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Biomedical subjects

J Girard

Publications and source records attributed to J Girard.

At least 127 records · Page 7Linked to original sources
PubMed1994

Development and regulation of glucose transporter and hexokinase expression in rat.

The ontogenesis of the glucose transporters GLUT-1, GLUT-2, and GLUT-4 and the hexokinases HK-I, HK-II, and HK-IV (glucokinase) was studied in rat tissues. In brown adipose tissue, high levels of GLUT-4 and HK-II were observed during fetal life; both decreased at birth and then increased throughout development. At birth, cold exposure increased GLUT-4 and HK-II expression in brown adipose tissue, whereas fasting decreased it. GLUT-1 and HK-I were present in fetal muscle, but GLUT-4 and HK-II were absent. The coordinate appearance of GLUT-4 and HK-II in skeletal muscle was concomitant with the acquisition of insulin sensitivity after weaning. In the heart, the glucose transporter isoform switched from GLUT-1 to GLUT-4 during the suckling period. The coordinate expression of GLUT-4 and HK-II in heart was observed after weaning. GLUT-2, detected in fetal liver, increased throughout development. GLUT-1 and HK-I were detectable in fetal liver, whereas glucokinase appeared after weaning. Consumption of a high-carbohydrate diet after weaning increased GLUT-4 and HK-II in muscle and GLUT-2 in liver, whereas consumption of a high-fat diet prevented these changes. These results showed that 1) GLUT-1 and HK-I are abundant in most fetal rat tissues, 2) GLUT-4 and HK-II expression is associated with the appearance of tissue insulin sensitivity, and 3) GLUT-2 is expressed early in liver, before the appearance of glucokinase.

Adipose Tissue, Brown↗
PubMed1994

Metabolic clearance of recombinant human growth hormone in health and chronic renal failure.

Despite the increasing therapeutic use of recombinant human growth hormone (rhGH), its metabolic clearance has not been investigated in detail. To evaluate the kinetics of rhGH as a possible function of GH plasma concentration and glomerular filtration rate (GFR), we investigated the steady state metabolic clearance rate (MCR), disappearance half-life, and apparent volume of distribution of rhGH at low and high physiological as well as supraphysiological plasma GH levels during pharmacological suppression of endogenous GH secretion in human subjects with normal and reduced renal function. GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance. In all subjects MCR decreased and plasma half-life increased with increasing plasma GH concentrations (P < 0.001). MCR of rhGH was approximately half in patients with chronic renal failure at each GH level and plasma half-life was increased by 25-50%. Allowing for the linear dependence of MCR on GFR and assuming single-compartment distribution, the estimated renal fraction of total MCR was 25-53 and 4-15% in controls and patients, respectively. Saturation of extrarenal disposal of GH was suggested by an inverse hyperbolic relationship between extrarenal MCR and plasma GH concentrations in all subjects. Fractional GH excretion was up to 1,000-fold higher in patients than in controls. We conclude that MCR of hGH is a function of plasma GH concentrations and GFR. Extrarenal elimination is saturable in the upper physiological range of GH concentrations, whereas renal MCR is independent of plasma GH levels. The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion.

Adolescent↗
PubMed1994

[Insulin resistance: role in type 2 diabetes].

Type 2, non-insulin-dependent, diabetes is a disease of glucose homeostasis involving up to 5% of the adult population. The percentage of the population with glucose intolerance is even greater, 10%. These later patients are not diagnosed as "diabetics", but 50% of them have non-insulin-dependent diabetes. Globally, 10% of the adult population has or will have Type 2 diabetes, a major health care problem. Characteristically, in patients with Type 2 diabetes, pancreatic insulin secretion is deficient, liver glucose production is increased during the post-absorption period and peripheral glucose consumption, particularly in striated muscles, is decreased due to insulin resistance. There has been much progress in our understanding of the pathogenic mechanisms involved. When clinical manifestations have become apparent, the relative roles of defective insulin secretion and insulin resistance are difficult to distinguish. However, in persons with oral glucose intolerance or in persons with a high risk of developing Type 2 diabetes, these two mechanisms are more easily differentiated. High risk patients can be identified on the basis of our knowledge of genetic factors in Type 2 diabetes. The incidence of Type 2 diabetes is considerably increased in subjects with two diabetic parents. In addition to genetic factors, environmental factors also influence the development of non-insulin-dependent diabetes, contributing to the multifactorial nature of Type 2 diabetes. In order to establish the relative importance of these different factors, it is useful to define the different stages with characteristic degrees of metabolic disorder, insulin secretion abnormalities and insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1994

Expression and cellular localization of glucose transporters (GLUT1, GLUT3, GLUT4) during differentiation of myogenic cells isolated from rat foetuses.

