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Biomedical subjects

F Rohner-Jeanrenaud

Publications and source records attributed to F Rohner-Jeanrenaud.

At least 73 records · Page 4Linked to original sources
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

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

Metabolic consequences of hyperinsulinaemia imposed on normal rats on glucose handling by white adipose tissue, muscles and liver.

The effects of hyperinsulinaemia imposed on normal rats on the subsequent insulin-responsiveness in vivo of 2-deoxy-D-glucose uptake of white adipose tissue and of various muscle types were investigated. This was done by treating normal rats with insulin via osmotic minipumps, and by comparing them with saline-infused controls. Hyperinsulinaemia produced by prior insulin treatment resulted in a well-tolerated hypoglycaemia. At the end of the treatment, the glucose utilization index of individual tissues was determined by euglycaemic/hyperinsulinaemic clamps associated with the labelled 2-deoxy-D-glucose method. Prior insulin treatment resulted in increased insulin-responsiveness of the glucose utilization index of white adipose tissue, and in increased total lipogenesis in white adipose tissue and fat-pad weight. In contrast, prior insulin treatment resulted in a decreased glucose utilization index of several muscles. These opposite effects of hyperinsulinaemia on glucose utilization in white adipose tissue and muscles persisted when the hypoglycaemia-induced catecholamine output was prevented (adrenomedullectomy, propranolol treatment), as well as when hypoglycaemia was normalized by concomitant insulin treatment and glucose infusion. Insulin suppressed hepatic glucose production during the clamps in insulin-treated rats as in the respective controls, whereas total hepatic lipid synthesis and liver fat content were greater in rats treated with insulin than in controls. It is concluded that hyperinsulinaemia itself could be one of the driving forces responsible for producing increased glucose utilization by white adipose tissue, increased total lipid synthesis with fat accumulation in adipose tissue and the liver, together with an insulin-resistant state at the muscular level.

Adipose Tissue↗
PubMed1990

Ocular complications in the old and glucose-intolerant genetically obese (fa/fa) rat.

Genetically obese fatty (fa/fa) male rats with abnormal oral glucose tolerance associated with initial hyperinsulinaemia as well as control lean (FA/FA) rats were investigated for the development of retinal microangiopathies. The animals were kept on a standard or sucrose supplemented diet. When tested at 60 weeks, the glucose intolerance of fa/fa rats was accompanied by an insulin response that was now either comparable to that of lean rats (standard diet) or close to nil (sucrose supplemented diet). At killing (68 weeks of age), retinal vasculature was examined by electron microscopy and morphological changes were quantitatively assessed by ultrastructural morphometry. A retinal microangiopathy was observed in all mutant animals which was more pronounced in the sucrose fed group, and which was characterized by: (1), an increase in focal thickenings and in nodules of the basement membrane adjacent to the perivascular glial cells: (2), a decrease in the number of pericyte nulei with concomitant signs of early degenerative cytoplasmic changes of pericytes; (3), an increase in the pinocytic activity of endothelial cells, indicative of presumptive changes in vascular permeability; (4), an increase in the number of intercellular endothelial junctions; (5), the presence of numerous stimulated platelets within capillaries. The fa/fa rat may thus be considered as a suitable model for studying the pathophysiology of ocular complications, in particular retinopathy accompanying non-insulin-dependent diabetes.

Animals↗
PubMed1990

Influence of long-term diabetes on liver glycogen metabolism in the rat.

Diabetes acutely impairs the ability of the liver to synthesize glycogen. However, the effect of chronic diabetes on the glycogenic function of the liver is not known. We measured hepatic glycogen contents in streptozotocin (STZ)-diabetic rats 3 weeks or 9 months after the induction of diabetes, in the fed state and following a 24-hour fast. In the fed state, liver glycogen levels were markedly decreased in short-term diabetic animals (5.8 +/- 2.0 v 33.9 +/- 2.3 mg/g, P less than .001), but not in long-term diabetic rats (18.3 +/- 4.4 v 20.7 +/- 1.3 mg/g, P = NS) as compared with age-matched nondiabetic animals, despite comparable hyperglycemia (portal plasma glucose levels of 424 +/- 21 and 449 +/- 24 mg/100 mL, short- and long-term diabetics, respectively). In the fasted state, on the other hand, liver glycogen was depleted in acute diabetes (4.5 +/- 2.2 mg/g v 1.9 +/- 0.5 of control rats), but significantly increased in chronic diabetes (10.1 +/- 3.1 v 0.2 +/- 0.03 mg/g, P less than .001). The latter finding was confirmed by electron-microscopical examination of liver cells. Furthermore, the percentage of hepatic glycogen synthase in the active form (synthase a) was lower than normal in short-term diabetic rats and in old nondiabetic rats. In long-term diabetic animals, on the other hand, synthase a was significantly higher than in old controls (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1990

