[Glucose and insulin in glucose homeostasis in the liver].
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Animals↗
Biomedical subjects
B Jeanrenaud
Publications and source records attributed to B Jeanrenaud.
[Possible role of opioid peptides in the control of energy homeostasis].
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Animals↗
A role for the vagus nerve in the etiology and maintenance of the hyperinsulinemia of genetically obese fa/fa rats.
It is demonstrated that pre-obese Zucker rats, studied before weaning (17 days of age), at a time when they were indistinguishable from lean controls, do hypersecrete insulin in response to glucose or arginine administration when compared to their lean littermates in spite of normal basal insulin levels. When arginine is used as the stimulus, it is shown that pre-obese pups hypersecrete glucagon as well as insulin, the net result of insulin and glucagon oversecretion being probably the observed normoglycemia of these animals. Furthermore, these early substrate-induced increases in pancreatic hormonal secretion could be reduced toward normal values by acute pre-treatment of the pre-obese rats with the cholinergic inhibitor, atropine. It is suggested the parasympathetic nervous system plays a role in genetically obese fa/fa rats in bringing about an early increased substrate-induced insulin release, a defect which could be one of the causes involved in the development of their obesity syndrome. In adult animals, the involvement of the parasympathetic nervous system in insulin oversecretion is less clear probably due to the presence of an increased B cell mass. However, using three different experimental approaches, it could be seen that an increased vagal tone acting at the B cells in obese animals participate to their insulin hypersecretion.
Animals↗
Growth hormone in obesity and diabetes: inappropriate hypothalamic control of secretion.
Some forms of obesity and diabetes may develop because of inappropriate hypothalamic function. Evidence for this hypothesis is presented here. The data suggest that a deficiency of growth hormone and an increase in insulin secretion results in excessive lipid accumulation and obesity. Hypothalamic involvement in the control of these two hormones has been well established. A role for growth hormone in the development of some forms of diabetes is also presented. Normally, high blood glucose suppresses growth hormone release. This suppression should result in an increase of insulin sensitivity and improve plasma glucose control. When there is inappropriate hypothalamic suppression of growth hormone, the anti-insulin activity of growth hormone acts to raise plasma glucose levels even higher. This may be why some forms of obesity precipitate the diabetic state and others do not.
Animals↗
Oversecretion of glucagon by pancreases of ventromedial hypothalamic-lesioned rats: a re-evaluation of a controversial topic.
Glucagon secretion by perfused pancreases of control and ventromedial hypothalamic-lesioned rats was studied in response to a mixture of 20 different amino-acids used at physiological or pharmacological concentrations, and under experimental conditions near to or different from physiological situations. When experimental conditions are too extreme (lack of glucose with 5 or 15 mmol/l final amino-acid concentration), there was no difference of glucagon secretion between pancreases of control and ventromedial hypothalamic-lesioned animals. However, when experimental conditions are as close as possible to those prevailing in vivo (presence of 5 mmol/l glucose with 2.5 or 5 mmol/l amino-acid concentration), pancreases from ventromedial hypothalamic-lesioned rats clearly oversecrete glucagon when compared with control rats (with 2.5 mmol/l amino-acid: controls: 7.9, ventromedialhypothalamic-lesioned: 17.1 ng/20 min, p less than 0.05; with 5 mmol/l amino-acid: controls: 12.6, ventromedialhypothalamic-lesioned: 31.0 ng/20 min, p less than 0.025). Upon extrapolating these results to a situation in vivo, this study indicates that ventromedial hypothalamic-lesioned rats secrete more glucagon than controls in response to physiological stimuli, at least at the level of the portal vein. This could explain why the lesioned rats, known to be hyperinsulinaemic, are nevertheless normoglycaemic and have increased plasma urea levels.
Amino Acids↗
Synthase activation is not a prerequisite for glycogen synthesis in the starved liver.