Skeletal muscle regeneration is mediated by the proliferation of myoblasts from stem cells located beneath the basal lamina of myofibres, the muscle satellite cells. They are functionally indistinguishable from embryonic myoblasts. The myogenic process includes the fusion of myoblasts into multinucleated myotubes, the biosynthesis of proteins specific for skeletal muscle and proteins that regulates glucose metabolism, the glucose transporters. We find that three isoforms of glucose transporter are expressed during foetal myoblast differentiation: GLUT1, GLUT3 and GLUT4; their relative expression being dependent upon the stage of differentiation of the cells. GLUT1 mRNA and protein were abundant only in myoblasts from 19-day-old rat foetuses or from adult muscles. GLUT3 mRNA and protein, detectable in both cell types, increased markedly during cell fusion, but decreased in contracting myotubes. GLUT4 mRNA and protein were not expressed in myoblasts. They appeared only in spontaneously contracting myotubes cultured on an extracellular matrix. Insulin or IGF-I had no effect on the expression of the three glucose transporter isoforms, even in the absence of glucose. The rate of glucose transport, assessed using 2-[3H]deoxyglucose, was 2-fold higher in myotubes than in myoblasts. Glucose deprivation increased the basal rate of glucose transport by 2-fold in myoblasts, and 4-fold in myotubes. The cellular localization of the glucose transporters was directly examined by immunofluorescence staining. GLUT1 was located on the plasma membrane of myoblasts and myotubes. GLUT3 was located intracellularly in myoblasts and appeared also on the plasma membrane in myotubes. Insulin or IGF-I were unable to target GLUT3 to the plasma membrane. GLUT4, the insulin-regulatable glucose transporter isoform, appeared only in contracting myotubes in small intracellular vesicles. It was translocated to the plasma membrane after a short exposure to insulin, as it is in skeletal muscle in vivo. These results show that there is a switch in glucose transporter isoform expression during myogenic differentiation, dependent upon the energy required by the different stages of the process. GLUT3 seemed to play a role during cell fusion, and could be a marker for the muscle's ability to regenerate.

Animals↗
PubMed1994

[Endocrine diagnosis in puberty--pathophysiologic bases].

Puberty is characterized by activation of the maturing gonads and by the thus started increased secretion of sexual steroids. Consequences are the appearance of secondary signs of puberty sensu strictori, i. e. the development of breasts in girls, the increase of testicle volume in boys, often followed by growing pubic hair, axillary hair, menarche or laryngeal growth (puberty vocal change) respectively. The most important accompanying symptom is the spurt of growth starting around 12 to 18 months after the onset of the development of the secondary pubertal signs. From the time sequence of the development and the possible delays, valuable diagnostic hints can be gained, giving rise to a more precise analysis of the hormonal phenomena of adolescence. In cases of pubertas tarda a primary malfunction must be differentiated from secondary hypogonadotropic functional defect. The syndromes should be classified correctly according to their etiology. The most frequent diagnosis is that of a simply delayed puberty. Acne, hypertrichosis, hirsutism are concomitant phenomena of puberty development which can indicate a hormonal imbalance (differential diagnosis AGS, ovarian hyperandrogeny). The swelling of breasts in boys (gynecomastia) is a common transitory phenomenon in male adolescence (DD, tumor of the gonads or Klinefelter syndrome). Interesting considerations of differential diagnosis apply also to the assessment of the enlargement of the thyroid gland in puberty, which affects more often girls than boys.