Vagal mediation of corticotropin-releasing-factor-induced increase in insulinemia in lean and genetically obese fa/fa rats.

The effects of intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) on plasma glucose and insulin levels were investigated in lean Zucker (FA/FA) rats; i.c.v. CRF induced a rapid (within 1 min), marked, but transient increase in insulinemia that was not accompanied by any change in glycemia. At a time when insulinemia already returned toward basal values, glycemia started to increase. The effect of i.c.v. CRF in stimulating plasma insulin levels was dose-dependent and could be blocked by pretreatment of the animals with atropine methylnitrate. Similar results were obtained when studying the acute effects of i.c.v. CRF in genetically obese (fa/fa) rats. Although, in absolute values, the amount of insulin released in response to i.c.v. CRF was higher in obese than in lean animals, it was similar in both groups of rats, when expressed as fold increase over basal insulin levels. In summary, i.c.v. CRF elicits a rapid, vagally mediated stimulatory effect on insulin secretion both in lean and genetically obese fa/fa rats with no qualitative or quantitative difference between the two groups of animals. The site(s) of action of this CRF effect on insulinemia remains to be elucidated.

Adrenocorticotropic Hormone↗
PubMed1990

Abnormal regulation of the hypothalamo-pituitary-adrenal axis in the genetically obese fa/fa rat.

Adrenalectomy has been shown to reverse most facets of the syndrome of the genetically obese fa/fa rat. However, a detailed analysis of the hypothalamo-pituitary-adrenal (HPA) axis in these animals is lacking. In the present study, morning corticosteronemia was higher in obese rats of both sexes than in lean ones, whereas evening corticosteronemia was higher only in obese male rats. The HPA axis was further investigated using stressful stimuli. Immobilization, ether, and cold stresses resulted in greater corticosterone levels in obese than in lean animals. These abnormalities consisted in upward shifts of the corticosterone response in obese females and absolute increases in that of obese males, indicating that such alterations were more pronounced in obese male than obese female rats. Due to this, the putative origin of the increased corticosterone output of obese rats was studied in males. Greater levels of ACTH were reached in obese than in lean rats when submitted to a cold stress (6 C). Dexamethasone produced a complete suppression of corticosterone output in both lean and obese rats. During the recovery from such suppression, corticosterone levels rose to higher values in obese than in lean rats. This observation together with the greater cold-induced ACTH output in obese rats suggest that the increased activity of the HPA axis of these animals is of central origin. Whatever its precise etiology within the central nervous system, it is proposed that the increased HPA axis activity in obese rats and its resultant hypercorticism play a role in the establishment and maintenance of their syndrome.

Animals↗
PubMed1990

Changes in the hypothalamo-pituitary-adrenal axis of genetically obese fa/fa rats: a structural, immunocytochemical, and morphometrical study.

