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Biomedical subjects

B Jeanrenaud

Publications and source records attributed to B Jeanrenaud.

At least 19 recordsLinked to original sources
PubMed1992

Glucose regulates its transport in L8 myocytes by modulating cellular trafficking of the transporter GLUT-1.

The effect of culture conditions simulating hypo- and hyper-glycaemia on glucose transport and on the subcellular localization of the glucose transporter GLUT-1 was studied in L8 myocytes. Incubation of the cells with 20 mM-glucose for 25 h decreased the rate of 2-deoxy-D-[3H]glucose (dGlc) uptake to 0.106 +/- 0.016 nmol/min per 10(6) cells compared with 0.212 +/- 0.025 in cells maintained at 2 mM-glucose (final glucose concentrations at the end of the incubation period were 16-17 mM and 0.7-1.0 mM respectively). An additional 5 h incubation of these cells with medium containing the opposite glucose concentration (i.e. change from 17 mM to 1 mM and from 1 mM to 17 mM) increased the transport rate to 0.172 +/- 0.033 nmol/min per 10(6) cells in cultures initially conditioned at high glucose, and decreased the transport to 0.125 +/- 0.029 in those conditioned at low glucose. Plasma-membrane- and microsomal-membrane-enriched fractions were prepared from these cells for [3H]cytochalasin B (CB) binding and Western-blot analysis with antibodies against GLUT-1 and GLUT-4. A decrease in glucose concentration increased the number of D-glucose-displaceable CB-binding sites and GLUT-1 protein in the plasma-membrane fraction to the same extent as the increase in dGlc transport. Under downregulatory conditions, the lower dGlc-transport capacity could be accounted for by a decreased number of transporters in the plasma membrane of the cells. No apparent modification of the intrinsic activity of the glucose transporters was observed in up- or down-regulated cells. Under downregulatory conditions, the CB-binding data indicated a large increase in the number of transporters in the intracellular membranes of the myocytes. Western blots of the same membranes also indicated an increase in GLUT-1 content. However, the interaction of the intracellular GLUT-1 protein with the polyclonal antibodies was much weaker than that of the plasma-membrane-associated GLUT-1. The GLUT-4 concentration was too low to permit quantification in membrane fractions. Our findings suggest that autoregulation of glucose transport in L8 myocytes is accompanied by parallel changes in the number of GLUT-1 transporters in the plasma membrane, and that the rate of transporter degradation may be augmented in the upregulated myocytes. These glucose-induced changes are fully reversible.

Animals↗
PubMed1992

Effect of a beta-adrenergic agonist on glucose transport and insulin-responsive glucose transporters (GLUT4) in brown adipose tissue of control and obese fa/fa rats.

A beta-adrenergic agonist specific for brown adipose tissue, Ro 16-8714, was administered to control and obese insulin-resistant fa/fa rats and glucose utilisation measured in brown adipose tissue using the euglycaemic hyperinsulinaemic clamp combined with the injection of 2-deoxyglucose. Treatment with the beta-agonist increased basal and insulin-stimulated glucose utilization in both groups, resulting in an increased effect of the hormone in treated animals. This effect is specific for brown adipose tissue and is not found in other insulin-sensitive tissue. The total number of insulin-responsive glucose transporters (GLUT4) measured in crude membrane preparations was similar in the two groups when expressed per total tissue. They were, however, decreased in the fa/fa group when expressed per milligram of tissue. Acute treatment with the beta-adrenergic agonist increased the total number of GLUT4 in both groups. The agonist also increased the amount of mRNA coding for GLUT4 suggesting an effect on the transcription and/or on the stability of GLUT4 mRNA.

2-Hydroxyphenethylamine↗
PubMed1992

The contribution of hyperglycaemia and hypoinsulinaemia to the insulin resistance of streptozotocin-diabetic rats.