To evaluate the contribution of phosphorylase and synthase interconversion as well as the availability of substrates to the onset of liver glycogen synthesis, this process was studied in rats starved overnight and refed for 4 h. On feeding, phosphorylase kinase and phosphorylase were inactivated in a cAMP-independent way, but the proportion of synthase a was unchanged and associated with increased hexoses 6-phosphate (glucose and fructose 6-phosphate), uridine diphosphoglucose (UDPG), and fructose 2,6-bisphosphate concentrations. These findings serve to support a "push" mechanism whereby substrate availability for synthase a concerted with phosphorylase inactivation provokes glycogen deposition. Anesthesia was compulsory for liver sampling and analysis. If such experiments were carried out in conscious rats killed by decapitation, artefactual cAMP-dependent phosphorylase activation and synthase inactivation were observed in starved animals. The phosphorylase activation persisted in refed animals but by a cAMP-independent mechanism.
Animals↗
Role of ventromedial hypothalamus on sympathetic efferents of brown adipose tissue.
Previous studies have suggested the presence, in hypothalamic obesity, of an impairment of the energy-dissipating capacity of brown adipose tissue ascribed to a functional disconnection of the sympathetic innervation of this tissue. The following observations demonstrate, with electrophysiological techniques, the presence of a functional link between the ventromedial hypothalamic (VMH) area and the interscapular brown adipose tissue (IBAT) in the rat: the spontaneous activity of the efferent sympathetic nerves reaching the IBAT of normal rats was increased in response to an acute cold stimulus, whereas this increase failed to occur in nerves of VMH-lesioned rats studied 4-7 days after the lesions; and the spontaneous activity of the efferent sympathetic nerves of IBAT decreased rapidly (by greater than or equal to 80% within 30 min) after acute lesions of the VMH area. It is suggested that the VMH area plays a role in increasing the activity of the efferent sympathetic nerves of IBAT during an acute cold stimulus and that alone or in relationship with other, as yet undetermined, central nervous system sites, it has a tonic stimulatory effect on the final common pathways that innervate the IBAT via the efferent sympathetic nerves.
Adipose Tissue, Brown↗
A pure enteroglucagon, oxyntomodulin (glucagon 37), stimulates insulin release in perfused rat pancreas.
Oxyntomodulin, a gut peptide recently purified, has been tested in isolated perfused pancreases of normal rats. It was shown to stimulate insulin release monophasically in the presence of a low (6 mM) glucose concentration in the medium. Furthermore, oxyntomodulin potentiated glucose-induced insulin release (10 mM glucose) in a dose-dependent manner, although it was less powerful in this respect than equimolar concentrations of pancreatic glucagon. As oxyntomodulin belongs to the gut glucagon-like immunoreactants which are released during digestion, it is suggested that oxyntomodulin might be one of the factors that could functionally link the gut and the endocrine pancreas and contribute, at least in part, to the regulation of postprandial insulin release.
Animals↗
Evidence for the presence of a neutral insulinotrophic peptide in the porcine duodenum.
A crude mixture of thermostable peptides extracted from porcine duodenum was fractionated by electrofocusing. A neutral fraction, different from the basic fractions of GIP, VIP, PHI, and CCK was found to promote insulin secretion when injected in vivo to normal rats. This neutral fraction, extracted from the crude mixture by chromatography, stimulated insulin output from an isolated rat pancreas and enhanced glucose-induced insulin release. The insulinotrophic effect of this partially purified duodeno-jejunal material disappeared following digestion with trypsin. The insulin-releasing activity was found to correspond to a compound of molecular weight higher than that of insulin (i.e. higher than 6000). No GIP-like immunoreactivity was found in this neutral fraction indicating that the active peptide(s) are not GIP related compounds. These observations suggest that porcine duodenum contains and incretin activity different from that of the insulinotrophic factors already reported.
Animals↗
[Dysfunctions of the existing axis between the central nervous system and the endocrine pancreas in experimental and genetic obesity in the rodent].
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Animals↗
Altered liver glycogen metabolism in fed genetically obese mice.
