RESUMEN
Glucose production and utilization and activities of key enzymes involved in liver and muscle glucose metabolism were studied in post-absorptive streptozotocin-diabetic rats after 12 h of severe hyperglycaemia (17.5 +/- 0.5 mmol/l) and insulinopenia (5 +/- 1 microU/ml). Basal glucose production was increased: 36.6 +/- 3.0 mg.kg.min-1, vs 24.4 +/- 2.5 in controls (p < 0.05); liver glycogen concentration was decreased by 40% (p < 0.05); liver phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities were increased by 375 and 156%, respectively (p < 0.001 and < 0.01). During a euglycaemic clamp at a plasma insulin level of 200 microU/ml, glucose production was totally suppressed in controls, but persisted at 20% of basal in diabetic rats. In these rats, glucose production was suppressed at a plasma insulin level of 2500 microU/ml. Basal whole body glucose utilization rate, 2-deoxy-1-[3H]-D-glucose ([3H]-2DG) uptake by muscles and muscle glycogen concentrations were similar in both groups, as well as total and active forms of pyruvate dehydrogenase and glycogen synthase activities. During the euglycaemic clamp, the total body glucose utilization rates and [3H]-2DG uptake by muscles were similar in control and diabetic rats at a plasma insulin level of 200 microU/ml, but lower in diabetic rats at a plasma insulin level of 2500 microU/ml. We conclude 1) in recent-onset severely insulinopenic rats, an excessive glucose production via gluconeogenesis prevailed, mainly accounting for the concomitant hyperglycaemia. This excess glucose output cannot be attributed to liver insulin resistance: the gluconeogenic pathway is physiologically less sensitive than glycogenolysis to the inhibition by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Hiperglucemia/fisiopatología , Resistencia a la Insulina , Hígado/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Glucemia/metabolismo , Desoxiglucosa/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Ácidos Grasos no Esterificados/sangre , Glucagón/sangre , Técnica de Clampeo de la Glucosa , Glucógeno/metabolismo , Glucólisis , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Insulina/sangre , Glucógeno Hepático/metabolismo , Masculino , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Especificidad de Órganos , Ratas , Ratas Wistar , Valores de ReferenciaRESUMEN
Glucose transport and phosphorylation are decreased in muscle and adipose tissue in diabetes mellitus. The glucose transporter GLUT-4 and hexokinase II (HK II) are the main isoforms of proteins involved in glucose transport and phosphorylation in insulin-sensitive tissues, adipose tissue, skeletal muscle, and heart. The molecular mechanisms responsible for the decrease of glucose transport and phosphorylation have been studied during the first 3 days after streptozotocin (STZ) administration in adult male Wistar rats. GLUT-4 mRNA and protein and HK II mRNA and enzyme activity were measured. After the injection of STZ (30 h), GLUT-4 and HK II mRNAs were decreased to 10 +/- 1 and 20 +/- 3% that found in nondiabetic rats, respectively; they remained at these low levels for 72 h. Normalization of the blood glucose level by phlorizin infusion did not restore GLUT-4 and HK II mRNA concentrations to normal. In contrast, normalization of the blood glucose level by physiological infusion of insulin resulted in a total normalization of GLUT-4 and HK II mRNA concentrations. When insulin therapy was stopped, GLUT-4 and HK II mRNA and protein concentrations fell in 6 h to 40 and 20% of control levels, respectively. Minimal changes of GLUT-4 and HK II mRNA, and of HK II activity, were observed in skeletal muscle and heart of diabetic rats. We conclude that GLUT-4 and HK II mRNA are coordinately expressed in white adipose tissue. They are rapidly affected by an acute decrease of the plasma insulin concentrations but are not modified by hyperglycemia. In contrast, skeletal muscle and heart GLUT-4 and HK II mRNA are not greatly affected by short-term diabetes.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Hexoquinasa/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares , Tejido Adiposo/metabolismo , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/sangre , Transportador de Glucosa de Tipo 4 , Hexoquinasa/genética , Insulina/sangre , Insulina/farmacología , Masculino , Proteínas de Transporte de Monosacáridos/genética , Músculos/metabolismo , Miocardio/metabolismo , Florizina/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
