RESUMEN
BACKGROUND: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome. METHODS: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed. RESULTS: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time. CONCLUSIONS: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.
Asunto(s)
Isquemia Encefálica/inmunología , Antígenos HLA-DR/sangre , Interleucina-6/sangre , Neumonía/etiología , Accidente Cerebrovascular/inmunología , Proteínas de Fase Aguda , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/complicaciones , Biomarcadores/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/complicaciones , Isquemia Encefálica/mortalidad , Proteínas Portadoras/sangre , Diabetes Mellitus , Femenino , Alemania , Humanos , Tolerancia Inmunológica , Inflamación/complicaciones , Interleucina-10/sangre , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana Edad , Neumonía/mortalidad , Estudios Prospectivos , España , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND AND PURPOSE: Myeloproliferative neoplasms (MPNs) - polycythemia vera, essential thrombocythemia and primary myelofibrosis - are associated with increased risk for ischaemic cerebrovascular events (ICVEs). Due to their low prevalence, MPNs often remain undiagnosed as the cause of ICVEs. METHODS: Case records at the University of Tübingen between 2014 and 2017 were screened to identify patients with MPN-related ICVEs. Clinical features, brain imaging, laboratory findings, applied treatments and neurological outcomes were assessed. RESULTS: In all, 3318 patients with ICVEs were identified, and amongst them 17 patients with MPN-related ICVEs were included in a retrospective study. In 58% of these patients, ICVEs were the first manifestation of the underlying MPN; 24% presented with transient ischaemic attack and 76% with ischaemic stroke. Potentially concurrent ICVE etiologies were noted in 70% of the patients. The majority (94%) of patients were positive for the JAK2 V617F mutation, whilst in 29% recurrent ICVEs (range two to three) were noted prior to MPN diagnosis. Early MPN diagnosis and management was the only significant prognostic factor for ICVE recurrence (P < 0.001). DISCUSSION: Evidence is provided that, although rare, MPNs represent an underdiagnosed cause of recurrent ICVEs. High clinical awareness is warranted to identify an underlying MPN in patients presenting with sustained, abnormal blood count findings. Clinical algorithms for prompt MPN diagnosis and initiation of MPN treatment (e.g. cytoreductive therapy, phlebotomy) are required. As MPN management comprises a significant protective factor against ICVE recurrence, induction of MPN treatment should be regarded as an integral component of secondary stroke prevention in MPN-associated ICVEs.
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Isquemia Encefálica/etiología , Trastornos Mieloproliferativos/complicaciones , Accidente Cerebrovascular/etiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios RetrospectivosRESUMEN
AIM: To combat diabetic complications strict glycaemic control is desirable in type 2 diabetes, but some patients are severely insulin resistant and it is not known whether high doses of insulin are effective. This study was designed to determine the acute dose-response effects of insulin in patients with type 2 diabetes and severe insulin resistance. METHODS: We included eight insulin-resistant (mean insulin dose: 186 IU/day; body mass index: 35) subjects with type 2 diabetes in a single-blinded, randomized crossover study. Each subject was studied on two occasions. On each occasion, subjects underwent two 3-h hyperinsulinaemic euglycaemic clamps. The subjects were randomized to two low-dose insulin infusions (0.5 and 1.5 mU/kg/min in random order) on one occasion and to two high-dose insulin infusions (3.0 and 5.0 mU/kg/min in random order) on another occasion. RESULTS: On all occasions, steady-state glucose infusion rates (SSGIRs) were accomplished and we observed a clear dose-response relationship with GIR values of 0.4 ± 0.2 (s.e.), 2.6 ± 0.6, 3.7 ± 0.8 and 4.9 ± 0.9 mg/kg/min during the 0.5, 1.5, 3.0 and 5.0 mU/kg/min insulin infusions, respectively (p < 0.001). Likewise, there was a dose-dependent suppression of endogenous glucose production (EGP) (p < 0.009), plasma free fatty acids (FFAs) (p < 0.001) and plasma glucagon (p = 0.001). CONCLUSIONS: Our results show that the insulin dose response in terms of GIR and EGP is preserved for insulin doses corresponding to >800 IU/day, suggesting effectiveness of very high insulin doses in severely insulin-resistant subjects.