The cyclic AMP and glycogen concentrations and the activities of phosphorylase kinase, phosphorylase a and glycogen synthase a were not different in livers from lean or ob/ob mice despite increased plasma glucose and insulin in the obese group. The liver water content was decreased by 10% in the obese mice. In hepatocytes isolated from lean mice and incubated with increasing glucose concentrations (14-112 mM), a sequential inactivation of phosphorylase and activation of glycogen synthase was observed. In hepatocytes from obese mice the inactivation of phosphorylase was not followed by an activation of synthase. The inactivation of phosphorylase occurred more rapidly and was followed by an activation of synthase in hepatocytes isolated from both groups of mice when in the incubation medium Na+ was replaced by K+ or when Ca2+ was omitted and 2.5 mM-EGTA included. The inactivation of phosphorylase and activation of synthase were not different in broken-liver-cell preparations from lean and obese animals. The re-activation of phosphorylase in liver filtrates in the presence of 0.1 microM-cyclic AMP and MgATP was inhibited by about 70% by EGTA and stimulated by Ca2+ and was always greater in preparations from ob/ob mice. The apparent paradox between the impairment of glycogen metabolism in isolated liver preparations and the situation in vivo in obese mice is discussed.
Animals↗
Lack of vasopressin receptors in liver, but not in kidney, of ob/ob mice.
The activity of phosphorylase a was measured in isolated hepatocytes from fed lean and ob/ob mice after addition of vasopressin, angiotensin, phenylephrine and glucagon. The binding of these hormones to purified liver plasma membranes was also determined. In hepatocytes of ob/ob mice, no increase in phosphorylase a was measured after addition of vasopressin, whereas the other hormones promoted an increase in the activity of the enzyme. No specific vasopressin receptors could be measured on purified liver plasma membrane of ob/ob mice. A decrease in the number of receptors for angiotensin and glucagon, without modification of the affinity, was also observed. No restoration of the number of vasopressin receptors was observed in liver of ob/ob mice starved for 3 days or in younger (5-6 weeks) animals. Vasopressin receptors and vasopressin-stimulated adenylate cyclase, measured on purified kidney medulla membranes, were similar in both lean and ob/ob mice. The data indicate a selective lack of vasopressin receptors and metabolic response in liver of the ob/ob mouse.
Animals↗
Fructose 2,6-bisphosphate in livers of genetically obese rats.
Livers of genetically obese (fa/fa) rats, starved for 24 h, contained more fructose 2,6-bisphosphate, glucose 6-phosphate, fructose 6-phosphate and glycogen, and more pyruvate kinase and phosphofructokinase 2 activities, than livers of control lean rats. These changes may be explained in terms of cyclic AMP concentration, which was decreased in livers of obese starved rats.
Animals↗
Effect of phenylephrine on pyruvate dehydrogenase activity in rat hepatocytes and its interaction with insulin and glucagon.
In isolated rat hepatocytes phenylephrine promotes a rapid increase in the amount of pyruvate dehydrogenase present in its active form (PDHa). This action is mediated by alpha 1-adrenergic receptors and is not observed in Ca2+-depleted hepatocytes. It is mimicked by the Ca2+ ionophore A23187. No changes in metabolites known to affect PDH activity are measured 3 min after addition of phenylephrine. Glucagon also increases PDHa, its action is additive to that of phenylephrine. The action of phenylephrine on PDHa could be explained by an increase in mitochondrial free Ca2+.
Animals↗
Identification of the D-glucose-inhibitable cytochalasin B binding site as the glucose transporter in rat diaphragm plasma and microsomal membranes.
[3H]Cytochalasin B binding and its competitive inhibition by D-glucose have been used to identify, the glucose transporter in plasma and microsomal membranes prepared from intact rat diaphragm. Scatchard plot analysis of [3H]cytochalasin B binding yields a binding site with a dissociation constant of roughly 110 nM. Since the inhibition constant of cytochalasin B for D-glucose uptake by diaphragm plasma membranes is similar to this value, this site is identified as the glucose transporter. Plasma membranes prepared from diaphragms bind approx. 17 pmol of cytochalasin B/mg of membrane protein to the D-glucose-inhibitable site. If 280 nM (40000 microunits/ml) insulin is present during incubation, cytochalasin B binding is increased roughly 2-fold without alteration in the dissociation constant of this site. In addition, membranes in the microsomal fraction contain 21 pmol of D-glucose-inhibitable cytochalasin B binding sites/mg of membrane protein. In the presence of insulin during incubation the number of these sites in the microsomal fraction is decreased to 9 pmol/mg of membrane protein. These results suggest that rat diaphragm contain glucose transporters with characteristics identical to those observed for the rat adipose cell glucose transporter. In addition, insulin stimulates glucose transport in rat diaphragm through a translocation of functionally identical glucose transporters from an intracellular membrane pool to the plasma membrane without an alteration in the characteristics of these sites.