We have studied the time course and relative effects of hypoinsulinaemia and hyperglycaemia on concentrations of uncoupling protein (UCP) and glucose transporter (GLUT4) and their mRNAs in brown adipose tissue (BAT) during the early phase of diabetes induced by streptozotocin. Two days after intravenous injection of streptozotocin, plasma insulin concentration was at its lowest and glycaemia was higher than 22 mmol/l. After 3 days, a 60% decrease in BAT UCP mRNA concentration and a 36% decrease in UCP was observed. Concomitantly, there was an 80% decrease in GLUT4 mRNA and a 44% decrease in GLUT4 levels. When hyperglycaemia was prevented by infusing phlorizin into diabetic rats, BAT UCP mRNA and protein levels were further decreased (respectively 90% and 60% lower than in control rats). In contrast, the marked decreases in GLUT4 mRNA and protein concentrations in BAT were similar in hyperglycaemic and normoglycaemic diabetic rats. Infusion of physiological amounts of insulin restored normoglycaemia in diabetic rats, and BAT UCP and GLUT4 mRNA and protein concentrations were maintained at the level of control rats. When insulin infusion was stopped, a 75% decrease in BAT UCP mRNA level and a 75% decrease in GLUT4 mRNA level were observed after 24 h, but UCP and GLUT4 concentrations did not decrease. This study shows that insulin plays an important role in the regulation of UCP and GLUT4 mRNA and protein concentrations in BAT. Hyperglycaemia partially prevents the rapid decrease in concentration of UCP and its mRNA observed in insulinopenic diabetes whereas it did not affect the decrease in GLUT4 mRNA and protein concentration. It is suggested that UCP is produced by a glucose-dependent gene.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Glucemia/metabolismo , Proteínas Portadoras/genética , Diabetes Mellitus Experimental/metabolismo , Insulina/sangre , Proteínas de la Membrana/genética , Proteínas de Transporte de Monosacáridos/genética , Proteínas Musculares , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Expresión Génica , Transportador de Glucosa de Tipo 4 , Insulina/uso terapéutico , Canales Iónicos , Masculino , Proteínas Mitocondriales , Florizina/uso terapéutico , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Proteína Desacopladora 1RESUMEN
GLUT-2, glucokinase (GK) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was studied in the liver of chronically catheterized diabetic rats during the 3 days after an intravenous injection of 65 mg of streptozotocin (STZ)/kg. At 6 h after the STZ injection, portal plasma insulin levels were 270 +/- 32 mu-units/ml and blood glucose was 1.4 +/- 0.4 mmol/l, owing to pancreatic beta-cell destruction. GLUT-2 and PEPCK mRNA concentrations were rapidly and dramatically decreased (> 90%), whereas GK mRNA was increased. After 30 h, plasma insulin concentrations were lower than 5 mu-units/ml and blood glucose was > 20 mmol/l. GLUT-2 and PEPCK mRNA concentrations increased 2-fold and GK mRNA disappeared progressively. In order to assess the relative roles of hyperglycaemia and insulinopenia, blood glucose was clamped at 6.4 +/- 0.5 mmol/l from 18 to 72 h after STZ injection by phlorizin infusion (0.5-2 g/day per kg) or at 6.6 +/- 0.3 mmol/l from 18 to 48 h after STZ injection by insulin infusion (0.25 unit/min per kg). GLUT-2 mRNA concentrations were 50% lower in phlorizin-infused than in untreated diabetic rats. The low levels of GK mRNA and the high levels of PEPCK mRNA were unaffected by normalization of hyperglycaemia in phlorizin-infused diabetic rats. In insulin-infused rats (portal plasma insulin levels of 40 mu-units/ml) GLUT-2 mRNA levels were 25% of those in untreated diabetic rats, and they increased rapidly 6 h after insulin infusion was stopped. Liver GLUT-2 protein concentration showed similar changes in response to STZ injection and to phlorizin or insulin treatment, but after a delay of several hours. From this work we conclude that GLUT-2 gene expression is dramatically and rapidly (< 6 h) decreased by portal hyperinsulinaemia and increased by hyperglycaemia.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Hiperglucemia/metabolismo , Insulina/sangre , Hígado/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Animales , Glucemia/metabolismo , Expresión Génica , Glucagón/sangre , Glucoquinasa/genética , Masculino , Proteínas de Transporte de Monosacáridos/genética , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , ARN Mensajero/genética , Ratas , Ratas WistarRESUMEN
The effect of insulin on the properties of liver carnitine palmitoyltransferase I (CPT I) was assessed in conscious starved rats with the euglycemic hyperinsulinemic clamp. A 24-hour clamp was necessary to fully reverse the effect of starvation on liver malonyl-CoA concentration, CPT I maximal activity, and apparent km and Ki for malonyl-CoA. Since glucagon was not decreased during the clamp, insulin is the major factor involved in the regulation of CPT I.