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperinsulinismo/tratamiento farmacológico , Resistencia a la Insulina , Insulina/administración & dosificación , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/prevención & control , Relación Dosis-Respuesta a Droga , Medicina Basada en la Evidencia , Femenino , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/prevención & control , Insulina/sangre , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
AIMS: Two long-acting insulin analogues, insulin glargine and insulin detemir, have been developed as alternatives to neutral protamine Hagedorn (NPH) insulin, which has been the preferred basal insulin preparation for decades. The aim was to directly compare the pharmacodynamic properties of the long-acting insulin analogues and NPH insulin after a single subcutaneous injection. METHODS: The study was conducted as a double-blind, controlled, three-arm, crossover study including 10 healthy lean male volunteers. On three different occasions, each subject was challenged with 0.4 U kg(-1) of either insulin glargine, insulin detemir or NPH insulin. Plasma glucose was maintained at 0.3 mmol l(-1) below fasting level by glucose clamping for 24 h. C-peptide, insulin, free fatty acids (FFAs) and counter regulatory hormones were measured throughout the clamp period, whereas endogenous glucose release (EGR) was assessed by isotope dilution technique (3-(3)H-glucose). RESULTS: The mean glucose infusion rate (GIR)-time profiles revealed no significant differences between the three preparations in the primary endpoints: Maximal GIR of approximately 3.4 mg kg(-1) min(-1) (P = 0.68), time to maximal GIR of approximately 10 h (TR(max)) (P = 0.35) and area under the GIR curve (GIR(AUC)) (P = 0.81). Compared with the other insulin preparations, EGR (see above)was lower for insulin detemir at the beginning of the clamp period (330-360 min) (P = 0.007) while GIR was lower (P = 0.005) and FFA concentrations were higher (P = 0.005) during the last 4 h of the clamp. CONCLUSIONS: In this experimental design, only minor pharmacodynamic differences were demonstrated between insulin detemir, insulin glargine and NPH insulin.
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Técnica de Clampeo de la Glucosa/métodos , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Insulina Isófana/farmacología , Insulina de Acción Prolongada/farmacología , Índice de Masa Corporal , Humanos , Hipoglucemiantes/administración & dosificación , Inyecciones Subcutáneas , Insulina Detemir , Insulina Glargina , Insulina Isófana/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Insulina de Acción Prolongada/farmacocinética , Masculino , Adulto JovenRESUMEN
The human kinome describes a major group of intracellular signalling molecules. In the last few years, many molecules in the group have become targets for therapeutic interventions. Due to the conserved reaction mechanism of catalysis, protein kinases seem well "drugable" by small molecular weight inhibitors, thus opening the chance to novel oral bioavailable drug development. A large number of small molecule weight inhibitors for protein kinases have already been introduced into research and these molecules are extensively analysed in regard to their efficiency, potency and selectivity. Here we summarise the use of small molecule protein kinase inhibitors relevant for acute and chronic inflammation based on their essential role in cellular signaling mechanisms in immune cells such as macrophages, lymphoytes and granulocytes. We describe the progress made to develop inhibitors against Toll-like receptor associated kinases (IRAKs), against the MAPK kinase kinases Cot/Tpl-2 and TAK1, against Inhibitor-kappaB kinases (IKKs), against MAPK kinases (MEKs, MKKs), against MAPKs (ERK2, p38, JNKs) and against their downstream kinases MNK1 and MK2/3. This overview should help to keep up with the fast developing field and the continuously growing number of protein kinase inhibitors.