The relative contribution of hyperglycaemia and hypoinsulinaemia was evaluated in rats made diabetic by streptozotocin administration. Four groups of rats were studied: untreated normal rats; streptozotocin-diabetic; streptozotocin-diabetic treated with phlorizin (0.4 mg/kg body weight per day); streptozotocin-diabetic mildly treated with insulin (0.7 IU/day). In all groups, insulin action (responsiveness) was assessed with the euglycaemic (5.3 mmol/l) hyperinsulinaemic (524 mU/l) clamp technique combined with 3H-2-deoxy-D-glucose method, enabling determination of the glucose utilization index in various tissues. Responsiveness of the overall glucose utilization process to insulin was reduced by 28% in streptozotocin-diabetic rats (12.0 +/- 1.2 vs 16.5 +/- 0.6 mg.kg-1.min-1, p less than 0.001). This was associated with a significant reduction (p less than 0.05) in the glucose utilization index in all muscles studied (average = 17.0 vs 32.1 ng.mg of tissue-1.min-1), in the heart (19.6 vs 39.5 ng.mg-1.min-1), brown adipose tissue (98.9 vs 178.0 ng.mg-1.min-1), skin (6.4 vs 13.1 ng.mg-1.min-1). Phlorizin treatment normalized plasma glucose levels without affecting those of insulin, and restored overall glucose utilization to normal (16.6 +/- 1.0 mg.kg-1.min-1). This normalization was accompanied by a normalization of the glucose utilization index in all muscle types studied (29.2 ng.mg-1.min-1), in the heart (50.0 ng.mg-1.min-1), brown adipose tissue (157.2 ng.mg-1.min-1), and skin (10.0 ng.mg-1.min-1). White adipose tissue, brain and gut were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Muscle insulin resistance may not be a primary etiological factor in the genetically obese fa/fa rat.

It is not known whether hyperinsulinemia of the genetically obese fa/fa rat occurs before insulin resistance and abnormal glucose handling or vice versa. Therefore, it was decided to study, as a function of age, the evolution of the insulin-stimulated glucose uptake measuring the in vitro uptake of its analog, 2-deoxy-D-glucose (2DG), by diaphragm. The expression of the insulin-sensitive glucose transporter (GLUT 4) mRNA and protein were also investigated in muscles. The maximum increase over baseline in 2DG uptake in response to increasing insulin concentrations in the medium was upward shifted in diaphragm from preweaned 21-day-old preobese rats relative to that in lean controls (increased responsiveness). By 31 days of age the maximum increase over baseline diaphragm 2DG uptake in response to insulin was similar in young lean and obese rats. At 70 days of age, the 2DG uptake muscle dose response to insulin was significantly downward shifted, i.e. clearly insulin resistant (decreased responsiveness). Muscle (diaphragm and extensor digitorum longus) expression of GLUT 4 mRNA and protein revealed no intergroup difference at any of the ages studied. Hyperinsulinemia was moderate in preobese animals and progressively increased with the duration of the obesity syndrome. Based on the observation that diaphragm glucose uptake of 21-day-old preobese rats was overresponsive to insulin, normoinsulin responsive at 31 days, and insulin resistant at a later time, it is concluded that muscle insulin resistance is not a primary etiological defect, but must be secondary to other pathological alterations, the nature of which remains to be elucidated.

Animals↗
PubMed1992

Acute intravenous corticotropin-releasing factor administration: effects on insulin secretion in lean and genetically obese fa/fa rats.

The effect of an i.v. administration of different doses (250, 500, and 1000 pmol) of ovine CRF (oCRF) on plasma glucose and insulin levels in lean and genetically obese fa/fa rats was investigated. In both phenotypes, i.v. CRF promoted a rapid (peak at 1 min) transient doubling of basal insulin levels without a concomitant change in glycemia. The dose-dependency of this early insulin response was bell-shaped in both lean and obese animals, with a maximal response at 500 pmol oCRF. After this early rise in insulinemia, glycemia increased in a dose-dependent manner in both lean and obese rats. It was accompanied by a bell-shaped insulin response in lean rats, while such a response was linear in obese rats. The early transient stimulatory effect of CRF on plasma insulin levels could not be prevented by the prior administration of an anti-CRF serum or the alpha-helical CRF-(9-41) antagonist, although administration of either one of these compounds was effective in preventing the CRF-induced changes in the pituitary-adrenal axis. The effect of CRF on the early insulin response was, however, completely suppressed by an acute cholinergic blockade (i.v. injection of atropine). It is suggested that i.v. CRF administration mimics the reflex, cephalic phase insulin secretion. Such cephalic phase insulin output is known to play a role in oral glucose tolerance and may be of physiopathological importance in the Zucker rat strain.