Asunto(s)
Carnitina O-Palmitoiltransferasa/metabolismo , Técnica de Clampeo de la Glucosa , Insulina/farmacología , Hígado/enzimología , Inanición/metabolismo , Animales , Femenino , Glucagón/sangre , Insulina/sangre , Cinética , Malonil Coenzima A/metabolismo , Concentración Osmolar , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
The mechanism responsible for the insulin resistance described in vivo in brown adipose tissue (BAT) of lactating rats was investigated. The effect of insulin on glucose metabolism was studied on isolated brown adipocytes of non-lactating and lactating rats. Insulin stimulation of total glucose metabolism is 50% less in brown adipocytes from lactating than from non-lactating rats. This reflects a decreased effect of insulin on glucose oxidation and lipogenesis. However, the effect of noradrenaline (8 microM) on glucose metabolism was preserved in brown adipocytes from lactating rats as compared with non-lactating rats. The number of insulin receptors is similar in BAT of lactating and non-lactating rats. The insulin-receptor tyrosine kinase activity is not altered during lactation, for receptor autophosphorylation as well as tyrosine kinase activity towards the synthetic peptide poly(Glu4-Tyr1). The defect in the action of insulin is thus localized at a post-receptor level. The insulin stimulation of pyruvate dehydrogenase activity during euglycaemic/hyperinsulinaemic clamps is 2-fold lower in BAT from lactating than from non-lactating rats. However, the percentage of active form of pyruvate dehydrogenase is similar in non-lactating and lactating rats (8.6% versus 8.9% in the basal state, and 37.0% versus 32.3% during the clamp). A decrease in the amount of pyruvate dehydrogenase is likely to be involved in the insulin resistance described in BAT during lactation.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Glucosa/metabolismo , Resistencia a la Insulina , Insulina/farmacología , Receptor de Insulina/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Animales , Animales Lactantes , Células Cultivadas , Femenino , Técnica de Clampeo de la Glucosa , Cinética , Lactancia , Fosforilación , Embarazo , Proteínas Tirosina Quinasas/metabolismo , Complejo Piruvato Deshidrogenasa/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Euglycemic-hyperinsulinemic clamps coupled with an injection of [2-3H]deoxyglucose were performed in rats 1 or 6 wk after lesion of the ventromedial hypothalamus (VMH) and their age-matched controls. In the basal state, glucose utilization was not different in controls and VMH rats in all the tissues studied except in white adipose tissue where it was greatly increased after the lesion. When insulinemia was clamped at 850 microU/ml, glucose utilization was less important in glycolytic and normal in oxidative muscles in animals 1 wk after the lesion (VMH1) compared with controls. In animals 6 wk after the lesion (VMH6), all the muscles utilized less glucose than those of controls. In white adipose tissue, glucose utilization was increased twice more in VMH1 and returned to normal in VMH6. These data demonstrate a progressive development of insulin resistance in muscles. Simultaneously, there is a transient insulin hypersensitivity in white adipose tissue. This, together with a hypersecretion of insulin, could contribute to the development of body fat mass by redirecting glucose towards adipose tissue.
