 diabetes (T2D), once considered an illness restricted to adulthood, is progressively affecting more and more adolescents, and represents now roughly 20-45% of new-onset cases in this age group. To unravel the pathogenesis of diabetes development during adolescence, many studies have focused on defining early defects in both insulin sensitivity and secretion that might be implicated in the natural history of the disease. Although a lot still need to be clarified, studies have shown that the progression from normal glucose tolerance to T2D involves intermediate stages of impaired fasting glucose and/or impaired glucose tolerance, also known as prediabetes. Insulin resistance and ß-cell dysfunction represent the two major key pathogenetic defects underlying the progression to diabetes in obese youth. In this review, we have sought to mainly describe the role of ß-cell function in relation to the ambient insulin resistance in the development of T2D in obese adolescents.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Obesidade/metabolismo , Estado Pré-Diabético/metabolismo , Adolescente , Criança , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Secreção de Insulina , Masculino , Obesidade/complicações , Obesidade/epidemiologia , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/etiologia , Prevalência , Fatores de Risco , Adulto JovemRESUMO
AIMS/HYPOTHESIS: A high but normal fasting plasma glucose level in adults is a risk factor for future development of type 2 diabetes mellitus and cardiovascular disease. We investigated whether normal fasting plasma glucose levels (<5.60 mmol/l) are associated with decreases in insulin sensitivity and beta cell function, as well as an adverse cardiovascular profile in obese youth. METHODS: We performed a cross-sectional analysis in a multiethnic sample of 1,020 obese youth (614 girls and 406 boys; mean age 12.9 years [CI 95% 12.7-13.1], BMI z score 2.34 [CI 95% 2.31-2.38]) with normal fasting plasma glucose. All participants had a standard OGTT, with calculation of indices of insulin sensitivity and beta cell function. For the analysis, prepubertal and pubertal participants were stratified into quartiles of normal fasting plasma glucose. RESULTS: We observed a significant increase in fasting insulin and AUC 2 h glucose across quartiles. Pronounced changes were observed in insulin sensitivity and secretion, particularly in the pubertal group. Moreover, the odds of presenting with impaired glucose tolerance increased by 4.5% with each 0.06 mmol/l increase in fasting plasma glucose. No significant differences in cardiovascular indices were seen across quartiles. CONCLUSIONS/INTERPRETATION: These data suggest that in obese youth, independent of age, BMI z score, sex, family history and ethnicity, insulin sensitivity and secretion decline when moving from low to high normal fasting plasma glucose. The simple measure of fasting plasma glucose could assist clinicians in identifying children for targeted diabetes screening and subsequent lifestyle management.
Assuntos
Glicemia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Obesidade/metabolismo , Adolescente , Análise de Variância , Área Sob a Curva , Criança , Estudos Transversais , Jejum , Feminino , Humanos , Insulina/sangue , Masculino , Valor Preditivo dos Testes , Análise de Regressão , Fatores de RiscoRESUMO
A standard oral glucose tolerance test (OGTT) was administered to 28 adults with Williams syndrome (WS). Three quarters of the WS subjects showed abnormal glucose curves, meeting diagnostic criteria for either diabetes or the pre-diabetic state of impaired glucose tolerance. Fasting mean glucose and median insulin levels did not differ significantly in the total WS cohort versus age-gender-BMI matched controls, though the glucose area under the curve was greater in the WS subjects. HbA1c levels were not as reliable as the OGTT in diagnosing the presence of diabetes. Given the high prevalence of impaired glucose regulation, adults with WS should be screened for diabetes, and when present should be treated in accordance with standard medical practice. Hemizygosity for a gene mapping to the Williams syndrome chromosome region (WSCR) is likely the major factor responsible for the high frequency of diabetes in WS. Syntaxin-1A is a prime candidate gene based on its location in the WSCR, its role in insulin release, and the presence of abnormal glucose metabolism in mouse models with aberrantly expressed Stx-1a.