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Inflamación/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/metabolismo , Animales , Citocinas/metabolismo , Humanos , Inflamación/enzimología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Cortisol's effects on lipid metabolism are controversial and may involve stimulation of both lipolysis and lipogenesis. This study was undertaken to define the role of physiological hypercortisolemia on systemic and regional lipolysis in humans. We investigated seven healthy young male volunteers after an overnight fast on two occasions by means of microdialysis and palmitate turnover in a placebo-controlled manner with a pancreatic pituitary clamp involving inhibition with somatostatin and substitution of growth hormone, glucagon, and insulin at basal levels. Hydrocortisone infusion increased circulating concentrations of cortisol (888 +/- 12 vs. 245 +/- 7 nmol/l). Interstitial glycerol concentrations rose in parallel in abdominal (327 +/- 35 vs. 156 +/- 30 micromol/l; P = 0.05) and femoral (178 +/- 28 vs. 91 +/- 22 micromol/l; P = 0.02) adipose tissue. Systemic [(3)H]palmitate turnover increased (165 +/- 17 vs. 92 +/- 24 micromol/min; P = 0.01). Levels of insulin, glucagon, and growth hormone were comparable. In conclusion, the present study unmistakably shows that cortisol in physiological concentrations is a potent stimulus of lipolysis and that this effect prevails equally in both femoral and abdominal adipose tissue.
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Tejido Adiposo/efectos de los fármacos , Glicerol/metabolismo , Hidrocortisona/farmacología , Lipólisis/efectos de los fármacos , Abdomen , Tejido Adiposo/metabolismo , Adulto , Glucemia , Calorimetría Indirecta , Espacio Extracelular/química , Espacio Extracelular/metabolismo , Ayuno/metabolismo , Ácidos Grasos no Esterificados/sangre , Glucagón/administración & dosificación , Glucagón/sangre , Glicerol/análisis , Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/sangre , Humanos , Hidrocortisona/sangre , Infusiones Intravenosas , Insulina/administración & dosificación , Insulina/sangre , Masculino , Microdiálisis , Palmitatos/metabolismo , Somatostatina/administración & dosificación , MusloRESUMEN
To explore the possible role of a reduced physical fitness for the diminished insulin sensitivity in first-degree relatives of NIDDM patients, 21 relatives and 22 matched control subjects were examined employing a hyperinsulinaemic (insulin infusion rate 0.6 mU/kg/min) euglycaemic clamp combined with the isotope dilution technique (3-3H-glucose), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) was significantly diminished in the relatives (p < 0.01). Maximal oxygen uptake (VO2 max) was 15% lower in the relatives than in the controls (p = 0.03). There was a highly significant correlation between Rd and VO2 max in both groups. In multiple linear regression analyses with Rd as the dependent variable VO2 max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. We concluded that the insulin resistance in healthyfirst degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether this finding is ascribable to environmental or genetic factors remains to be determined.
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Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina , Músculo Esquelético/metabolismo , Aptitud Física , Adulto , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Consumo de OxígenoRESUMEN
First degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are often reported to be insulin resistant. To examine the possible role of reduced physical fitness in this condition 21 first degree relatives of NIDDM patients and 22 control subjects without any history of diabetes were examined employing a 150-min hyperinsulinaemic (0.6 mU insulin. kg-1.min-1) euglycaemic clamp combined with the isotope dilution technique (3-(3)H-glucose, Hot GINF), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) and forearm glucose extraction were significantly diminished in the relatives (p < 0.01 and p < 0.05), but glucose oxidation and the suppressive effect on hepatic glucose production were normal. Arteriovenous differences across the forearm of the gluconeogenic precursors lactate, alanine and glycerol as well as the increments in forearm blood flow during hyperinsulinaemia were similar in the two groups. Maximal oxygen uptake (VO2 max) was lower in the relatives than in the control subjects (36.8 +/- 1.9 vs 42.1 +/- 2.0 ml.kg-1.min-1; p = 0.03). There was a highly significant correlation between Rd and VO2 max in both relatives and control subjects (r = 0.68 and 0.66, respectively; both p < 0.001). Comparison of the linear regression analyses of insulin-stimulated Rd on VO2 max in the two groups showed no significant differences between the slopes (0.10 +/- 0.03 vs 0.09 +/- 0.02) or the intercepts. In stepwise multiple linear regression analyses with insulin-stimulated Rd as the dependent variable VO2 max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. In conclusion, the insulin resistance in healthy first degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether, this finding is ascribable to environmental or genetic factors (e.g. differences in muscle fibre types, capillary density etc) remains to be determined.