Asunto(s)
Insulina/metabolismo , Obesidad/fisiopatología , Núcleo Hipotalámico Ventromedial/fisiología , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal , Femenino , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Hiperinsulinismo/metabolismo , Insulina/sangre , Secreción de Insulina , Músculos/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Ratas , Ratas Endogámicas , Valores de ReferenciaRESUMEN
The effects of maternal hypoglycemia and/or hyperketonemia on glucose utilization by individual fetal rat tissues have been studied in vivo. To decrease blood glucose and to raise fetal blood ketone body concentrations, 19-day pregnant rats were submitted to 48 or 96 h of starvation. To differentiate between the effects of decreased blood glucose and increased ketone body concentrations, fed pregnant rats were infused for 2 h with DL-beta-hydroxybutyrate. After 96 h of maternal starvation, fetal 2-deoxy-D-glucose (2DG) uptake decreased from 13.6 +/- 0.5 to 8.6 +/- 1.15 micrograms.min-1.g-1. This was mainly due to a decrease in 2DG uptake by fetal hindlimb muscles and heart. By contrast, 2DG uptake in fetal liver and brain was not affected by maternal starvation. Acute hyperketonemia in fed pregnant rats induced a 23% decrease in 2DG uptake by the whole fetus mainly as the result of a lowered 2DG uptake in fetal hindlimb muscles. These data suggest that fetal 2DG uptake does not simply depend on lowered blood glucose level during maternal starvation but that other hormonal, cardiovascular, or metabolic adaptations are implicated. In the rat, most of the fetal tissues including brain are protected against maternal hypoglycemia.
Asunto(s)
Desoxiazúcares/metabolismo , Desoxiglucosa/metabolismo , Feto/metabolismo , Hidroxibutiratos/farmacología , Cuerpos Cetónicos/sangre , Intercambio Materno-Fetal , Inanición , Ácido 3-Hidroxibutírico , Animales , Glucemia/metabolismo , Ayuno , Femenino , Glucólisis , Insulina/sangre , Embarazo , Ratas , Ratas Endogámicas , Valores de ReferenciaRESUMEN
1. Concentrations of amino acids (AA) in blood obtained from arterial and portal permanent catheters were measured together with the portal hepatic blood flow-rate during a post-prandial period of 8 h, in nine conscious pigs (initial mean body-weight 49.3 (SEM 1.8) kg) receiving experimental meals (500, 600 or 1000 g) at 3-4 d intervals from 6-8 to 20 d after the surgical implantation of the catheters and electromagnetic flow probe. The semi-synthetic starch-based diets contained variable amounts of fish meal giving crude protein (nitrogen x 6.25; CP) concentrations (g/kg) of 80 (seven meals), 120 (seven meals), 160 (five meals) and 240 (three meals). 2. During the post-prandial period, variations in the individual blood AA concentrations were parallel to those of total amino-N (Rérat et al. 1988) to a greater or lesser extent according to the AA considered. Portal concentrations, which always exceeded arterial ones (except for glutamic acid and glutamine), increased quickly and, after a peak, returned slowly to reach initial values (small intake) or above (large intake) after 8 h. 3. Relations between amounts of each AA appearing during 8 h after the meal and amounts ingested were characterized by a highly significant linear regression (with the exceptions of glutamic acid and cystine). There were also close and significant relations between amounts of AA absorbed during the first 2 and 4 h after the meal and the amounts ingested. 4. For a mean intake of 90 g CP, aromatic AA showed the highest hourly absorption coefficients (about 0.10/h), and sulphur-AA (0.07/h), lysine (0.07/h) and arginine (0.056/h) the lowest ones. Alanine was synthesized (amounts absorbed within 8 h exceeding those ingested) at the expense of glutamic acid (absorption coefficient 0.01/h). 5. For a given period of time, the AA absorption coefficients decreased with increasing intake, but not in the same proportions for all AA, resulting in an enrichment (lysine, arginine, serine, proline) or depletion (branched-chain AA, histidine) of the absorbed mixture. 6. Some substances of the urea cycle were synthesized in rather large amounts in the gut wall (for a mean level of intake of 90 g CP: citrulline 2.41 g/8 h, ornithine 1.09 g/8 h). Blood glutamine was taken up by the gut wall in larger amounts (4.28 g/8 h).
