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J Girard

Publications and source records attributed to J Girard.

At least 109 records · Page 6Linked to original sources
PubMed1995

Induction of fatty-acid-synthase gene expression by glucose in primary culture of rat hepatocytes. Dependency upon glucokinase activity.

Fatty acid synthase (FAS) expression is low in liver and adipose tissue of suckling rats and increases markedly after weaning on to a high-carbohydrate low-fat diet. It has been shown previously that glucose alone, via an increase in intracellular glucose-6-phosphate level, stimulated the accumulation of FAS mRNA in cultured white adipose tissue of suckling rats. The regulation of FAS expression by glucose and hormones (insulin, dexamethasone and triiodothyronine) was studied in cultured hepatocytes from suckling rats. In hepatocytes cultured for 48 h in the absence of hormones and glucose, FAS mRNA, as well as glucokinase mRNA, levels remained undetectable. Glucose alone was unable to stimulate FAS expression. The combination of hormones, in the absence of glucose, has a marginal effect on FAS mRNA levels. However, FAS mRNA levels were increased in the presence of both glucose and the combination of hormones. This demonstrated that the hormonal induction of FAS mRNA was dependent on the presence of glucose in the culture medium. We have then investigated if glucokinase expression could be a prerequisite for the stimulation of FAS expression in response to glucose. Hepatocytes were cultured for 48 h in the absence of glucose but in the presence of insulin, dexamethasone and triiodothyronine. In these conditions, glucokinase mRNA and activity were markedly increased but there was no accumulation of FAS mRNA. When these hepatocytes were then exposed to various levels of glucose, FAS mRNA rapidly accumulated. Glucose stimulation of FAS expression was observed only in hepatocytes which expressed glucokinase activity. The importance of glucokinase expression for the induction of FAS mRNA by glucose is supported by the striking correlation between glucose-6-phosphate concentrations and the levels of FAS mRNA. This study clearly demonstrates that: (a) glucose metabolism is directly involved in the regulation of FAS gene expression; (b) the effect of hormones is partly due to their capacity to induce in the hepatocytes the capacity for glucose phosphorylation.

Animals↗
PubMed1995

Excessive glucose production, rather than insulin resistance, accounts for hyperglycaemia in recent-onset streptozotocin-diabetic rats.

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)

Adipose Tissue↗
PubMed1995

Route of nutrient delivery affects insulin sensitivity and liver glucose transporter expression in rat.

To optimize artificial nutrition (AN) techniques for patients suffering from malnutrition or reduced intestinal absorption, utilization of energy fuels, especially glucose, requires better understanding. Because the liver plays a key role in glucose homeostasis, the aim of this study was to assess the effects of continuous intragastric and intravenous nutrition on insulin secretion and several markers of liver glucose metabolism, especially glucose transporter GLUT-2. Wistar male rats underwent catheterization of either stomach (intragastric) or vena cava (intravenous) and received 24 h/day the same all-in-one formula over 7 to 14 days. The metabolic parameters from intragastrically fed rats did not differ significantly from those from orally fed control rats. Intravenous nutrition induced insulin resistance (marked hyperinsulinemia and/or mild hyperglycemia) and reduced liver GLUT-2 protein and mRNA levels. The decrease in liver GLUT-2 gene expression might be mediated either by an inhibitory role of hyperinsulinemia or by the decrease in gut or portal factors. These results suggest that the route of nutrient delivery influences their utilization by the liver.

Animals↗
PubMed1995

Protein content of the evening meal and nocturnal plasma glucose regulation in type-I diabetic subjects.