Most metabolic disorders of genetically obese Zucker rats are reversed by adrenalectomy and are restored by corticosterone treatment, thus suggesting that a functional hypercorticosteronemic state is involved in the pathogenesis of the obesity syndrome in fa/fa rats. However, the hormone content and morphology of the hypothalamo-pituitary-adrenal axis of this animal model have to our knowledge not yet been described. We, thus, investigated morphologically and morphometrically the hypothalamic regions involved in CRF synthesis and secretion in male fa/fa rats. To ascertain if the brain is selectively or uniformly affected, we studied the main nuclei of the lateral and mediobasal hypothalamus, i.e. arcuate, lateral hypothalamic, and ventromedial nucleus and the parvicellular portion of the paraventricular nucleus. Moreover, after immunocytochemical labeling, we analyzed densitometrically the CRF-bearing axons of the median eminence and the ACTH-containing cells of the anterior and intermediate lobe of the pituitary gland. Finally, we investigated the adrenal glands by qualitative light microscopy. In fa/fa rats most hypothalamic nuclei were structurally changed. Furthermore, hypothalamic CRF and anterior pituitary ACTH contents as well as adrenal weight were increased, the zona fasciculata of the adrenal cortex was hypertrophic, and the ACTH content of the intermediate lobe was reduced. In conclusion, our results demonstrate that the obesity syndrome in genetically obese fa/fa rats is associated with lesions of the hypothalamo-pituitary-adrenal axis consistent with hyperadrenocorticism due to hyperactivity of the whole adrenal axis. Alterations also occur in the hypothalamic nuclei controlling glycemia, insulinemia, and circadian corticosterone secretion.

Animals↗
PubMed1990

Hyperinsulinemia increases the amount of GLUT4 mRNA in white adipose tissue and decreases that of muscles: a clue for increased fat depot and insulin resistance.

To mimick a state of hyperinsulinemia, normal rats were infused with insulin for 4 days via minipumps, and compared to saline infused rats. At the end of the experimental period, the abundance of mRNA was increased in white adipose tissue (WAT) and decreased in muscles of "insulinized" rats compared to controls. These findings were accompanied, in all tissues considered, except the diaphragm, by parallel changes in the amount of the glucose transporter protein and by parallel changes in the in vivo glucose utilization index. Hyperinsulinemia is thus a driving force in stimulating adipose tissue metabolic activity, while bringing about incipient muscle insulin resistance.

Adipose Tissue↗
PubMed1989

The effects of islet activating protein on oral glucose tolerance in the genetically obese fa/fa rat.

When tested in insulin-deficient animal models of diabetes, islet activating protein (IAP) has been shown to increase the secretion of insulin and to improve glucose intolerance. The genetically obese fa/fa rat is an animal model of impaired oral glucose tolerance that does not have reduced insulin secretion. In this model IAP treatment increases basal insulin levels, resulting in lower basal glycemia. However, glucose tolerance following an oral glucose load was worsened by IAP. This was found to be due to an exaggerated stimulation of hepatic glucose production (HGP) following glucose, a defect that is already present in the absence of IAP. IAP has been reported to inhibit (by ADP ribosylation) the inhibitory regulatory protein (Ni) of adenylate cyclase. It is therefore suggested that the increased HGP following oral glucose in fa/fa rats either in the absence or in the presence of IAP treatment may result from a cAMP-mediated mechanism. A beta adrenergic activation or a stimulation of glucagon output could therefore be potential candidates responsible for glucose intolerance in obese fa/fa rats.

Adenylate Cyclase Toxin↗
PubMed1989

Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats.

The genetic obesity of the fa/fa rat is due to or accompanied by perturbances in the autonomic nervous control of different target tissues (e.g. endocrine pancreas, brown adipose tissue). These disorders are likely to be secondary to central dysregulation(s), which could lie somewhere within or in relationship with the hypothalamus. 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 at a dose (5 micrograms/day) that did not affect the pituitary-adrenal axis. oCRF treatment stopped the excessive weight gain of the obese animals; oCRF-treated animals gained only 1 g over 6 days, while the vehicle-treated ones gained 29 g (P = 0.044). 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 10-15% increase in body weight observed in vehicle-infused obese rats within 1 week by modulating the impaired autonomic nervous control of different target tissues. This does not occur in lean rats.

Adipose Tissue↗
PubMed1989

In vivo response of microfabricated glucose sensors to glycemia changes in normal rats.

A planar glucose sensor based on an amperometric detection of H2O2 is presented. The transducer part which is a planar three-electrode cell consisting of two Pt-electrodes and one Ag/AgCl-thin film electrode is realized using microelectronic technology. The overall dimensions are 0.8 mm x 3 mm x 0.38 mm and the working electrode area is 0.1 mm2. GOD is immobilized using glutaraldehyde as a cross-linking agent and bovine serum albumin as a carrier protein. The resulting membrane has a typical thickness of 25 microns. Also, an outer polyurethane membrane is dip-coated all around the tip of the electrode. The influence of pO2 on the sensor response as well as the sensor temperature coefficient, sensitivity and linear range have been investigated. The sensor has been tested in vivo in a subcutaneous tissue of anaesthetised rats. During experiments, blood sampling allows to measure changes in venous plasma glucose using a Beckman analyzer. The sensor response following hyperglycaemic clamps as well as intravenous glucose loads is discussed.