Assuntos
Estado Pré-Diabético/complicações , Estado Pré-Diabético/epidemiologia , Síndrome de Williams/complicações , Síndrome de Williams/epidemiologia , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Insulina/sangue , Masculino , Estado Pré-Diabético/sangue , Prevalência , Caracteres Sexuais , Estados Unidos , Síndrome de Williams/sangueRESUMO
INTRODUCTION: Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. OBJECTIVES: To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. METHODS: Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic-related air pollution was characterized as vehicle traffic volume on major roads within a 1 km residential buffer, and as residential nitrogen dioxide (NO2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. RESULTS: Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150 U/L to almost 200 U/L as residential traffic volume increased from 220 000 vehicle-km to 330 000 vehicle-km, after adjustment for baseline CK-18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140 U/L to 200 U/L (a 1.5 standard deviation increase in CK-18) as NO2 increased from 8 to 10 ppb. CONCLUSIONS: Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry.
Assuntos
Poluição do Ar/efeitos adversos , Queratina-18/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade Infantil/complicações , Poluição Relacionada com o Tráfego/efeitos adversos , Poluentes Atmosféricos/análise , Apoptose/fisiologia , Biomarcadores/sangue , Criança , Feminino , Seguimentos , Humanos , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/etiologia , Estudos Prospectivos , Fatores de Risco , Transaminases/sangue , Emissões de Veículos/análiseRESUMO
BACKGROUND: An important area of research in childhood obesity is the identification of factors that predict or moderate the responses to obesity intervention programmes, yet few studies have examined the impact of self-esteem and family functioning on obesity treatment outcomes. OBJECTIVES: We sought to determine whether baseline self-esteem and family functioning predicted or moderated childhood obesity intervention outcomes at 6 months. METHODS: From 2009 to 2011, seventy-five 10-16 year old, racially/ethnically diverse obese youths with abnormal glucose tolerance were randomized to 6 months of an intensive family-based obesity lifestyle intervention (Bright Bodies) or routine outpatient Clinic Care. We examined youth self-concept, parent-rated family functioning and 6-month outcomes (youths' glucose tolerance, weight, body mass index and percent fat). We set the significance threshold as P ≤ 0.05 for moderator and predictor analyzes. RESULTS: Having poor family functioning and self-concept scores indicating high anxiety and low self-esteem at baseline predicted poor 6-month outcomes overall (Bright Bodies and Clinic Care groups combined). Additionally, baseline self-esteem and family functioning moderated treatment effects such that Bright Bodies outperformed Clinic Care in youths with low self-esteem and poorly functioning families, whereas youths with high self-esteem and high-functioning families did similarly well with either intervention. DISCUSSION: Our findings suggest intensive family-based lifestyle programmes are particularly beneficial for youth with low self-esteem and poorly functioning families.
Assuntos
Obesidade Infantil/psicologia , Autoimagem , Programas de Redução de Peso/métodos , Adolescente , Índice de Massa Corporal , Peso Corporal , Criança , Etnicidade , Feminino , Humanos , Masculino , Pais , Obesidade Infantil/terapia , Resultado do TratamentoRESUMO
Altered glucose metabolism in obese youth is an emerging phenomenon of the last 2 decades, strongly associated with the increase in the prevalence of childhood obesity. Peripheral insulin resistance, tightly coupled with obesity in this age group, seems to be the major driving force of deteriorating glucose metabolism. Patterns of lipid partitioning, mainly an increased deposition of fat in the intramyocellular and visceral compartments are strongly associated with insulin resistance in this population. Impaired glucose tolerance in this age group is characterized by a decline in first phase sensitivity of the beta cell while a combined decline of first and second phase sensitivity is the hallmark of type 2 diabetes. The dynamics of impaired glucose metabolism in childhood seem to be faster than in adults, representing a limited window of opportunity for successful preventive intervention.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Resistência à Insulina/fisiologia , Adolescente , Criança , Intolerância à Glucose/diagnóstico , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Obesidade/metabolismoRESUMO