The effect of two isocaloric evening meals (low protein-high fat vs. high protein-low fat content) on plasma glucose regulation during the night were compared. Eight C-peptide-deficient type-I diabetic subjects without autonomic neuropathy were treated with fixed doses of continuous infusions of insulin during 2 nights. At 7 p.m. they received in random order either a low protein-high fat (5% of total energy protein, 60% fat, 35% carbohydrate) or a high protein-low fat (35% protein, 30% fat, 35% carbohydrate) evening meal. Venous plasma samples were drawn hourly thereafter. Plasma glucose concentrations were similar postprandially during the 2 nights between 7 p.m. and 11 p.m., but they were higher in the early morning hours after the high protein meal (p < 0.02 vs. the low protein meal). Two subjects developed symptomatic hypoglycemia after the low protein meal. Plasma glucagon concentrations were higher (p = 0.023) and serum free insulin lower (p < 0.05) after the high protein-low fat meal. Plasma cortisol and growth hormone were not significantly different between the two diets. Therefore, an increase in the protein content of the evening meal (fat content diminished) increases plasma glucose concentrations several hours later in the night, possibly due to protein-induced glucagon secretion and to lower plasma free insulin levels. Patients with type-I diabetes with a tendency to develop hypoglycemia during the night may avoid this problem by increasing the protein content of the evening meal.

Blood Glucose↗
PubMed1995

Overexpression of GLUT3 placental glucose transporter in diabetic rats.

The localization of the two major placental glucose transporter isoforms, GLUT1 and GLUT3 was studied in 20-d pregnant rats. Immunocytochemical studies revealed that GLUT1 protein is expressed ubiquitously in the junctional zone (maternal side) and the labyrinthine zone (fetal side) of the placenta. In contrast, expression of GLUT3 protein is restricted to the labyrinthine zone, specialized in nutrient transfer. After 19-d maternal insulinopenic diabetes (streptozotocin), placental GLUT3 mRNA and protein levels were increased four-to-fivefold compared to nondiabetic rats, whereas GLUT1 mRNA and protein levels remained unmodified. Placental 2-deoxyglucose uptake and glycogen concentration were also increased fivefold in diabetic rats. These data suggest that GLUT3 plays a major role in placental glucose uptake and metabolism. The role of hyperglycemia in the regulation of GLUT3 expression was assessed by lowering the glycemia of diabetic pregnant rats. After a 5-d phlorizin infusion to pregnant diabetic rats, placental GLUT3 mRNA and protein levels returned to levels similar to those observed in nondiabetic rats. Furthermore, a short-term hyperglycemia (12 h), achieved by performing hyperglycemic clamps induced a fourfold increase in placental GLUT3 mRNA and protein with no concomitant change in GLUT1 expression. This study provides the first evidence that placental GLUT3 mRNA and protein expression can be stimulated in vivo under hyperglycemic conditions. Thus, GLUT3 transporter isoform appears to be highly sensitive to ambient glucose levels and may play a pivotal role in the severe alterations of placental function observed in diabetic pregnancies.

Animals↗
PubMed1995

[Regulation of expression of genes coding for lipogenesis enzymes during development in the rat].

In vivo studies in the rat during the weaning period and in vitro studies on cultured cells have shown that nutriments and pancreatic hormones play a major role in lipogenic enzyme gene expression in liver and adipose tissue. Activation of lipogenic enzyme gene expression in liver and adipose tissue is dependent upon the increased supply of glucose and the concomitant hyperinsulinemia that occur after weaning. In contrast, an elevated supply of polyunsaturated or an increased plasma glucagon level prevent lipogenic enzyme gene expression in liver and adipose tissue. Glucose-6-phosphate seems to be the intracellular metabolite that mediates the transcriptional activation of lipogenic enzyme genes in response to glucose.

ATP Citrate (pro-S)-Lyase↗
PubMed1995

[Role of free fatty acids in the insulin resistance of non-insulin-dependent diabetes].