Animals↗
PubMed1992

Vanadate treatment markedly increases glucose utilization in muscle of insulin-resistant fa/fa rats without modifying glucose transporter expression.

The present study examined the effects of chronic treatment with vanadate on in vivo insulin-stimulated glucose uptake by various tissues of obese and insulin-resistant fa/fa rats. It further determined whether the substantial improvement induced by vanadate administration was associated with altered expression of the insulin-responsive glucose transporter (GLUT4). Since oral Na3VO4 caused decreases in food intake and body weight, vanadate-treated fa/fa rats were compared with controls, fed ad libitum, and pair-fed rats. The animals in the three groups were submitted to hyperinsulinemic clamps combined with the 2-deoxyglucose method. At similar levels of imposed hyperinsulinemia, the glucose infusion rate (milligrams per kg.min-1) required to maintain euglycemia, extremely low in controls (0.8 +/- 0.3) and pair-fed rats (1.2 +/- 0.6), was strikingly improved in vanadate-treated rats (9.5 +/- 0.3). Correspondingly, the insulin-mediated glucose utilization indices were 2- to 3-fold higher in all types of muscle in treated rats: hindlimb skeletal muscle, diaphragm, and heart. Glucose utilization remained unaffected in white adipose tissue and jejunum, whereas it was increased by mere food restriction in brown adipose tissue of pair-fed rats. The amounts of GLUT4 and GLUT4 mRNA were then measured in the insulin-sensitive tissues of the three groups of animals. Vanadate treatment induced no change in GLUT4 mRNA or GLUT4 protein levels in any of the examined tissues. It even prevented the rise in GLUT4 protein expression caused by calorie restriction in brown adipose tissue of pair-fed rats. In conclusion, chronic administration of vanadate markedly increases the insulin-mediated glucose uptake in muscle of insulin-resistant fa/fa rats without altering GLUT4 number. A functional improvement of glucose transporters due to more efficient translocation and/or increased intrinsic activity or changes in the insulin signaling pathway is, thus, likely to play a major role in the beneficial effects of vanadate.

Adipose Tissue, Brown↗
PubMed1992

Beneficial effect of intravenous bolus of corticotropin-releasing factor on glucose intolerance of genetically obese (fa/fa) rats.

The effect of an ovine corticotropin-releasing factor (oCRF) bolus administered intravenously at the onset of glucose ingestion during oral glucose tolerance tests (OGTTs) was evaluated in conscious lean (FA/FA) and genetically obese (fa/fa) rats. When the amount of oCRF was purposely small to not stimulate the hypothalamo-pituitary-adrenal (HPA) axis, it normalized the glucose intolerance of genetically obese rats as tested during OGTTs and decreased their insulin output, whereas it had no effect in lean rats. In obese rats, plasma xylose levels measured after the ingestion of a xylose load were unaltered by the intravenous oCRF bolus, indicating that the beneficial effect of oCRF on glucose intolerance of fa/fa rats was unlikely to be dependent on glucose absorption. When the intravenous bolus of oCRF was doubled at the onset of OGTTs, it stimulated the HPA axis and produced a worsening of glucose intolerance in obese rats together with an increase in their insulin response. Again, it had no effect in lean rats. The abnormal intravenous glucose tolerance of obese rats was unaffected by the administration of an oCRF bolus: This is in keeping with previous data showing that bypassing the oral cavity fails to elicit several sensory reflexes that markedly influence subsequent glucose clearance. It has been suggested that obese rats may have deficient oropharyngeal reflexes that could be reactivated by the oCRF bolus, thereby being responsible for the normalization of their impaired OGTT, which lies in the hepatic glucose production process.