IDDM subjects lose the ability to release glucagon during hypoglycemia. Because replacement of basal levels of amino acids enhances the glucagon response to hypoglycemia in healthy subjects, we tested whether raising amino acid levels during hypoglycemia could reverse the defective alpha-cell response in IDDM patients. For this purpose, 11 IDDM patients (HbA1 9.4 +/- 0.6%) and 8 healthy, nondiabetic subjects received two hypoglycemic insulin clamp studies (0.8 mU.kg-1 x min-1) in which plasma glucose was clamped at 55 mg/dl (3.08 mM) for 180 min. During one of the studies, an infusion of amino acids was superimposed between 120 and 180 min (0.3 g.kg-1 x h-1). This dose of amino acids had a small effect on plasma glucagon levels during euglycemic hyperinsulinemia that was comparable in normal and IDDM subjects. In healthy control subjects, plasma glucagon rose by 80% during the initial hypoglycemic phase of the study. The addition of amino acids produced a further sharp (200-250 ng/L, P < 0.02) rise in plasma glucagon, such a change did not occur in the absence of amino acids. In contrast, plasma glucagon in IDDM patients failed to increase during hypoglycemia alone and rose by only 40-50 ng/L (P < 0.05 vs. controls) when amino acid infusion was superimposed, even though plasma amino acid levels rose to the same extent in IDDM and control subjects. More importantly, the rise in glucagon produced by amino acids was comparable during hypoglycemic and euglycemic hyperinsulinemia in the IDDM patients, results strikingly different from those observed in nondiabetic control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Aminoácidos Essenciais/farmacologia , Aminoácidos/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Glucagon/sangue , Hipoglicemia/sangue , Insulina/farmacologia , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Aminoácidos Essenciais/administração & dosagem , Peptídeo C/sangue , Feminino , Glucagon/metabolismo , Técnica Clamp de Glucose , Humanos , Infusões Intravenosas , Insulina/sangue , Sistemas de Infusão de Insulina , Masculino , Valores de ReferênciaRESUMO
To examine the impact of diabetes and its treatment on plasma free-fatty acid (FFA) and oxidative fuel metabolism during hypoglycemia, we combined indirect calorimetry with [3-3H]glucose during a 4-h low-dose insulin infusion (plasma insulin approximately 2-fold above basal) in six poorly controlled and nine well-controlled insulin-dependent diabetes mellitus (IDDM) patients and in six healthy subjects. Diabetic subjects received insulin overnight to maintain euglycemia before study. Although free-insulin levels and counterregulatory hormone responses were similar, the plasma glucose fall was more pronounced in well-controlled diabetic subjects. In well-controlled diabetic and healthy subjects, the small increment in insulin rapidly suppressed plasma FFA and fat oxidation by approximately 50% and stimulated carbohydrate oxidation by approximately 80%. In contrast, plasma FFA levels did not fall in poorly controlled diabetic subjects, and glucose oxidation was not stimulated. To determine whether this resistance to the antilipolytic effect of insulin occurs in the absence of hypoglycemic counterregulation, we used a sequential low-dose euglycemic insulin clamp (0.2, 0.3, and 0.5 mU.kg-1.min-1). In healthy subjects, plasma FFA was nearly maximally suppressed at the lowest insulin dose. In contrast, plasma FFA remained persistently elevated in poorly controlled diabetic subjects at each insulin dose. However, the insulin dose-response curve for suppression of plasma FFA was near normal in well-controlled subjects. We conclude that poorly controlled IDDM diabetic patients are resistant to the antilipolytic effects of insulin and show impaired stimulation of glucose oxidation during insulin-induced hypoglycemia. Amelioration of these defects in well-controlled patients may be another factor contributing to the higher risk of hypoglycemia during intensified insulin therapy.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Adulto , Glicemia/fisiologia , Calorimetria , Diabetes Mellitus Tipo 1/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Técnica Clamp de Glucose , Humanos , Hipoglicemia/induzido quimicamente , Infusões Intravenosas , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Masculino , OxirreduçãoRESUMO