Non-insulin-dependent diabetes (NIDDM) is characterized by overproduction of glucose, decreased effects of insulin on glucose utilization and production, and a defect in glucose-induced insulin secretion. NIDDM is also associated with defects in fatty acid metabolism, i.e. enhanced lipolysis and impaired suppression of adipose tissue lipolysis in response to insulin, and increased plasma free fatty acid levels. It has been suggested that the "glucose-fatty acid cycle" is enhanced in NIDDM and could contribute to disturbed glucose homeostasis. Although the use of intralipid + heparin infusion and inhibitors of lipolysis or fatty acid oxidation indicates that the glucose-fatty acid cycle exists both in normal and NIDDM subjects, it does not seem to be the primary cause of distributed glucose homeostasis in lean NIDDM subjects or their first-degree relatives. However, the glucose-fatty acid cycle could contribute to overproduction of glucose (by stimulating gluconeogenesis) and muscle insulin resistance in obese NIDDM subjects. Studies performed in the rat suggest that impaired glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels. The role of the glucose-fatty acid cycle in normal subject must be clarified, and its contribution to decreased glucose-induced insulin secretion in NIDDM requires further investigation.

Diabetes Mellitus, Type 2↗
PubMed1994

Regulation of lipogenic enzyme and phosphoenolpyruvate carboxykinase gene expression in cultured white adipose tissue. Glucose and insulin effects are antagonized by cAMP.

In cultured adipose tissue of suckling rats, glucose alone is able to induce the appearance of fatty-acid synthase and acetyl-CoA carboxylase mRNA by a mechanism involving glucose-6-phosphate accumulation; insulin alone has no effect but potentiates the effect of glucose. In the present study, we have analysed in cultured adipose tissue the effects of other hormones on the expression of these enzymes as well as on phosphoenolpyruvate carboxykinase. Triiodothyronine has only a marginal effect on fatty-acid synthase expression, in the absence or presence of glucose and insulin. A synthetic glucocorticoid, dexamethasone, opposes the inductive effect of glucose and insulin on fatty-acid synthase expression but increases the expression of phosphoenolpyruvate carboxykinase. A beta-agonist, isoproterenol totally inhibits the inductive effect of glucose and insulin on acetyl-CoA carboxylase and fatty-acid synthase expression whereas it increases the expression of phosphoenolpyruvate carboxykinase. Similarly, glucagon and cAMP have antagonistic effects on glucose and insulin-induced fatty-acid synthase expression. These inhibitory effects cannot be explained only by a reduction in glucose-6-phosphate concentration. We conclude that, in adipose tissue, dexamethasone and cAMP-generating hormones are negative regulators of lipogenic enzyme expression. Finally, the regulation of phosphoenolpyruvate carboxykinase expression in adipose tissue is similar to that found in the liver, i.e. inhibition by insulin and glucose and activation by glucocorticoids and cAMP.

Acetyl-CoA Carboxylase↗
PubMed1994

Initial expression of glucokinase gene in cultured hepatocytes from suckling rats is linked to the synthesis of an insulin-dependent protein.

The initial accumulation of glucokinase mRNA in response to insulin in cultured hepatocytes from 10-day-old suckling rats was characterized by a delay of 18-24 h with a maximal level reached after 48 h. This delay is not observed in cultured adult rat hepatocytes. When hepatocytes from 10-day-old suckling rats were cultured for 48 h in the presence of insulin (to obtain a maximal accumulation of glucokinase mRNA) and then deprived of insulin for 18 h, glucokinase mRNA returned to very low levels. Reexposure of these cultured hepatocytes to insulin allowed a rapid accumulation of glucokinase mRNA, with a maximal level reached after 8 h, as in adult rat hepatocytes. The aim of the present study was to investigate the factors responsible for the delay in insulin action during first exposure to insulin. The difference in the kinetics of glucokinase mRNA accumulation after the first and secondary exposure to insulin was due to differences in the rate of transcriptional activity of the glucokinase gene, as shown by a run-on assay on isolated nuclei. The half-life of glucokinase mRNA was similar after the first and second exposure to insulin. The delay in the initial accumulation of glucokinase mRNA in response to the first exposure to insulin was not due to elevated levels of cAMP (a potent inhibitor of glucokinase gene expression) or to a defect in insulin signalling (insulin inhibited without delay phosphoenolpyruvate carboxykinase gene expression). In contrast, it was markedly dependent upon whether glucokinase has been already expressed in vivo. Hepatocytes from rats that had already expressed glucokinase in vivo (suckling rats force-fed with glucose or rats weaned to a high-carbohydrate diet) showed no delay in their response to insulin in culture, whereas hepatocytes from rats that have never expressed glucokinase in vivo (suckling rats or rats weaned to a high-fat diet) showed a delay of 24 h. Two different inhibitors of protein synthesis (cycloheximide and puromycin) prevented the initial accumulation of glucokinase mRNA in response to the first exposure to insulin but not to the secondary accumulation of glucokinase mRNA in response to reexposure to insulin. This suggests that the synthesis of one or several insulin-dependent proteins is necessary for the first activation of glucokinase gene transcription in response to the first exposure to insulin.