Animals↗
PubMed1992

Hyperinsulinemia and its impact on obesity and insulin resistance.

The impact of hyperinsulinemia on the establishment of insulin resistance was investigated. This was done by treating normal rats with insulin for 3-4 days via osmotic minipumps, and by comparing them with saline-treated controls. Hyperinsulinemia produced by prior insulin treatment (i.e. prior insulinization of the normal rats) resulted in a well tolerated hypoglycemia, increased food intake and body weight gain. Euglycemic-hyperinsulinemic clamps were carried out at the end of the insulinization to assess the acute effects of insulin in control and insulinized rats. It was found that prior insulinization of normal rats resulted in increases in total insulin-stimulated glucose utilization and hepatic lipogenesis, while hepatic glucose production (HGP) was normally suppressed by the hormone. Glucose utilization index by individual tissues was then measured (labelled 2-deoxy-D-glucose method). Prior insulinization of normal rats resulted in increased insulin-stimulated glucose utilization index of white adipose tissue, accompanied by increased insulin-stimulated de novo lipogenesis and glycogen synthesis. In contrast, prior insulinization of normal rats resulted in a decreased insulin-stimulated glucose utilization index of most muscles studied. The decreased insulin-stimulated muscle glucose utilization index brought about by prior insulinization persisted in adrenomedullectomized or propranolol-treated rats, ruling out a role of catecholamines in the effects observed. It is concluded that hyperinsulinemia is a pathological driving force in producing both incipient obesity by overstimulating white adipose tissue and liver metabolic activity, and concomitantly producing incipient muscle insulin resistance.

Adipose Tissue↗
PubMed1991

Increased gene expression of lipogenic enzymes and glucose transporter in white adipose tissue of suckling and weaned obese Zucker rats.

Previous experiments have shown that insulin-induced glucose utilization is increased in white adipose tissue of young obese Zucker rats. We have investigated the possible role of over-expression of the muscle/fat glucose transporter (Glut 4) and key lipogenic enzymes in this increased insulin-responsiveness. The amount or activity and the mRNA concentrations of Glut 4, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) were measured before and after weaning in white adipose tissue of obese and lean Zucker rats. Comparison of the levels of Glut 4 and lipogenic-enzyme expression in 15-day-old suckling and 30-day-old weaned rats on a high-carbohydrate diet shows a marked increase in the latter group. The increase was, in lean and obese rats respectively, 6- and 7-fold for the amount of Glut 4 and 2- and 3-fold for its mRNA concentrations, 40- and 100-fold for the activity of lipogenic enzymes (FAS and ACC) and 30- and 10-fold for their mRNA concentrations. Furthermore, all these parameters, except the amount of Glut 4, were 2-5-fold higher in obese rats, both before and after weaning. Changes at weaning were largely blunted when rats were weaned on to a high-fat diet, although the differences between lean and obese rats persisted, and even became significant for the amount of Glut 4. Whatever the experimental conditions, plasma insulin levels were significantly higher in obese than in lean rats. These results indicate the existence of an enhanced expression of Glut 4, FAS and ACC in white adipose tissue of young obese fa/fa rats which could be related to the increased plasma insulin levels.

Acetyl-CoA Carboxylase↗
PubMed1991

Glucose transporters: structure, function, and regulation.