Studies performed in adults with long-standing obesity suggest a reduced lipolytic sensitivity to catecholamines in subcutaneous abdominal adipose tissue (AT). We used microdialysis to study the in situ lipolytic effects of dobutamine (selective beta1-agonist) and terbutaline (selective beta2-agonist) on glycerol release (lipolytic index) in abdominal subcutaneous AT in 10 obese girls aged 13-17 years, BMI 38 +/- 2.1 kg/m2, and in 7 lean girls aged 11-17 years, BMI 21 +/- 1.1 kg/m2, and compared them with 10 obese women aged 21-39 years, BMI 36 +/- 1.6 kg/m2, and 10 lean women aged 18-42 years, BMI 21 +/- 0.4 kg/m2. Terbutaline at 10(-6) mol/l stimulated glycerol release more efficiently in lean girls than in obese girls (peak response approximately 350 vs. 150% of control, P < 0.01). At the lower concentration of agonist, no significant difference was seen. In women, terbutaline was more effective in lean than in obese women in stimulating glycerol release at both 10(-8) mol/l (peak response lean approximately 175% vs. obese 125% of control) and 10(-6) mol/l (approximately 300 vs. 150% of control, P < 0.05). No significant difference in glycerol release between obese and lean girls or women was detected with selective beta1-stimulation. Our data demonstrate a specific impairment in the capacity of beta2-adrenergic agonists to promote lipolysis in subcutaneous abdominal adipose tissue of obese adolescent girls and women. Thus, decreased mobilization of fat during activation of the adrenergic system might be present early in the development of adolescent obesity.
Assuntos
Tecido Adiposo/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Dobutamina/farmacologia , Lipólise/efeitos dos fármacos , Obesidade/metabolismo , Terbutalina/farmacologia , Abdome , Adolescente , Adulto , Feminino , Glicerol/sangue , Glicerol/metabolismo , Humanos , Microdiálise , Concentração Osmolar , Valores de ReferênciaRESUMO
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
We used microdialysis to distinguish the effects of hyperinsulinemia and hypoglycemia on glucose, gluconeogenic substrate, and catecholamine levels in adipose and muscle extracellular fluid (ECF). Ten lean humans (six males and four females) were studied during baseline and hyperinsulinemic (3 mU x kg-1 x min-1 for 3 h) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). In muscle and adipose, basal ECF glucose was lower (muscle, 3.5 +/- 0.2 mmol/l; adipose tissue, 3.3 +/- 0.2 mmol/l) and lactate was higher (muscle, 2.2 +/- 0.2 mmol/l; adipose, 1.5 +/- 0.3 mmol/l) than respective plasma values (glucose, 4.9 +/- 0.1 mmol/l; lactate, 0.7 +/- 0.1 mmol/l), whereas alanine was higher in muscle ECF (379 +/- 22 micromol/l) than adipose tissue (306 +/- 22 micromol/l) and plasma (273 +/- 33 micromol/l). Plasma catecholamines (unchanged during euglycemia) rose during hypoglycemia with epinephrine, increasing approximately fivefold more than norepinephrine. In contrast, the hypoglycemia-induced increments in muscle dialysate norepinephrine and epinephrine were similar, suggesting local generation of norepinephrine. Compared with euglycemia, hypoglycemia produced a greater increase in lactate and a smaller reduction in alanine in muscle ECF, whereas hypoglycemia caused a greater relative fall in ECF glucose concentrations in muscle (72 +/- 16%) and adipose tissue (69 +/- 9%) than in plasma (42 +/- 3%) (P < 0.05). We conclude that hypoglycemia increases the generation of norepinephrine and gluconeogenic substrates in key target tissues, while increasing the plasma-tissue concentration gradient for glucose. These changes suggest the stimulation of glucose extraction by peripheral tissues, despite systemic counterregulatory hormone release and local sympathetic activation.
Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Epinefrina/sangue , Hipoglicemia/metabolismo , Insulina/farmacologia , Músculo Esquelético/metabolismo , Norepinefrina/sangue , Adolescente , Adulto , Alanina/metabolismo , Peso Corporal , Espaço Extracelular/metabolismo , Feminino , Gluconeogênese , Glucose/metabolismo , Técnica Clamp de Glucose , Homeostase , Humanos , Hiperinsulinismo , Insulina/administração & dosagem , Cinética , Lactatos/metabolismo , Masculino , Microdiálise , 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
In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone-releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 micrograms/kg i.v. GRF 1-40 was administered to nine poorly controlled IDDM subjects (HbA1 greater than 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (approximately 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 +/- 90 pM) and hyperglycemia (16.5 +/- 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 +/- 11 vs. 20 +/- 4 micrograms/L without insulin infusion, P less than 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 +/- 7 micrograms/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 +/- 84 pM) and hyperglycemia (16.41 +/- 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Hormônio do Crescimento/metabolismo , Insulina/farmacologia , Fragmentos de Peptídeos/farmacologia , Hipófise/metabolismo , Adulto , Diabetes Mellitus Tipo 1/sangue , Hemoglobinas Glicadas/análise , Hormônio do Crescimento/sangue , Humanos , Hiperglicemia/fisiopatologia , Hiperinsulinismo , Sistemas de Infusão de Insulina , Masculino , Hipófise/efeitos dos fármacosRESUMO
To determine whether changes in food intake produced by leptin involve targeting the hormone to distinct central nervous system regions, guide cannulas were positioned stereotaxically into three brain regions--the ventromedial hypothalamus (VMH) (bilaterally, n = 6), the dorsal raphe nucleus (n = 3), and the lateral ventricle (n = 3)--of nonobese male rats (400-500 g). Daily food intake and body weight changes were measured during twice-daily injections of saline (0.1 microl) followed by recombinant human leptin (0.05 microg) for 3 days via the brain cannulas. VMH-injected rats also were followed during a postleptin saline recovery interval. This small dose of leptin did not change food intake or body weight from that during the preceding saline injection period in ventricle-injected or dorsal raphe-injected rats. In sharp contrast, VMH-injected rats ate much less food (56 +/- 8% basal) and lost 9 +/- 3 g/day or 5% of their body weight during 3 days of leptin administration. VMH-injected animals fully recovered from leptin-induced effects within 3 days. We conclude that small doses of leptin that do not effect eating behavior when delivered to the ventricle or the dorsal raphe (another brain region believed to regulate feeding), suppress food intake when injected into the VMH. These data suggest that the VMH or a brain region in close proximity to it is a key target for the biological actions of leptin.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Proteínas/farmacologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/fisiologia , Humanos , Injeções Intraventriculares , Leptina , Masculino , Microinjeções , Obesidade , Proteínas/administração & dosagem , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Técnicas Estereotáxicas , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3. Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not suggest a significant effect of UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption or respiratory quotient at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.
Assuntos
População Negra/genética , Proteínas de Transporte/fisiologia , Metabolismo Energético/fisiologia , Mitocôndrias , Processamento Alternativo , Povo Asiático/genética , Proteínas de Transporte/genética , Ligação Genética , Hispânico ou Latino , Homeostase , Humanos , Canais Iônicos , Desequilíbrio de Ligação , Proteínas Mitocondriais , Proteína Desacopladora 3 , População Branca/genéticaRESUMO
Acromegaly is a rare disease that, in the majority of cases, is due to the presence of a benign growth hormone (GH)-producing tumor of the pituitary. Growth hormone has profound effects on linear bone growth, bone metabolism, and bone mass. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. The Autors describe a case of patient affected by acromegaly without hypogonadism with serious osteoporosis and biological signs of osteomalacia.