Adolescent↗
PubMed1993

[Growth hormone and its significance beyond growth. Current aspects of the effects of this model anabolic hormone].

Somatotropin is an anabolic hormone with an essential and pivotal regulatory function not only in the growing organism. Its actions are anabolic, carbohydrate-conserving, i.e. hyperglycemic and lipolytic. They are only in part direct. Important general and local mediators are local and circulating growth factors, in particular IGF 1 or somatomedin C. The production of the latter is somatotropin-dependent. They also explain the unexpected effects of the "growth"-hormone on the skeleton of the adult, the modifications in body composition and effects on the gonads etc. Endogenous regulation of somatotropin secretion is very intricate. Since its secretion occurs in bursts, plasmatic concentrations vary widely. Study of somatotropin secretion depends thus on tests after stimuli or suppressive maneuvers or more recently by determinations in urine. Values for the induced IGF 1 in the blood appear to be steadier and are useful for screening mainly for conditions of excessive somatotropin secretion. The availability of unlimited biosynthetic somatotropin has promoted its potential usefulness for short term anabolic treatments in the postoperative phase, for major burns and injuries or in glucocorticoid treatment. The established use is however still in children with growth retardation due to partial somatotropin deficiency.

Adult↗
PubMed1993

Glucose administration induces the premature expression of liver glucokinase gene in newborn rats. Relation with DNase-I-hypersensitive sites.

Glucokinase first appears in the liver of the rat 2 weeks after birth and its activity rapidly increases after weaning on to a high-carbohydrate diet. The appearance of glucokinase is principally due to the increase of plasma insulin and to the decrease of plasma glucagon concentrations. Oral glucose administration to 1- or 10-day-old suckling rats induced an increase in plasma insulin and a fall in plasma glucagon and allowed a rapid accumulation of liver glucokinase mRNA, secondarily to a stimulation of gene transcription. When unrestrained late pregnant rats were infused with glucose during 36 h to induce an increase in fetal plasma insulin and a decrease in fetal plasma glucagon concentrations, glucokinase mRNA was detectable in fetal liver but the level was 100-fold lower than that observed in 1- or 10-day-old suckling rats. It is suggested that the hormonal environment did not allow glucokinase gene expression to be induced in fetal liver and that the absence of expression of glucokinase in suckling rat liver is due to the presence of low plasma insulin and high plasma glucagon levels. The chromatin structure of the glucokinase gene was examined during development by identification of DNase-I-hypersensitive sites from the region comprised between -8 kb upstream and +4 kb downstream of the cap site. Five hypersensitive sites were found: four liver-specific sites upstream of the cap site and one non-specific site in the first intron. These sites are already present in term fetus but the intensity of the two proximal sites located upstream of the cap site increase markedly after birth. This suggests that these sites could be implicated in the regulation of glucokinase gene expression by insulin and glucagon. Full DNase-I-hypersensitivity of these two proximal sites seems necessary for the mature response of glucokinase gene in response to changes in pancreatic hormones concentrations.

Animals↗
PubMed1993

Evidence for a transient inhibitory effect of insulin on GLUT2 expression in the liver: studies in vivo and in vitro.

The glucose transporter GLUT2 is expressed predominantly in the liver. Previous studies have shown that glucose increases GLUT2 mRNA concentration in primary cultures of rat hepatocytes. Since insulin controls the glucose metabolism in the liver, it could be involved in the regulation of GLUT2 gene expression. In vivo, hyperinsulinaemia induced a transient inhibitory effect on liver GLUT2 gene expression, the maximal inhibition of GLUT2 mRNA concentration (93 +/- 6%) being observed after 6 h. When hyperglycaemia was associated with hyperinsulinaemia, the decrease in liver GLUT2 mRNA concentration was partially prevented. The respective effects of glucose and insulin were studied in vitro by primary culture of rat hepatocytes. Insulin alone exerted a transient inhibitory effect on GLUT2 mRNA concentration. When insulin and glucose (10-20 mM) were associated, the stimulatory effect of glucose on GLUT2 gene expression was predominant. In conclusion, the present study shows that GLUT2 mRNA concentration was conversely regulated by insulin and glucose, both in vitro and in vivo.