Asunto(s)
Aminoácidos/sangre , Proteínas en la Dieta/administración & dosificación , Productos Pesqueros , Absorción Intestinal , Aminoácidos Esenciales/sangre , Animales , Proteínas en la Dieta/metabolismo , Hidrólisis , Cinética , Masculino , PorcinosRESUMEN
Glucose utilization by the placenta and individual fetal tissues was studied in vivo in conscious pregnant rabbits at 29 days of gestation. In the fed state, the rate of glucose utilization was similar in the placenta and the gravid uterus, suggesting that the rate of fetal glucose utilization was approximately 40 nmol/min/g. A 96-h maternal fast induced a significant decrease in glucose utilization by the myoendometrium and in the glucose utilization index by fetal liver and brown adipose tissue. No modification was observed in other fetal tissues. These results indicate that glucose utilization by the placenta and the whole fetus from 96-h fasted rabbits does not decrease despite profound changes in endocrine and metabolic maternal parameters.
Asunto(s)
Ayuno , Feto/metabolismo , Glucosa/metabolismo , Placenta/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Glucemia/metabolismo , Ácidos Grasos/sangre , Femenino , Insulina/sangre , Hígado/metabolismo , Embarazo , Conejos , Factores de TiempoRESUMEN
In utero, glucose utilization by fetal muscles (heart and hindlimb) displays important interspecies differences. In the fed state, it is 5-fold higher in rat than in rabbit fetal muscles. Maternal fasting induces a decrease in glucose utilization in fetal muscles of the rat but not of the rabbit.
Asunto(s)
Ayuno , Feto/metabolismo , Glucosa/metabolismo , Músculos/metabolismo , Animales , Glucemia/metabolismo , Femenino , Músculos/embriología , Embarazo , Conejos , Ratas , Ratas Endogámicas , Especificidad de la EspecieRESUMEN
In vivo measurement of glucose utilization by individual tissues of 19-day rat fetuses have been performed using radioactive 2-deoxy-D-glucose technique. In the basal state, glucose metabolic index was 13.6 +/- 0.5 ng.min-1.mg-1 for the whole fetus, 21 +/- 1 in the hindlimb muscles, 13 +/- 2 in the liver, and 16 +/- 2 in the brain, whereas the fetal heart had the highest value: 62 +/- 5 ng.min-1.mg-1. To raise the fetal glycemia, the basal maternal blood glucose concentration of 0.78 +/- 0.02 g/l was elevated to 1.04 +/- 0.02 g/l by mean of hyperglycemic clamps. The fetal hyperglycemia increased glucose metabolic index by 30-100% over basal values in all the tissues tested except in the brain. To raise fetal insulinemia, maternal euglycemic clamp with supraphysiological insulin concentrations were performed, then a fraction (1%) of exogenous insulin crossed the placenta. Fetal plasma insulin concentrations were thus elevated to 180 +/- 32 and 255 +/- 23 microU/ml. The fetal heart increased significantly its glucose metabolic index in response to the lower insulin level. Glucose metabolic index in hindlimb muscles and liver was increased by 50-100% for the highest insulin level, whereas the brain was unaffected by exogenous insulin. We conclude that glucose metabolic index is stimulated by physiological hyperglycemia in individual fetal tissues and that fetal tissues (heart, liver, and muscle) are sensitive to exogenous insulin.