Animals↗
PubMed1988

Abnormal regulation of pancreatic glucagon secretion in obese fa/fa rats.

The results reported in the literature regarding glucagonaemia in genetically obese fa/fa rats are conflicting: normal, increased or decreased plasma glucagon levels have been reported. Due to the existence of several molecules endowed with glucagon-like immunoreactivity, it was thought that the conflicting data could be related to the degree of specificity of the different glucagon antibodies. Three antibodies that all qualified as being specific for pancreatic glucagon were used. It was found that, depending on the antibody, absolute values of basal glucagonaemia or arginine-induced glucagon output varied quantitatively and qualitatively in both lean and obese rats. When non-extracted basal or stimulated plasma samples were passed on a G-50 Sephadex column, glucagon-like immunoreactivity was present over a wide range of molecular weights, indicating the presence of non-pancreatic glucagon molecules. When an ethanol extraction was used, the fractions eluting from the G-50 Sephadex column contained only pancreatic glucagon immunoreactivity. It is concluded that ethanol extraction is necessary for the measurement of the 3500 daltons glucagon. Using this methodology it was found that: (1) basal glucagonaemia was low but identical in the two groups of rats; (2) arginine-induced glucagon secretion was greater in obese than in lean animals; (3) glucagonaemia was decreased by glucose administration in lean but not in obese rats. It is concluded that there are, in obese animals, dysfunctions of glucagon output that may play a role in their abnormal glucose tolerance.

Animals↗
PubMed1988

Taste-induced changes in plasma insulin and glucose turnover in lean and genetically obese rats.

Cephalic-phase insulin release (CPIR) and the changes in glucose turnover induced by saccharin ingestion were studied in freely moving lean and genetically obese fa/fa rats equipped with chronic catheters for blood sampling. Six-hour-fasted lean and obese rats were trained to drink 1 ml sodium saccharin (0.15%) or 1 ml glucose (70%), and blood samples were taken before and after the stimuli. As early as 1-1.5 min poststimulus, there was a significant increase in CPIR in lean and obese rats. The amplitude of the CPIR induced either by saccharin or by glucose in the obese rats was significantly higher than it was in the lean rats. The effect of saccharin ingestion on the hepatic glucose production (HGP) and the rate of glucose disappearance (Rd) was studied in 6-h-fasted lean and obese rats, under non-steady-state conditions, according to a method previously validated. Saccharin ingestion produced a significant increase in HGP and Rd in lean and obese rats compared with basal values. The saccharin-induced increments in HGP and Rd were higher in the obese than in the lean animals. We conclude that saccharin (through taste) appears to elicit parasympathetic (insulin release) and sympathetic (HGP increase) reflexes in lean and obese rats. These taste-induced changes in plasma insulin and glucose turnover are exaggerated in the obese rats and may participate in obesity and in insulin resistance of the overall syndrome.

Animals↗
PubMed1987

Non-steady-state measurement of glucose turnover in rats by using a one-compartment model.

One of the tracer methods often employed to measure glucose turnover in the non-steady state uses the one compartment model of Steele (Ann. NY Acad Sci 1959). However, this model gives adequate results when it is assumed that only a fraction of the glucose pool takes part in rapid changes of glucose specific activity, thereby being necessary to use a correction factor called the "pool fraction." The aim of this study was to experimentally determine the best pool fraction needed in the rat for the calculation of glucose turnover using a one-compartment model. This is important as no data are available so far in this widely used species. For this purpose, glucose turnover was measured in anesthetized lean and genetically obese fa/fa rats, using two different experimental designs. In all conditions, the error in estimating the total rate of glucose appearance was lowest when 0.5 was used as the pool fraction. The error was greater with an increase and a decrease in the pool fraction value. It is concluded that in the rat the one-compartment model measures changes in glucose turnover with reasonable accuracy in non-steady-state conditions and that a pool fraction of 0.5 gives the best results.

Animals↗