Assuntos
Acromegalia/diagnóstico , Adenoma Cromófobo/diagnóstico , Osteomalacia/diagnóstico , Osteoporose/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Acromegalia/tratamento farmacológico , Acromegalia/etiologia , Acromegalia/cirurgia , Adenoma Cromófobo/complicações , Adenoma Cromófobo/cirurgia , Adulto , Androgênios/uso terapêutico , Densidade Óssea , Hormônio do Crescimento Humano/sangue , Humanos , Hipogonadismo/diagnóstico , Masculino , Osteomalacia/tratamento farmacológico , Osteomalacia/etiologia , Osteomalacia/cirurgia , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/cirurgia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Reoperação , Testosterona/uso terapêutico , Resultado do TratamentoRESUMO
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
The effect of human recombinant insulin-like growth factor I (rhIGF-1) on glucose stimulated insulin secretion was studied in 14 healthy human volunteers. Each subject received a primed-continuous infusion of rhIGF-1 (20 micrograms kg prime, 0.4 micrograms kg-1 min-1) or saline while plasma glucose was raised +2.8 mmol/l (+50 mg/dl) (n = 6) or +7.0 mmol/l (+125 mg/dl) (n = 8) above baseline for 2 h using the hyperglycemic clamp technique. Total IGF-1 levels during the IGF-1 studies increased from 196 +/- 37 to 449 +/- 71 ng/ml. At the +2.8 mmol/l (+50 mg/dl) stimulus, first and second phase C-peptide levels were suppressed during IGF-1 infusion vs control (885 +/- 157 vs 544 +/- 99 pmol/l, p < 0.05 and 1379 +/- 246 vs 832 +/- 130 pmol/l, p < 0.05, respectively), whereas insulin levels were suppressed during the second phase only (215 +/- 43 vs 151 +/- 28 pmol/l, p < 0.05). Despite this, the rate of glucose metabolism was two-fold higher in the IGF-1 infused group (8.0 +/- 0.5 vs 3.5 +/- 0.1 mg kg-1 min-1, p < 0.01). At the higher glucose stimulus +7.0 mmol/l (+125 mg/dl) only second phase C-peptide levels were significantly reduced (1922 +/- 251 vs 1466 +/- 74 pmol/l, p < 0.05). Again, rates of glucose metabolism were higher during IGF-1 infusion (11.8 +/- 1.2 vs 8.9 +/- 0.8 mg kg-1 min-1, p < 0.01). These data suggest that rhIGF-1 inhibits glucose-stimulated insulin secretion in humans, but that this inhibitory effect is partially overcome by increasing the hyperglycemic stimulus. Moreover, despite the decrease in insulin secretion, glucose disposal is accelerated by rhIGF-1.
Assuntos
Glucose/farmacologia , Antagonistas da Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Insulina/metabolismo , Adolescente , Adulto , Glicemia/análise , Peptídeo C/sangue , Feminino , Glucose/metabolismo , Técnica Clamp de Glucose , Humanos , Hiperglicemia/sangue , Insulina/sangue , Secreção de Insulina , Masculino , Proteínas Recombinantes , Valores de ReferênciaRESUMO
To examine mechanisms underlying the development of insulin resistance during normal puberty, sequential 8 and 40 mU/m2.min euglycemic insulin clamp and hyperglycemic clamp studies were performed in 14 healthy prepubertal and 19 pubertal children. Both groups had comparable rates of glucose turnover and plasma levels of branched chain amino acids and FFA at baseline. The low as well as the high insulin dose stimulated peripheral glucose uptake much more effectively in prepubertal children (P less than 0.05). In contrast, suppression of hepatic glucose production (60% at low dose in both groups, pNS) and lowering of substrates in response to insulin was not affected by puberty at either dose. During the hyperglycemic clamp pubertal children showed enhanced insulin responses and in turn a sharper fall in amino acids (P less than 0.05 vs. prepubertals). Our data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism. Selective insulin resistance leading to compensatory hyperinsulinemia may serve to amplify insulin's effect on amino acid metabolism, thereby facilitating protein anabolism during this period of rapid growth.