Asunto(s)
Glucemia/metabolismo , Feto/metabolismo , Hiperglucemia/metabolismo , Insulina/sangre , Animales , Femenino , Tasa de Depuración Metabólica , Embarazo , Ratas , Distribución TisularRESUMEN
Placental glucose metabolism and its regulation have been investigated in vivo in the rat using the radioactive 2-deoxyglucose technique. In the basal state, placental glucose utilization rates were similar on days 19 and 21 of gestation: 139 +/- 5 and 155 +/- 22 nmol/min/g at maternal blood glucose concentrations of 4.3 +/- 0.1 and 4.2 +/- 0.1 mmol/1. During hyperglycemic clamps, maternal glycemia was raised to 5.5 mmol/liter, a value similar to that during a meal in the rat. In this condition, the rate of placental glucose utilization at 19 days of gestation was increased by 85%. This was due not only to hyperglycemia but also to glucose-induced hyperinsulinemia. Indeed during hyperinsulinemic euglycemic clamps, placental glucose utilization showed a dose-response relationship to insulin (400 and 5000 microU/ml). At 21 days of gestation, placental glucose utilization was not affected by hyperglycemia or by hyperinsulinemia suggesting that in term placenta, glucose metabolism is no longer regulated. When 19-day pregnant rats were fasted for 48 and 96 h, the resulting low blood glucose and plasma insulin concentrations and the high ketone body concentrations induced, respectively, a 40 and 47% reduction of placental glucose utilization. The decrease in placental glucose utilization probably was due to both maternal hypoglycemia and long term adaptation to hyperketonemia. Indeed, the acute hyperketonemia in fed rats did not alter glucose utilization rate in placenta at 19 days of gestation. These data suggest that glucose metabolism in the preterm rat placenta is modulated in vivo by the maternal metabolic environment, particularly by maternal blood glucose and insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glucemia/metabolismo , Glucosa/metabolismo , Insulina/sangre , Cuerpos Cetónicos/sangre , Placenta/metabolismo , Animales , Femenino , Sangre Fetal/metabolismo , Intercambio Materno-Fetal , Embarazo , Ratas , Ratas EndogámicasRESUMEN
The effects of fasting on glucose metabolism in the conscious resting rat were studied. Fasting decreased whole-body glucose utilization by 40%. The fast induced a decrease in glucose utilization in muscles which are constantly working even in the resting state, i.e. heart, diaphragm and postural muscles. No modification was observed in other tissues.
Asunto(s)
Ayuno , Glucosa/metabolismo , Tejido Adiposo/metabolismo , Animales , Encéfalo/metabolismo , Femenino , Músculos/metabolismo , Ratas , Ratas Endogámicas , Distribución TisularRESUMEN
This study was undertaken to determine the effects of pentobarbital anesthesia (50 mg/kg ip) on glucose kinetics and individual tissue glucose utilization in vivo, in chronically catheterized rats. Glucose turnover studies were carried out using [3-3H]glucose as tracer. A transient hyperglycemia and an increased glucose production were observed 3 min after induction of anesthesia. However, 40 min after induction of anesthesia, glycemia returned to the level observed in awake animals, whereas glucose turnover was decreased by 30% as compared with unanesthetized rats. These results are discussed with regard to the variations observed in plasma insulin, glucagon, and catecholamine levels. Glucose utilization by individual tissues was studied by the 2-[1-3H]deoxyglucose technique. A four- to fivefold decrease in glucose utilization was observed in postural muscles (soleus and adductor longus), while in other nonpostural muscles (epitrochlearis, tibialis anterior, extensor digitorum longus, and diaphragm) and other tissues (white and brown adipose tissues) anesthesia did not modify the rate of glucose utilization. A decrease in glucose utilization was also observed in the brain.