Glucose is transported into the cell by facilitated diffusion via a family of structurally related proteins, whose expression is tissue-specific. One of these transporters, GLUT4, is expressed specifically in insulin-sensitive tissues. A possible change in the synthesis and/or in the amount of GLUT4 has therefore been studied in situations associated with an increase or a decrease in the effect of insulin on glucose transport. Chronic hyperinsulinemia in rats produces a hyper-response of white adipose tissue to insulin and resistance in skeletal muscle. The hyper-response of white adipose tissue is associated with an increase in GLUT4 mRNA and protein. In contrast, in skeletal muscle, a decrease in GLUT4 mRNA and a decrease (tibialis) or no change (diaphragm) in GLUT4 protein are measured, suggesting a divergent regulation by insulin of glucose transport and transporters in the 2 tissues. In rodents, brown adipose tissue is very sensitive to insulin. The response of this tissue to insulin is decreased in obese insulin-resistant fa/fa rats. Treatment with a beta-adrenergic agonist increases insulin-stimulated glucose transport, GLUT4 protein and mRNA. The data suggest that transporter synthesis can be modulated in vivo by insulin (muscle, white adipose tissue) or by catecholamines (brown adipose tissue).

Adipose Tissue↗
PubMed1991

In-vivo behaviour of hypodermically implanted microfabricated glucose sensors.

The in-vivo behaviour of microfabricated GOD (glucose oxidase)/H2O2 glucose sensor implanted subcutaneously in normal anaesthetized rats has been studied. The sensor consists of a planar, three-electrode microcell, an enzyme membrane (glucose oxidase and bovine serum albumin cross-linked with glutaraldehyde) and an outer diffusion limiting polyurethane membrane. The sensor behaviour during hyperglycaemic (13.8 mM and 11.2 mM), euglycaemic (7.8 mM) and hypoglycaemic (3.5 mM) plateau levels was determined. The values of the in-vivo sensitivity (0.64 +/- 0.05 nA/mM) and background current (1.25 +/- 0.4 nA) were determined using a two-point calibration method and then used to calculate apparent subcutaneous glucose concentrations. The results show the presence of a good correlation between all the plasma glucose levels (G) and the apparent subcutaneous tissue concentrations (G'), with G' = 0.997.G - 0.066, r = 0.9782.

Animals↗
PubMed1991

Effects of a peroxisome proliferator on beta-oxidation and overall energy balance in obese (fa/fa) rats.

The aim of the study was to examine in the obese Zucker (fa/fa) rats the effect of a peroxisome proliferator nafenopin on liver and brown adipose tissue peroxisomal and mitochondrial beta-oxidation enzyme activities and on the overall energy dissipation. A 17-day nafenopin treatment increased liver wet weight 2.1-fold and liver total acyl-CoA oxidase and mitochondria beta-oxidative activities 32- and 4.6-fold, respectively. It increased the interscapular brown adipose tissue (IBAT) acyl-CoA oxidase activity 2.1-fold but had no effect on the mitochondria beta-oxidative activity. Because nafenopin was found to decrease food intake by 22%, obese nafenopin-treated rats were compared with a group of obese pair-fed rats. Both food restriction and nafenopin treatment decreased body weight gain, but a decrease (14%) in fat content was only observed in nafenopin-treated rats. Food restriction of obese rats decreased the mean metabolic rate by 13%, and nafenopin treatment prevented this decrease. Both food restriction and nafenopin treatment decreased the mean daily respiratory quotient (RQ). However, the RQ of nafenopin-treated rats was steadily lower than that of control, whereas that of food-restricted rats was the same as that of control animals during the feeding period and decreased when food supply was exhausted. The increase in liver and IBAT fatty acid beta-oxidative activities may be the cause of the decreased lipid accretion measured in obese rats.

Adipose Tissue↗
PubMed1991

Insulin secretory response to secretagogues by perifused islets from chronically glucose-infused rats.

Perifused islets from rats infused for 7 days with 40% glucose exhibited an altered secretory response to selected stimuli. Both phases of insulin release were blunted when 20 mM L-leucine was tested; the secretory response to a subsequent leucine stimulation was also blunted compared with the control group. The ability of 20 mM alpha-ketoisocaproate to stimulate the release of insulin was also greatly diminished in islets from glucose-infused rats. The secretory response to 50 microM tolbutamide plus 7 mM glucose by perifused islets from glucose-infused rats was 45% lower than in the control group. In addition, the response to a subsequent 10 mM glucose stimulation was lost. On the other hand, islets from glucose-infused rats responded to 20 microM forskolin plus 16.7 mM glucose with on significant change in the amount of insulin released during both phases of stimulation compared with the control group. The response to 100 nM phorbol 12-myristate 13-acetate was 3.1-fold higher in islets from glucose-infused compared with saline-infused rats. The finding that chronic infusions of glucose lead to selective impairment of the secretory response to fuel stimuli and agents such as tolbutamide that act on metabolically regulated K+ channels gives support to the notion that alterations in the generation of metabolic coupling signals might be involved in the phenomenon described here.