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Músculo Esquelético/metabolismo , Aptitud Física/fisiología , Adulto , Análisis Químico de la Sangre , Glucemia/análisis , Glucemia/efectos de los fármacos , Femenino , Antebrazo/irrigación sanguínea , Antebrazo/fisiología , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo , Insulina/sangre , Insulina/metabolismo , Modelos Lineales , Masculino , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Consumo de Oxígeno , Selección de Paciente , Flujo Sanguíneo Regional/fisiologíaRESUMEN
Amylin has been reported to decrease glycogen storage in rodent skeletal muscles and produce insulin resistance in intact rats. To test the acute effect of a human amylin analog (AC137) on glucose metabolism in man, seven IDDM patients were infused in a randomized, double blind, cross-over study with AC137 (100 micrograms/h, n = 1; 50 micrograms/h, n = 6) or placebo for 330 min during a two-step euglycemic clamp (insulin infusion rates, 0.2 and 0.6 mU/kg.min; basal and hyperinsulinemic period, respectively) followed by a hyperinsulinemic hypoglycemic clamp (insulin infusion rate, 1.5 mU/kg.min; hypoglycemic period). During euglycemia, no differences were found in glucose disposal (step 1, 2.43 +/- 0.20 vs. 2.03 +/- 0.26; step 2, 4.28 +/- 0.54 vs. 4.11 +/- 0.45 mg/kg.min; AC137 vs. placebo, mean +/- SEM), arteriovenous substrate balances across the forearm, or hepatic glucose production. During hypoglycemia, glucose fluxes were also similar. However, lactate release from the forearm was more pronounced (P < 0.05) with the analog than with placebo (area under the curve, -11.2 +/- 4.6 vs. -1.4 +/- 2.2 mmol/min.L). Despite similar plasma glucose nadirs (2.7 +/- 0.0 vs. 2.6 +/- 0.1 mmol/L; AC137 vs. placebo), circulating cortisol and GH rose to significantly higher levels during hypoglycemia with the amylin analog (P < 0.05). In conclusion, acute administration of the amylin analog AC137 did not influence insulin-stimulated glucose metabolism during euglycemic conditions. During imposed hypoglycemia, lactate release from skeletal muscle was, however, enhanced, and the rise in cortisol and GH was augmented.
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Amiloide/farmacología , Diabetes Mellitus Tipo 1/metabolismo , Metabolismo Energético/efectos de los fármacos , Hipoglucemia/metabolismo , Hipoglucemiantes/farmacología , Insulina/farmacología , Adulto , Amiloide/efectos adversos , Amiloide/farmacocinética , Antebrazo/irrigación sanguínea , Glucosa/metabolismo , Hormonas/sangre , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Valores de Referencia , Flujo Sanguíneo Regional , Factores de TiempoRESUMEN
Insufficient metabolic control in diabetes mellitus is associated with a reversible reduction in nerve conduction velocity, but the mechanism behind this phenomenon is unknown. To examine the effect of acute hyperglycaemia on nerve conduction eight non-diabetic men (20-49 years of age) with no signs of peripheral neuropathy were studied before and after 3 h of hyperglycaemic clamping (plasma glucose approximately 15 mmol/l), while insulin secretion was suppressed by somatostatin [Study 1]. Nerve conduction velocity, as determined in the proximal part of the median nerve, fell by 2.8 +/- 3.0 m/s (2p-value: 0.033). However, during euglycaemic clamping (plasma glucose approximately 5 mmol/l) in five non-diabetic men (19-38 years of age) infused solely with somatostatin [Study 2], a comparable decrement in nerve conduction velocity was found (1.7 +/- 1.3 m/s, 2p-value: 0.043). In both studies relative hypoinsulinaemia was present. Serum-sodium decreased significantly (143 +/- 1 mmol/l vs 137 +/- 1 mmol/l [Study 1] and 143 +/- 1 mmol/l vs 142 +/- 2 mmol/l [Study 2]), while serum-potassium increased. In conclusion, the slight but significant reduction in nerve conduction velocity observed in both studies appears to be correlated to electrolyte changes. However, an effect of hypersomatostatinaemia or the hormonal changes associated with this cannot be excluded, while short-term hyperglycaemia per se seems to be without effect on nerve conduction velocity.