Asunto(s)
Glucosa/metabolismo , Pentobarbital/farmacología , Animales , Glucemia/metabolismo , Catecolaminas/sangre , Glucagón/sangre , Insulina/sangre , Hígado/metabolismo , Músculos/metabolismo , Ratas , Factores de TiempoRESUMEN
In 12-day lactating rats blood glucose and plasma insulin were decreased by, respectively, 20 and 35% when compared with nonlactating rats, despite a 25% increase of their glucose turnover rate. Then, by using the euglycemic hyperinsulinemic clamp technique, dose-response curves for the effects of insulin on glucose production and utilization in lactating and nonlactating rats were performed. Glucose production rate was totally suppressed at 250 microU/ml of insulin in lactating rats and for plasma insulin concentrations higher than 500 microU/ml in nonlactating rats. Plasma insulin level inducing half-maximal inhibition of glucose production was decreased by 60% during lactation. The maximal effect of insulin on glucose utilization rate and glucose metabolic clearance rate was, respectively, increased 1.5- and 2.4-fold during lactation and was obtained for plasma insulin concentrations lower in lactating than in nonlactating rats (250 vs. 500 microU/ml). Insulin concentrations inducing half-maximal stimulation of glucose utilization and glucose metabolic clearance were decreased by 50% during lactation. In conclusion, this study has shown that insulin sensitivity and responsiveness of liver and peripheral tissues are improved at peak lactation in the rat.
Asunto(s)
Insulina/farmacología , Lactancia/fisiología , Animales , Glucemia/metabolismo , Femenino , Glucosa/biosíntesis , Insulina/sangre , Tasa de Depuración Metabólica , Embarazo , Ratas , Ratas EndogámicasRESUMEN
In vivo studies have shown that insulin resistance in late pregnancy results from a decreased sensitivity of liver and peripheral tissues. In the present study, measurements of the rates of glucose utilization by skeletal muscles (soleus, extensor digitorum longus, epitrochlearis, and diaphragm), white adipose tissue, and brain of virgin and 19-day pregnant rats were performed in the basal condition and during a euglycemic, hyperinsulinemic (400 microU/ml) clamp to quantify the partition of glucose utilization and to identify the tissues other than liver responsible for insulin resistance. Fetal and placental glucose utilization rates were also measured in pregnant rats. The fetal glucose utilization rate (22 mg/min/kg) was very high and was not stimulated by physiologic maternal hyperinsulinemia. By contrast, the placental glucose utilization rate (29 mg/min/kg) was increased by 30% during hyperinsulinemia. The glucose utilization rate of the conceptus represented 23% of the maternal glucose utilization rate in the basal state. Glucose utilization rates in the basal condition were not statistically altered by pregnancy in brain, skeletal muscles, and white adipose tissue. During hyperinsulinemia (400 microU/ml), glucose utilization rates in extensor digitorum longus, epitrochlearis, and white adipose tissue were 30-70% lower in pregnant than in virgin rats. Insulin sensitivity of glucose metabolism in all the tissues tested other than brain was 50% lower in pregnant than in virgin rats. We conclude that skeletal muscles and, to a smaller extent, adipose tissue are involved in the insulin resistance of late pregnancy.
Asunto(s)
Glucosa/metabolismo , Insulina/metabolismo , Preñez , Tejido Adiposo/metabolismo , Animales , Encéfalo/metabolismo , Bovinos , Femenino , Feto/metabolismo , Cobayas , Caballos , Hiperinsulinismo/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Músculos/metabolismo , Placenta/metabolismo , Embarazo , Conejos , Ratas , Ratas Endogámicas , Ovinos , PorcinosRESUMEN
The postprandial release of immunoreactive insulin, glucagon, gastrin, somatostatin, pancreatic polypeptide (PP), and gastric inhibitory polypeptide (GIP) was studied in parallel with the absorption of sugars and amino acids in conscious pigs. Six pigs fitted with permanent catheters in the portal vein and arterial blood system as well as within an electromagnetic flow probe around the portal vein received successively at 3-day intervals, three meals of 800 g each containing 0, 14, or 28% protein (semisynthetic diets based on fish protein). Blood samples were collected and portal blood flow was recorded during a postprandial period of 8 h. For the same level of feed intake, an increase in the dietary protein concentration led to a higher alpha-amino nitrogen absorption and to a lower appearance of reducing sugars in the portal vein; in addition, the carbohydrate absorption efficiency (amounts absorbed as a percentage of amounts