Animals↗
Energy fuel and hormonal profile in experimental obesities.
Several types of experimental obesities are characterized by the occurrence of an early hypersecretion of insulin that produces an increase in both triglyceride secretion by the liver and fat deposition in adipose tissue. This hypersecretion of insulin, together with other ill-defined factors, is subsequently responsible for a state of insulin resistance. The early oversecretion of insulin in hypothalamic and genetic (e.g. fa/fa rats) obesities can be experimentally demonstrated. Thus, within 20 min of acute lesion of the ventromedial hypothalamus (VMH), glucose-induced insulin secretion is greater in lesioned than in non-lesioned control rats; this increase can be blocked by superimposed, acute vagotomy. Moreover, an infusion of glucose to 17-day-old, pre-weaned control and genetically pre-obese rats (i.e. animals genetically-determined to become obese but with a normal body weight at this age) elicits much greater insulinaemia in the pre-obese than in the controls, despite similar basal, pre-infusion values in both. This increased insulin secretion in the pre-obese rats can be restored to normal by pre-treating them acutely with the cholinergic inhibitor, atropine. Thus, in these two types of obesity, an increased vagal tone appears to be of importance for the early occurrence of insulin over-secretion. Hyperinsulinaemia produced by increased tone of the vagus nerve appears to be reinforced by the decreased activity of the sympathetic system observed in obese rodents. In many obese rodents, plasma growth hormone levels are abnormally low. The inadequate secretion of this hyperglycaemic hormone may explain why, in some types of obesity syndrome, hyperglycaemia is not necessarily present, despite insulin resistance. Insulin resistance in experimental obesities has been shown to occur at the level of the adipose tissue, the muscles and more recently, the liver. The latter has been demonstrated using the in vivo euglycaemic clamp technique; thus, glycogenolysis of genetically obese (fa/fa) rats could not be shut off, as in controls, by either basal or increased plasma insulin levels. This particular pathway is therefore insulin resistant. The precise etiology of the early over-secretion of insulin in VMH-lesioned rats is, however, unknown: with VMH lesions, the origin is clearly the central nervous system (CNS), but the pathways actually interrupted by the lesions and those responsible for the hyperactivity of the vagus, remain to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
Adipose Tissue↗
Dysregulation of glucose transport in hearts of genetically obese (fa/fa) rats.
Overall D-glucose metabolism and 3-0-methylglucose transport were measured in the perfused heart preparation of lean and genetically obese (fa/fa) rats. Absolute values of basal and insulin-stimulated glucose metabolism were decreased in hearts of 15-week-old obese rats when compared to lean age-matched controls. Basal and maximally stimulated (i.e., by the combined addition of insulin and increasing perfusion pressure) 3-0-methylglucose transport was normal in hearts from young obese rats (5-week-old). However, when only one stimulus was used (insulin or increasing perfusion pressure alone), 3-0-methylglucose transport was stimulated to values that were lower than those of lean rats. Basal 3-0-methylglucose transport was four times lower in hearts from older obese rats (15-week-old) than in lean ones of the same age. At this age, stimulation of 3-0-methylglucose transport by insulin alone, by increasing perfusion pressure alone or by the combination of both stimuli, reached values in obese rats that were only half those of lean animals. It is concluded that: (a) in the early phase of the syndrome, the basal glucose transport system in hearts of obese rats is normal, but its response to stimulation becomes abnormal and; (b) at a later phase of obesity, the glucose transport system becomes abnormal even under basal conditions and its responsiveness to various stimuli is markedly impaired.
3-O-Methylglucose↗
A simple electrode for intact nerve stimulation and/or recording in semi-chronic rats.
A cuff electrode for extracellular nerve stimulation and/or recording is described. It can be made from common laboratory material without the need of special equipment, and consists of a tubular silicone rubber holder enclosing the nerve and keeping it in position against two platinum wires. The assembly is sufficiently insulated to be kept amidst the surrounding tissue, hereby preventing the nerve to dry during recording periods. It can be attached to an adjoining structure, thus allowing further manipulation of the animal.
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