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Glucemia/metabolismo , Hiperglucemia/fisiopatología , Insulina/metabolismo , Neuronas Motoras/fisiología , Conducción Nerviosa/fisiología , Neuronas Aferentes/fisiología , Somatostatina/farmacología , Adulto , Técnica de Clampeo de la Glucosa , Hormona del Crecimiento/sangre , Humanos , Insulina/sangre , Secreción de Insulina , Masculino , Persona de Mediana Edad , Neuronas Motoras/efectos de los fármacos , Conducción Nerviosa/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Concentración Osmolar , Valores de Referencia , Umbral Sensorial/efectos de los fármacos , Sodio/farmacologíaRESUMEN
Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GH-deficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 micrograms/kg.h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH.
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Glucemia/metabolismo , Hormona del Crecimiento/deficiencia , Hormona del Crecimiento/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Insulina/sangre , Adulto , Péptido C/sangre , Interacciones Farmacológicas , Ingestión de Alimentos , Metabolismo Energético/efectos de los fármacos , Femenino , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Hormona del Crecimiento/farmacología , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
The present study was designed to examine the effect of pulsatile versus continuous insulin delivery on glucose and lipid metabolism in insulin-resistant subjects. Six obese women (body mass index, 40.0 +/- 2.8 kg/m2) underwent a euglycemic glucose clamp (plasma glucose, 90 mg/dL) twice. In random order, insulin was infused intravenously for 375 minutes either at a constant rate (0.4 mU/kg/min) or in a pulsatile manner (2.4 mU/kg/min for 2 minutes followed by an off interval of 10 minutes). Endogenous insulin release was suppressed by infusion of somatostatin (250 micrograms/h). Mean circulating insulin concentrations were similar during the two protocols (pulsatile v continuous infusion, 60 +/- 10 v 56 +/- 9 mU/L), but pulsatile infusion was accompanied by oscillations with an amplitude of 120 mU/L. After 6 hours of pulsatile versus continuous insulin, isotopically determined total glucose disposal (3-3H-glucose) and hepatic glucose production (HGP) were comparable (pulsatile v continuous, 2.80 +/- 0.56 v 2.82 +/- 0.51 and 0.37 +/- 0.14 v 0.32 +/- 0.17 mg/kg/min). However, the rate of glucose oxidation (indirect calorimetry) was augmented (P < .05), whereas lipid oxidation tended to be diminished (.10 > P > .05) following pulsatile infusion. In addition, blood glycerol was more suppressed with pulsatile (31 +/- 9 nmol/L) than with continuous infusion (36 +/- 10 nmol/L, P < .05), whereas blood lactate, alanine, and 3-hydroxybutyrate were similar in the two infusion protocols.(ABSTRACT TRUNCATED AT 250 WORDS)
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Glucosa/metabolismo , Insulina/administración & dosificación , Metabolismo de los Lípidos , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Adulto , Glucemia/análisis , Ácidos Grasos no Esterificados/metabolismo , Femenino , Técnica de Clampeo de la Glucosa , Glucógeno Sintasa/metabolismo , Humanos , Infusiones Intravenosas , Insulina/sangre , Insulina/farmacología , Persona de Mediana Edad , Flujo Pulsátil , Somatostatina/farmacología , Factores de Tiempo , Triglicéridos/sangreRESUMEN
Many reports have suggested that hyperandrogenaemic patients with the polycystic ovary syndrome (PCOS) may be insulin resistant. However, there have also been suggestions that their insulin resistance may relate to obesity and android fat distribution. To assess whether PCOS induces metabolic disturbances independently of obesity, we studied seven lean patients with PCOS (age, 27.1 +/- 2.0 yr; body mass index, 22.2 +/- 0.78 kg/m2; waist/hip ratio, 0.79 +/- 0.02; fat-free mass, 46.38 +/- 1.13 kg) and seven normal women (age, 25.7 +/- 1.4 yr; body mass index, 21.3 +/- 0.69 kg/m2; waist/hip ratio, 0.74 +/- 0.02; fat-free mass, 50.1 +/- 1.51 kg) for 3 h in the basal period and 2 h during a hyperinsulinemic (0.4 mU/kg.min) euglycemic clamp. In the basal state, comparable metabolic indices were recorded: serum insulin, 35.9 +/- 7.7 (PCOS) vs. 37.3 +/- 2.87 pmol/L (controls); plasma C-peptide, 364.1 +/- 66.2 vs. 397.2 +/- 66.2 pmol/L; plasma glucose, 4.95 +/- 0.09 vs. 4.77 +/- 0.09 mmol/L; forearm arterio-venous difference in glucose, 0.17 +/- 0.04 vs. 0.15 +/- 0.07 mmol/L; isotopically determined endogenous glucose production, 1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min; and serum nonesterified fatty acids, 545 +/- 40 vs. 617 +/- 54 mumol/L (all P > 0.05). During the clamp, all recordings were again similar: serum insulin, 282.7 +/- 21.5 vs. 270.5 +/- 13.6 pmol/L; plasma C-peptide, 331.0 +/- 33.1 vs. 364.1 +/- 66.2 pmol/L; plasma glucose, 4.99 +/- 0.07 vs. 4.99 +/- 0.05 mmol/L; glucose arterio-venous difference, 1.01 +/- 0.18 vs. 0.85 +/- 0.12 mmol/L; endogenous glucose production, -0.9 +/- 0.1 vs. -0.5 +/- 0.2 mg/kg.min; amount of exogenous glucose necessary to maintain euglycemia, 4.0 +/- 0.4 vs. 3.8 +/- 0.5 mg/kg.min; and nonesterified fatty acids, 205 +/- 7 vs. 246 +/- 18 mumol/L (all P > 0.05). By showing normal basal and insulin-stimulated substrate metabolism in lean hyperandrogenemic PCOS patients, these data suggest that insulin resistance may be an epiphenomenon, rather than a primary feature of PCOS.