Animals↗
PubMed1991

Evolution of insulin secretory response to glucose by perifused islets from lean (FA/FA) rats chronically infused with glucose.

Chronic infusion of nondiabetic rats with glucose for up to 7 days modified the insulin secretory response by subsequently perifused islets. Thus, on the 1st day of infusion with 40% glucose, the islets responded to 16.7 mM glucose with a 3.9-fold increase in insulin release during the first 10 min with no significant change during the second-phase insulin output compared with the control group. On the 2nd day, there was a 2-fold enhancement of insulin release during the initial 10 min of stimulation, the second phase being a similar to control islets. On the 5th day of infusion, the pattern of insulin release was not significantly different from the control group. After 7 day of infusion, there was a 46% decrease in first-phase and a 33% decrease in second-phase insulin response to glucose. The response to 10 mM arginine plus 5 mM glucose was not modified by chronic glucose infusion. Priming experiments indicate that islets from rats infused for 7 days were not able to recover the normal pattern of secretion in vitro. Islets from 7-day glucose-infused rats contained 75% more protein and had a significantly higher insulin content than control islet, suggesting that insulin synthesis is not involved in the loss of the response observed. Glucose metabolism by the islets was modified by glucose infusion with a significant increase in glucose utilization and no changes in glucose oxidation, suggesting that alterations in mitochondrial oxidative events are involved in the phenomenon of desensitization.

Animals↗
PubMed1991

Aspects of neuroregulation of body composition and insulin secretion.

Perturbances in the autonomic nervous control of different target tissues (e.g. endocrine pancreas, brown adipose tissue) are present in the genetically obese (fa/fa) rat. These disorders are probably secondary to central dysregulation(s). In view of the reported effects of CRF in stimulating sympathetic nerve-mediated mechanisms while inhibiting vagus nerve-mediated ones, ovine CRF (oCRF) was administered for 7 days into the cerebral ventricles of fa/fa rats. oCRF treatment stopped the excessive weight gain of the obese animals. The oCRF effect was unrelated to changes in food intake, as the two groups were pair-fed. oCRF-treated obese rats were characterized by a decrease in basal hyperinsulinemia, increases in brown adipose tissue weight and activity, and decreases in hepatic glycogen content and epididymal fat pad weight. It is suggested that intracerebroventricular oCRF administration to obese fa/fa rats prevents the increase in body weight observed in vehicle-infused obese rats by modulating the impaired autonomic nervous control of different target tissues. This does not occur in lean rats.

Adipose Tissue↗
PubMed1990

Contribution of glycerol and alanine to basal hepatic glucose production in the genetically obese (fa/fa) rat.

Increased hepatic glucose production has been reported to occur in the insulin-resistant genetically obese fa/fa rats. The possible existence of an increased basal gluconeogenesis in obese rats was investigated, upon comparing the metabolic fate of glycerol and alanine in liver of fed anaesthetized lean and genetically obese (fa/fa) rats. Glycerol turnover rate in obese animals was 3 times that of the lean. This increase in glycerol turnover rate was associated with an increase in blood glycerol levels in obese animals. The contribution of glycerol to glucose production was significantly increased in obese animals. In contrast, the contribution of alanine to the hepatic glucose production was similar to lean and obese animals. A higher incorporation of glucose, glycerol and alanine into hepatic lipids was observed in obese animals than in controls. It is concluded that in fed genetically obese (fa/fa) rats the high blood glycerol concentrations is a major driving force for the increased basal hepatic conversion of this substrate into glucose.

Alanine↗