Aging↗
PubMed1994

Expression of liver carnitine palmitoyltransferase I and II genes during development in the rat.

The enzyme activity and the expression (protein and mRNA concentrations) of genes encoding for hepatic carnitine palmitoyl-transferases (CPT) I and II were studied during neonatal development, in response to nutritional state at weaning and during the fed-starved transition in adult rats. The activity, the protein concentration and the level of mRNA encoding CPT I are low in foetal-rat liver and increase 5-fold during the first day of extra-uterine life. The activity and gene expression of CPT I are high during the entire suckling period, in the liver of 30-day-old rats weaned at 20 days on to a high-fat diet and in the liver of 48 h-starved adult rats. The activity and CPT I gene expression are markedly decreased in the liver of rats weaned on to a high-carbohydrate diet. By contrast, the activity, the protein concentration and the level of mRNA encoding CPT II are already high in the liver of term foetuses and remain at this level throughout the suckling period, irrespective of the nutritional state of the animals either at weaning or in the adult.

Aging↗
PubMed1994

Hepatic ketogenesis in newborn pigs is limited by low mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity.

In newborn-pig hepatocytes, the rate of oleate oxidation is extremely low, despite a very low malonyl-CoA concentration. By contrast, the sensitivity of carnitine palmitoyltransferase (CPT) I to malonyl-CoA inhibition is high, as suggested by the very low concentration of malonyl-CoA required for 50% inhibition of CPT I (IC50). The rates of oleate oxidation and ketogenesis are respectively 70 and 80% lower in mitochondria isolated from newborn-pig liver than from starved-adult-rat liver mitochondria. Using polarographic measurements, we showed that the oxidation of oleoyl-CoA and palmitoyl-L-carnitine is very low when the acetyl-CoA produced is channelled into the hydroxymethylglutaryl-CoA (HMG-CoA) pathway by addition of malonate. In contrast, the oxidation of the same substrates is high when the acetyl-CoA produced is directed towards the citric acid cycle by addition of malate. We demonstrate that the limitation of ketogenesis in newborn-pig liver is due to a very low amount and activity of mitochondrial HMG-CoA synthase as compared with rat liver mitochondria, and suggest that this could promote the accumulation of acetyl-CoA and/or beta-oxidation products that in turn would decrease the overall rate of fatty acid oxidation in newborn- and adult-pig livers.

Animals↗
PubMed1994

Tissue-specific correction of lipogenic enzyme gene expression in diabetic rats given vanadate.