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Metabolismo Energético , Insulina/farmacología , Síndrome del Ovario Poliquístico/metabolismo , Adulto , Peso Corporal , Metabolismo Energético/efectos de los fármacos , Femenino , Gluconeogénesis , Glucosa/metabolismo , Humanos , Insulina/sangre , Resistencia a la Insulina , Metabolismo de los LípidosRESUMEN
To elucidate the effects of insulin-like growth factor I (IGF-I) on fuel oxidation and insulin sensitivity, eight healthy subjects were treated with saline and recombinant human (IGF-I (10 micrograms/kg.h) during 5 d in a crossover, randomized fashion, while receiving an isocaloric diet (30 kcal/kg.d) throughout the study period. On the third and fourth treatment days, respectively, an L-arginine stimulation test and an intravenous glucose tolerance test were performed. A euglycemic, hyperinsulinemic clamp combined with indirect calorimetry and a glucose tracer infusion were performed on the fifth treatment day. IGF-I treatment led to reduced fasting and stimulated (glucose and/or L-arginine) insulin and growth hormone secretion. Basal and stimulated glucagon secretion remained unchanged. Intravenous glucose tolerance was unaltered despite reduced insulin secretion. Resting energy expenditure and lipid oxidation were both elevated, while protein oxidation was reduced, and glucose turnover rates were unaltered on the fifth treatment day with IGF-I as compared to the control period. Enhanced lipolysis was reflected by elevated circulating free fatty acids. Moreover, insulin-stimulated oxidative and nonoxidative glucose disposal (i.e., insulin sensitivity) were enhanced during IGF-I treatment. Thus, IGF-I treatment leads to marked changes in lipid and protein oxidation, whereas, at the dose used, carbohydrate metabolism remains unaltered in the face of reduced insulin levels and enhanced insulin sensitivity.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Insulina/farmacología , Metabolismo de los Lípidos , Proteínas/metabolismo , Adulto , Arginina/farmacología , Calorimetría , Ácidos Grasos no Esterificados/sangre , Femenino , Glucagón/sangre , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Hormona del Crecimiento/sangre , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/efectos adversos , Masculino , Oxidación-Reducción/efectos de los fármacos , Distribución AleatoriaRESUMEN
Patients with microvascular angina (syndrome X) may be insulin resistant. We designed a study to establish whether this is the case. 11 patients with microvascular angina were compared with 9 matched subjects with noncardiac chest pain. Patients and controls were evaluated by coronary sinus catheterisation, and by isotopic measurement of glucose turnover, indirect calorimetry, and forearm technique during a 3 h baseline period after overnight fast and during a 2 h hyperinsulinaemic euglycaemic clamp. Pace-induced increase in coronary sinus blood flow was less in patients than in controls, whereas forearm blood flow did not differ between groups. Baseline measures of glucose metabolism were normal. During the clamp, glucose production and lipolysis were equally