ingested) was reduced, showing the competition between the absorption of amino acids and glucose. The largest absorption occurred during the first 4 h after the meal, but neither the digestion of proteins nor that of carbohydrates were finished 8 h after the meal since portoarterial differences could still be observed. All test meals induced a rise of portal and peripheral concentrations of insulin, gastrin, somatostatin, and PP, and of the systemic level of GIP. Glucagon increased after the 28% protein meal only. The rise of plasma insulin paralleled that of blood glucose, and bore a significant positive relationship to the systemic GIP level in the early postprandial period. In terms of absolute amounts, portoarterial concentration gradients increased postprandially. Insulin release was significantly the highest after intake of the 14% protein diet. The gastrin response was significantly correlated to the amount of protein. Similarly the release of glucagon and somatostatin tended to increase with increasing dietary amount, but differences failed to reach significance (P less than 0.05), except for glucagon 2 h after the meal. There were very close relationships between the hourly amounts of alpha-amino nitrogen absorbed and gastrin and glucagon production, as between insulin and PP secretions. From the present results, the induction of physiological increments of plasma peptide concentration in 60-kg pigs would require infusion rates of about 50-250 micrograms/h for insulin, 1-4 micrograms/h for gastrin 17, 5-10 micrograms/h for glucagon and somatostatin, and 5-50 micrograms/h for PP.
Asunto(s)
Proteínas en la Dieta/farmacología , Aminoácidos/metabolismo , Animales , Carbohidratos de la Dieta/metabolismo , Carbohidratos de la Dieta/farmacología , Proteínas en la Dieta/metabolismo , Polipéptido Inhibidor Gástrico/metabolismo , Gastrinas/metabolismo , Glucagón/metabolismo , Insulina/metabolismo , Secreción de Insulina , Masculino , Polipéptido Pancreático/metabolismo , Péptidos/metabolismo , Somatostatina/metabolismo , Porcinos , Factores de TiempoRESUMEN
To further characterize the role of insulin in glucose metabolism during fasting and refeeding, euglycemic-hyperinsulinemic clamps were performed in control, 3 day-fasted, and 3 day-fasted then 3 day-refed rats. Glucose production and utilization were measured by using [3-3H]glucose. In control and refed rats, hepatic glucose production was totally suppressed at insulin concentration higher than 500 microU/ml; by contrast, during fasting, hepatic glucose production was not suppressed even at insulin concentration tenfold higher. Maximal increment of glucose utilization was lower in fasted than in control rats. Three days of refeeding restored almost entirely normal responses to insulin for glucose utilization. Blood glucose concentration was clamped at a different level in fasted and in control and refed rats; however, increment in glucose clearance in response to insulin was lower in fasted rats than in the two other groups. Thus fasting produces a state of insulin unresponsiveness both at the hepatic and peripheral levels, normal responsiveness being restored after 3 days of refeeding.
Asunto(s)
Ingestión de Alimentos , Ayuno , Insulina/farmacología , Animales , Glucemia/análisis , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Glucosa/biosíntesis , Glucosa/metabolismo , Hígado/metabolismo , Fisiología/métodos , Ratas , Ratas EndogámicasRESUMEN
The magnitude and composition of amino acid intestinal efflux was followed over a light-dark cycle in rats ingesting the same daily amount of protein administered either in a mixed diet (12% casein) or as a separate meal (70% casein concentrate) fed 2 hours after the onset of the light period with a protein-free diet available at all times. Intestinal efflux was determined by an instant porto-aortic difference measured on pooled samples from six rats at time-points spaced every 3 hours over a light-dark cycle. During protein digestion (dark for the mixed-fed rats) and (light for the separately-fed ones), essential amino acid composition of intestinal output fell into line with that of the protein ingested (casein) while non-essential amino acid composition did not. The discrepancy bore on alanine and glycine which were released in excess and on aspartic and glutamic acids, glutamine and serine which were released in deficit from their content in casein. From the follow-up of individual amino acid release and uptake, we concluded that intestinal efflux reflects the composition of the dietary protein only with respect to the amino acids, mostly essential, that are not metabolized by the intestinal wall.