Animals↗
PubMed1993

Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney.

The tissue-specific expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene was studied in 15-day-old suckling rats. The mRNA and protein were present in liver, intestine and kidney, but were absent from brain, heart, skeletal muscles, brown and white adipose tissues. Kidney-cortex mitochondria from suckling rats were able to produce low amounts of ketone bodies from oleate. Hepatic, intestinal and renal HMG-CoA synthase mRNA levels increased slowly during foetal life and markedly after birth. The postnatal increase in liver HMG-CoA synthase mRNA could be due to the increase in plasma glucagon levels, since it rapidly induced the accumulation of HMG-CoA synthase mRNA in cultured foetal hepatocytes. Hepatic, intestinal and renal HMG-CoA synthase mRNA levels remained elevated throughout the suckling period or in rats weaned on to a high-fat carbohydrate-free diet (HF), but decreased by 50% in the liver and totally disappeared from the intestine and the kidney of rats weaned on to a high-carbohydrate low-fat diet (HC). When HC-weaned rats were fed on a HF-diet for a week, HMG-CoA synthase mRNA was re-induced in the intestine and the kidney. The role of hormones and nutrients in the regulation of HMG-CoA synthase gene expression is discussed.

Animals↗
PubMed1993

Changes in uncoupling protein and GLUT4 glucose transporter expressions in interscapular brown adipose tissue of diabetic rats: relative roles of hyperglycaemia and hypoinsulinaemia.

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.

Adipose Tissue, Brown↗
PubMed1993

A top-down control analysis in isolated rat liver mitochondria: can the 3-hydroxy-3-methylglutaryl-CoA pathway be rate-controlling for ketogenesis?

We incubated isolated liver mitochondria with palmitoyl-CoA, 2,4-dinitrophenol and malonate. Under these conditions all the flux of carbon from palmitoyl-CoA was directed towards acetoacetate synthesis. We measured the rate of acetyl-CoA formation from palmitoyl-CoA (by measuring the rate of oxygen consumption) and the rate of acetoacetate production from acetyl-CoA at three different acetyl-CoA/CoA ratios. Using the top-down approach of metabolic control analysis we calculated the control over ketogenesis exerted by (a) the conversion of extramitochondrial palmitoyl-CoA to intramitochondrial acetyl-CoA and by (b) the conversion of acetyl-CoA to acetoacetate (the 'HMG-CoA pathway'). The overall flux control coefficients of the groups of enzymes involved in (a) and (b) over ketogenesis were 0.28 and 0.72, respectively. Our results show that it is possible for significant control to be exerted over ketogenesis by the enzymes of the HMG-CoA pathway.

Acetoacetates↗
PubMed1993

Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism.

Liver insulin resistance and glucagon-stimulated hepatic glucose production are characteristics of the diabetic state. To determine the potential role of glucose toxicity in these abnormalities, we examined whether phlorizin treatment of streptozotocin-diabetic rats resulted in altered expression of genes involved in key steps of hepatic glucose metabolism. By inhibiting renal tubular glucose reabsorption, phlorizin infusion to diabetic rats induced normoglycaemia, did not significantly alter low circulating insulinaemia, but caused a marked decrease in hyperglucagonaemia. Glucokinase and L-type pyruvate kinase mRNA levels were reduced respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of phlorizin infusion partially restored glucokinase mRNA and activity (40% of control levels), but had no effect on L-type pyruvate kinase mRNA and activity. In contrast to the glycolytic enzymes, mRNA and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase were increased (10- and 2.2-fold, respectively) in fed diabetic rats. Phlorizin administration decreased phosphoenolpyruvate carboxykinase mRNA to values not different from those in control rats, while phosphoenolpyruvate carboxykinase activity remained 50% higher than that in control rats. The 50% rise in liver glucose transporter (GLUT 2) mRNA and protein, produced by diabetes, was also corrected by phlorizin treatment. In conclusion, we propose that phlorizin treatment of diabetic rats may induce a partial shift of the predominating gluconeogenesis, associated with hepatic glucose overproduction, into glycolysis, by correction of impaired pre-translational regulatory mechanisms. This could be essentially mediated through improved pancreatic alpha-cell function and subsequent lowering of hyperglucagonaemia. These observations suggest that glucagon-stimulated hepatic glucose production may result, in part, from glucose toxicity.