suppressed in both groups. Mean (SE) total insulin-induced glucose uptake was significantly impaired in patients compared with controls (3.9 [0.7] vs 6.4 [0.7] mg/kg per min; p < 0.01), and insulin-stimulated glucose uptake in the forearm was significantly reduced in patients (0.88 [0.10] vs 1.6 [0.30] mmol/L; p < 0.001). Reduced oxidative and nonoxidative metabolism accounted for the defect in overall glucose uptake in patients. No correlation between changes in coronary sinus blood flow and total body glucose uptake was seen. We found that microvascular angina was associated with substantial insulin resistance. Whether this relation is causal or coincidental is as yet unsettled.
Asunto(s)
Angina de Pecho/fisiopatología , Resistencia a la Insulina/fisiología , Alanina/sangre , Angina de Pecho/sangre , Angina de Pecho/metabolismo , Metabolismo Basal , Glucemia/metabolismo , Péptido C/sangre , Dolor en el Pecho/sangre , Dolor en el Pecho/metabolismo , Dolor en el Pecho/fisiopatología , Circulación Coronaria/fisiología , Metabolismo Energético , Ácidos Grasos no Esterificados/sangre , Femenino , Antebrazo/irrigación sanguínea , Glucagón/sangre , Gluconeogénesis , Técnica de Clampeo de la Glucosa , Hormona del Crecimiento/sangre , Humanos , Insulina/sangre , Lactatos/sangre , Masculino , Microcirculación , Persona de Mediana Edad , Flujo Sanguíneo Regional/fisiología , SíndromeRESUMEN
Underestimation of glucose turnover rates has been a problem in clamp studies using primed-constant [3-3H]-glucose infusion technique. Due to slow mixing in interstitial compartments concealed specific activity gradients may arise between plasma and interstitial compartments during intravenous unlabelled glucose infusion. Such specific activity gradients, however, can be prevented if plasma specific activity is maintained constant. Two euglycaemic clamp studies (insulin infusion 40 mU m-2 min-1) were performed in six lean normal subjects. Using conventional unlabelled glucose infusates plasma specific activity declined by 74%, tracer determined glucose appearance was smaller than actual glucose infusion rates (317 +/- 11 vs 366 +/- 15 mg m-2 min-1, p < 0.001), and erroneous negative values were calculated for glucose production (- 49 +/- 7 mg m-2 min-1). Average underestimation during the first 2 h correlated with glucose infusion rates (r = 0.88, p < 0.02). In contrast, when plasma specific activity was maintained constant, using appropriately labelled glucose infusates, tracer determined glucose appearance and glucose infusion rates were similar (385 +/- 16 vs 385 +/- 17 mg m-2 min-1), and negative errors for glucose production were avoided. In conclusion, using unlabelled glucose infusates, as in previous studies, suppression of glucose production is overestimated and stimulation of glucose utilization is underestimated. As errors were greater with larger glucose infusions, the mistakes may have been greatest in insulin sensitive control subjects, and smaller in insulin resistant subjects. Therefore, re-evaluation of hepatic insulin sensitivity seems appropriate in diabetes, obesity, and other insulin resistant states.