Vanadium is a potent insulinomimetic agent. In vivo, its blood glucose lowering action in insulin-deficient diabetic rats is associated with corrected expression of genes involved in hepatic glucose metabolism. In this study, we investigated whether vanadate treatment also reverses the impaired expression of genes coding for key enzymes of lipogenesis in diabetic liver and white adipose tissue. Oral administration of vanadate to streptozotocin-rats caused a 55% fall in plasma glucose levels after feeding without modifying low insulinaemia. It also partially corrected the low thyroid hormone concentrations. In untreated diabetic animals, hepatic mRNA levels of acetyl-CoA carboxylase and fatty acid synthase were reduced by more than 80 and 90%, respectively, in close correlation with changes in enzyme activities. Three weeks of vanadate treatment totally restored acetyl-CoA carboxylase mRNA and partially restored fatty acid synthase mRNA (71% of control levels). The activities of both lipogenic enzymes were increased 3.5 to 4-fold, to reach 45 to 65% of control values. By contrast, in white adipose tissue, vanadate modified neither expression nor activity of both lipogenic enzymes, which remained blunted (< 10% of control levels). In conclusion, vanadate treatment partially restores the activities of two key lipogenic enzymes in liver, but not in white adipose tissue, of diabetic rats. This correction results from a reversal of impaired pre-translational regulatory mechanisms possibly mediated by an improvement of thyroid function and a selective restoration of liver glycolytic flux.

Acetyl-CoA Carboxylase↗
PubMed1994

Apparent growth hormone levels in plasma and urine. Methodological "artefacts".

Urinary growth hormone reflects plasma levels, if a normal renal function is assured. It offers the advantages of easy repetition over prolonged periods of time. It is an easy tool to assess physiological and pathophysiological aspects of the "amount" of growth hormone secreted in a given clinical situation. It can be used to control therapy and reassess the "growth hormone status" at any time during a treatment period. It cannot, however, replace the assessment of responses of the system to a given stimulus and will not reflect the pulsatility of plasma levels.

Aging↗
PubMed1994

Developmental expression of Glut1 glucose transporter and c-fos genes in human placental cells.

Glut1, the brain/erythrocyte glucose transporter is one major isoform of the human placenta and displays an age-specific pattern of expression with mRNA levels five-fold higher in first trimester than in term placenta. By contrast, the mRNA level of the insulin-regulatable glucose transporter Glut4 remains at the limit of detection throughout pregnancy indicating a very low expression of this isoform in the placenta. The nuclear proto-oncogenes c-fos and c-myc were also detectable in the human placenta, but c-fos only exhibited an age-specific pattern of expression with levels higher in third trimester than in term placenta. Primary cultures of human trophoblast cells from term placenta were used to further study the expression and regulation of Glut1 and c-fos genes. Fetal calf serum rapidly and transiently (15 to 60 min) stimulated c-fos and Glut1 gene expression suggesting that both genes share similar growth factor-controlled pathways. Glucose inhibited Glut1, but not c-fos expression. An eight-fold decrease in Glut1 mRNA was observed when glucose concentration in the medium was increased from 0 to 25 mM, whereas c-fos mRNA levels remained very low. These results suggest that in the human placenta, the expression of Glut1 is specifically regulated by glucose concentration. These data demonstrate that (1) Glut1 and c-fos mRNA transcripts are expressed in the human placenta exhibiting an age-specific pattern of expression, (2) In cultured trophoblast cells, both genes are stimulatable by fetal calf serum and in contrast to c-fos, Glut1 is negatively regulated by glucose. This differential regulation of Glut1 and c-fos genes could be relevant to specific metabolic and mitogenic pathways implicated in placental growth and differentiation.

Cells, Cultured↗
PubMed1994

Regulation of lipogenic enzyme gene expression by nutrients and hormones.

In vivo and in vitro experiments strongly support the view that marked increases in the levels of mRNA and in the activities of lipogenic enzymes that occur in liver and white adipose tissue of the rat after weaning to a high-carbohydrate diet are dependent on an increase in plasma glucose and insulin concentrations. An increased glucose metabolism is necessary for the expression of insulin effects on fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) mRNA accumulation in white adipose tissue, as insulin is ineffective in vitro in the absence of glucose. It is suggested that intracellular glucose-6-phosphate could play an important role in the effect of insulin on lipogenic enzyme gene expression in white adipose tissue. Other hormones and substrates could also play a role in the surge of lipogenesis after weaning. The fall in plasma glucagon after weaning to a high-carbohydrate diet could reinforce the insulin-induced accumulation of FAS and ACC mRNA, as this hormone inhibits the accumulation of lipogenic enzyme mRNA in liver and white adipose tissue. The decrease in the dietary supply of fat after weaning to a high-carbohydrate diet could also potentiate the accumulation of FAS and ACC mRNA in liver because long-chain poly-unsaturated fatty acids are potent inhibitors of the expression of the genes encoding liver lipogenic enzymes. A direct effect of fatty acids on a cis-acting element of the lipogenic enzyme genes could be involved, as the regulatory region of FAS gene contains a polyunsaturated fatty acid response element that shares some similarity with the peroxisome proliferator-activated receptor recently described.