Animals↗
PubMed1993

Effect of acarbose on glucose homeostasis, lipogenesis and lipogenic enzyme gene expression in adipose tissue of weaned rats.

Acarbose is a potent intestinal glucosidase inhibitor which could have an anti-obesity property by reducing postprandial plasma glucose and insulin levels, potentially responsible for high rates of lipid synthesis in adipose tissue. We have tested this hypothesis by studying rats during the weaning period, when the lipogenic capacity of the adipose tissue develops. Rats were treated from age 19 days onwards with acarbose (10 mg/100 g diet) and studied at age 30 days. Acarbose was efficient in reducing postprandial excursions of both blood glucose and plasma insulin. Acarbose-treated rats behave like rats continuously infused with glucose with no metabolic signs of carbohydrate deprivation since gluconeogenesis was not activated. There was no massive caecal fermentation of carbohydrate since volatile fatty acids did not significantly increase in the portal blood. One of the most striking features of the acarbose-treated rats was the reduction of adipose tissue weight due to a reduced adipocyte size. This was concomitant with a reduced lipogenic capacity from glucose in isolated adipocytes under insulin stimulation. The activity of fatty acid synthase and acetyl-CoA carboxylase was decreased concomitantly with a reduced expression of their specific mRNA. This study allows the conclusion that postprandial hyperinsulinaemia and hyperglycaemia have a major role in the control of expression of lipogenic enzymes and thus on adipose tissue lipogenic capacity.

Acarbose↗
PubMed1993

An application of Ajzen's theory of planned behaviour to predict mothers' intention to use oral rehydration therapy in a rural area of Benin.

The aim of this study was to identify the psychological factors influencing mothers' intentions to use oral rehydration therapy (ORT) for the treatment of children's diarrhea in rural areas in South Benin. The subjects were 128 illiterate and animist mothers, selected at random in the areas of Pahou and Avlekete. Mothers were interviewed at home, using a pre-tested instrument investigating predictors of motivation as defined in Ajzen's theory of planned behaviour. The variables measured were intentions, attitudes, subjective social norm, perceived behavioural control and socio-demographic indicators. The regression of intention on all variables yielded an adjusted R2 of 0.40 (P < 0.0001), with perceived consequences of using ORT, perceived barriers to its use, and the zone of habitation being the significant predictors. The results suggest that the promotion of the use of ORT for treatment of diarrhea, in these areas, should be facilitated if the mothers perception of the advantages of using ORT is reinforced and if they have easier access to the health care services offered by local village health workers.

Adult↗
PubMed1993

Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism: effects on glycolytic and gluconeogenic enzymes, and on glucose transporter GLUT2.

The trace element vanadium is a potent insulinomimetic agent in vitro. Oral administration of vanadate to rats made diabetic by streptozotocin (45 mg/kg i.v.) caused a 65% fall in plasma glucose levels without modifying low insulinemia. We studied whether the hypoglycemic effect of vanadate was associated with altered expression of genes involved in key steps of hepatic glucose metabolism. Glucokinase (GK) and L-type pyruvate kinase (L-PK) mRNA levels were decreased respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of vanadate treatment partially restored GK mRNA and activity (40% of control levels), and totally restored L-PK parameters. In contrast to the glycolytic enzymes, mRNA levels and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) were increased (15- and 2-fold, respectively) in fed diabetic rats. Vanadate treatment normalized both PEPCK mRNA and activity in diabetic rat liver. The 2-fold increase in liver glucose transporter (GLUT2) mRNA and protein, produced by diabetes, was also corrected by this treatment. In conclusion, oral vanadate given to diabetic rats induces a shift of the predominating gluconeogenic flux, with subsequent high hepatic glucose production, into a glycolytic flux by pretranslational regulatory mechanisms.

Animals↗
PubMed1993

Regulation of glucose transporter and hexokinase II expression in tissues of diabetic rats.

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.

Adipose Tissue↗