Asunto(s)
Glucemia/metabolismo , Técnica de Clampeo de la Glucosa , Adulto , Glucemia/biosíntesis , Estudios de Evaluación como Asunto , Femenino , Humanos , Infusiones Intravenosas , Insulina/administración & dosificación , Masculino , Persona de Mediana Edad , Trazadores Radiactivos , TritioRESUMEN
The effect of glucagon infusion on hepatic glucose production during euglycaemia was evaluated in seven Type 1 (insulin-dependent) diabetic patients and in ten control subjects. In the diabetic subjects normoglycaemia was maintained during the night preceding the study by a variable intravenous insulin and glucose infusion. During the study endogenous insulin secretion was suppressed by somatostatin (450 micrograms/h) and replaced by insulin infusion (0.15 mU.kg-1.min-1). 3H-glucose was infused for isotopic determination of glucose turnover. Plasma glucose was clamped at 5 mmol/l for 2 h 30 min and glucagon (1.5 ng.kg-1.min-1) was then infused for the following 3 h. Hepatic glucose production and glucose utilisation were measured during the first, second and third hour of the glucagon infusion. Basal hepatic glucose production (just prior to glucagon infusion) was similar in diabetic (1.2 +/- 0.3 mg.kg-1.min-1) and control (1.6 +/- 0.1 mg.kg-1.min-1) subjects. In diabetic patients hepatic glucose production rose slowly to 2.1 +/- 0.5 mg.kg-1.min-1 during the first hours of glucagon infusion and stabilized at this level (2.4 +/- 0.5 mg.kg-1.min-1) in the third hour. In control subjects hepatic glucose production increased sharply to higher levels than in the diabetic subjects (3.4 +/- 0.3 mg.kg-1.min-1) during the first and second hour of glucagon infusion (p less than 0.05) and then gradually fell (2.9 +/- 0.4 mg.kg-1.min-1) during the third hour. In conclusion, when stimulated with glucagon at a physiologic plasma concentration diabetic patients had 1) an overall reduced hepatic glucose production response and 2) an abnormal sluggish response pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Glucagón/farmacología , Glucosa/metabolismo , Hígado/metabolismo , Ácido 3-Hidroxibutírico , Adulto , Alanina/sangre , Glucemia/metabolismo , Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Ácidos Grasos no Esterificados/sangre , Femenino , Glucagón/administración & dosificación , Glucagón/sangre , Glicerol/sangre , Hormona del Crecimiento/sangre , Hormona del Crecimiento/farmacología , Humanos , Hidroxibutiratos/sangre , Infusiones Intravenosas , Insulina/sangre , Insulina/metabolismo , Insulina/farmacología , Secreción de Insulina , Cinética , Lactatos/sangre , Hígado/efectos de los fármacos , Masculino , Valores de Referencia , Factores de TiempoRESUMEN
Tagliareni, Sherman, Waters, and Mengel report on an important associate degree program effort to incorporate nursing home care and geriatrics into the education program. Educators and practitioners found out that they had a lot to learn and a lot to share.