Acetyl-CoA Carboxylase↗
PubMed1994

The value of inferior petrosal sinus sampling in diagnosis and treatment of Cushing's disease.

OBJECTIVE: While microsurgical selective adenomectomy is the best method available at present for the treatment of Cushing's disease, its success depends to a large degree on precise preoperative intrapituitary microadenoma localization. This study compares the results of intrapituitary adenoma localization obtained with inferior petrosal sampling, computerized tomography and magnetic resonance imaging with the adenoma localization as found at surgery. DESIGN: The results of inferior petrosal sampling for intrapituitary localization of ACTH-producing pituitary adenomas were compared in a retrospective study with the results of computerized tomography, magnetic resonance imaging, surgical and pathological findings. Special attention was paid to the intersinus ACTH relation. PATIENTS: Thirty-eight patients (33 women and 5 men) of 11-68 years of age suffering from pituitary-dependent Cushing's disease were studied. Patients with ectopic ACTH-secreting tumours and recurrent pituitary adenomas were excluded. MEASUREMENTS: Blood samples were obtained simultaneously from both inferior petrosal sinuses and a peripheral vein before and 5, 10, 15 and 20 minutes after stimulation with 60 micrograms/m2 human corticotrophin-releasing hormone (hCRH). RESULTS: Of the adenomas in our series, 42% had a diameter of 3 mm or less. Only 6 of 20 adenomas examined by computerized tomography and 11 of 29 examined by magnetic resonance imaging were identified correctly. Inferior petrosal sinus sampling produced significantly better results, particularly when combined with a stimulation test with hCRH: for 29 of 38 adenomas examined, the location was predicted correctly with these techniques. Analysis of the intersinus adrenocorticotrophin concentration ratio showed that the best right-central-left discrimination was obtained with values of 1.3 and 1.4. CONCLUSIONS: We conclude that inferior petrosal sinus ACTH sampling after hCRH stimulation is the best method available for the intrapituitary localization of microadenomas causing Cushing's disease provided that the appropriate technique of blood sampling is used meticulously.

Adenoma↗
PubMed1994

Acinar zonation of the hormonal regulation of cytosolic aspartate aminotransferase in the liver.

The zonation of the expression and regulation of the cytosolic aspartate aminotransferase (cAspAT) mRNAs in the liver acinus was investigated in diabetic and/or adrenalectomized rats. Dexamethasone increased cAspAT activity two- to threefold alone and up to sixfold in combination with streptozotocin-induced diabetes. Northern blot analysis showed that the cAspAT mRNAs were increased by those treatments; the effect of streptozotocin was reversed by the administration of insulin. In situ hybridization experiments showed that basal cAspAT mRNAs were uniformly distributed within the liver acinus. However, cAspAT mRNAs were induced by glucocorticoids specifically in the periportal zone and by streptozotocin in a larger area including the periportal and intermediary zone. The alpha 2u-globulin mRNAs which are specifically expressed in the perivenous hepatocytes are also induced by glucocorticoids in this zone, suggesting that the specific regulation of the cAspAT gene by glucocorticoids in the periportal zone is not due to the absence of functional glucocorticoid receptors in the other zones. We conclude that the regulation of the cAspAT housekeeping gene is zone specific in the liver. Furthermore, this zonation depends on the gene and on the type of hormonal or pharmacological treatment.

Adrenalectomy↗