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Biomedical subjects

B Jeanrenaud

Publications and source records attributed to B Jeanrenaud.

At least 199 records · Page 11Linked to original sources
PubMed1978

Longitudinal study on the establishment of insulin resistance in hypothalamic obese mice.

A longitudinal in vivo and in vitro analysis of the genesis of insulin resistance has been carried out in mice made obese by chemical made obese by chemical lesion (goldthioglucose, GTG) of the hypothalamus. Six weeks after GTG administration, glycemia and glucose disposal were normal but associated with increased insulin concentration, suggesting incipient insulin resistance. The in vitro counterpart of the latter in obese mice was observed in soleus muscle that was somewhat less responsive to insulin than controls, in liver that had increased basal lipogenesis but was uninfluenced by insulin, and in hepatic plasma membranes in which a slight decrease of insulin binding was measured. At this stage of obesity, basal adipose tissue lipogenesis was increased but the tissue responded in a normal fashion to insulin. These relatively discrete early metabolic changes were corroborated in vivo by a normal hypoglycemic effect of exogenous insulin. Sixteen weeks after GTG administration, hyperglycemia and gross hyperinsulinemia were recorded. This insulin resistance was evidenced in vivo by the lack of hypoglycemic effect of exogenous insulin unless considerable amounts of the hormone were administered. It coincided in vitro with a poor response of soleus muscle to insulin, an absence of a stimulatory effect of the hormone upon both adipose tissue and liver tissue, and a marked decrease in insulin binding to liver plasma membranes. It appears that insulin resistance is a multifactorial and progressive abnormality that might involve both insulin receptor and intracellular metabolic alterations.

Adipose Tissue↗
PubMed1977

Comparative effects of native insulin and insulin-dextran complexes on the metabolism of adipose tissue.

Insulin-dextran complexes have been prepared and their biological activities compared to that of native insulin. Complexes referred to as T-70 had a molecular weight of about 450 000, T-2000 being more than 2 million. Insulin-dextran T-70 was stable and no release of free insulin from the complex was observed upon its incubation with adipose tissue. Insulin-dextran T-70 mimicked the effects of native insulin upon adipose tissue metabolism. It also lowered blood sugar. These effects necessitated, on an insulin molar basis, concentrations of the complex that were 10-times greater than those needed for native insulin. Maximal concentrations of insulin complex T-70 or native insulin elicited similar quantitative effects. This suggested that when the concentration of insulin-dextran T-70 was high enough, the complex occupied a sufficient number of receptor sites to produce maximal stimulation of the tissue. In contrast, insulin-dextran T-2000 was barely effective, indicating that, probably due to its size, it was unable to reach receptor sites. The size, stability and metabolic effects of insulin-dextran T-70 observed in this study give additional support to the concept that insulin action is probably mediated via a series of events initiated at the level of the plasma membrane of adipocytes.

Adipose Tissue↗
PubMed1977

Immediate effect of lesion of the ventromedial hypothalamic area upon glucose-induced insulin secretion in anaesthetized rats.

Insulin secretion, measured in vivo following an intravneous load of glucose to anaesthetized rats, was markedly increased ten minutes after bilateral electrolytic lesions of the ventromedial hypothalamic (VMH) area when compared to both sham-operated and unoperated controls. The successful lesioning of the VMH area was assessed by the subsequent occurrence of hyperphagia, as estimated by the increase in body weight. It is concluded that the ventromedial hypothalamic area exerts an inhibitory influence upon the secretory activity of the B-cells. Furthermore, the rapid disappearance of such inhibitory influence following lesions of the VMH suggests that this area of the brain may be of importance in the minute to minute regulation of insulin secretion. The precise anatomical location of the hypothalamic "nucleus" (or "nuclei") involved, as well as the neural or humoral nature of its inhibitory effect upon the endocrine pancreas remain to be elucidated.

Animals↗
PubMed1977

Inhibitory effect of colchicine on amylase secretion by rat parotid glands. Possible localization in the Golgi area.

Colchicine inhibited amylase secretion by isolated rat parotid glands only 6 h after administration of the drug in vivo. This delayed effect was not the result of the inability of the drug to reach its reaction site. When parotid glands were emptied of their secretory granules by isoproterenol treatment, the subsequent replenishment of cells with granules was inhibited by colchicines. Colchicine concomitantly produced alterations of the Golgi complexes, the cisternae of which were reduced in size and surrounded by clusters of microvesicles. Incubation of parotid glands with colchicines for prolonged durations failed to alter stored amylase secretion as stimulated by isoproterenol, but it inhibited the release of de novo synthesized enzyme. Another colchicines-binding activity, firmly bound to the particular fraction of homogenates, was found, of which a part may represent membrane located microtubular protein. An assembly-disassembly cycle of microtubules appears to exist in the parotid gland, as in the liver. However, only 14 percent of tubulin was found to be polymerized as microtubules in parotid glands as opposed to 40 percent in the liver. The present data suggest that colchicine primarily inhibits the transfer of secretory material towards or away from the Golgi complexes but not the hormone-stimulated secretion of stored amylase.

Amylases↗
PubMed1977

Consequences of ventromedial hypothalamic lesions on metabolism of perfused rat liver.

Metabolism of perfused livers from control and ventromedial hypothalamus (VMH)-lesioned rats has been studied. To eliminate the possibility that observed metabolic abnormalities could be realted to hyperphagia, VMH-lesioned rats were placed on restricted diet matching that of controls. Ten days postoperatively, VMH-lesioned rats had hyperinsulinemia, hypertriglyceridemia, increased blood urea nitrogen levels, together with decreased plasma free fatty acid (FFA) and glucose levels. Insulin release produced in vivo by a glucose load was much higher in VMH-lesioned than in control rats. Perfused livers from VMH-lesioned rats secreted more triglycerides and produced more urea than controls, whereas production of glucose and ketone bodies was reduced. Lipogenesis, newly synthesized triglyceride secretion, and the activity of acetyl-CoA carboxylase and fatty acid synthetase were greatest in livers from VMH-lesioned rats. Fasting abolished hyperinsulinemia and most of these observed metabolic alterations. After treatment with anti-insulin serum, the high rate of lipogenesis observed in livers from VMH-lesioned rats was restored toward normal. It is suggested that hyperinsulinemia may be partly responsible for the metabolic disorders observed in livers from nonhyperphagic VMH-lesioned rats.

Acetyl-CoA Carboxylase↗
PubMed1977

Effect of fasting and streptozotocin in the obese-hyperglycemic (ob/ob) mouse. Apparent lack of a direct relationship between insulin binding and insulin effects.

The decrease of insulin binding to plasma membranes of liver, adipose, and muscle tissues observed in obese-hyperglycemic (ob/ob) mice was reversed towards normal by prolonged fasting or streptozotocin treatment. The extent of this reversal was related to that of the decrease in hyperinsulinemia of the obese mice. In contrast, binding of glucagon to liver plasma membranes was little influenced by fasting or streptozotocin treatment of obese animals. The relationship between insulin binding and metabolic effects of the hormone did not appear to be identical in all tissues. In muscle, insulin binding and insulin effect on glucose uptake and metabolism changed in parallel--i.e., when binding increased, tissue sensitivity to the hormone increased. In the liver, the increase in insulin binding that followed fasting or streptozotocin treatment was not accompanied by any detectable metabolic effect of insulin on hepatic metabolism. A similar situation appeared to prevail in adipose tissue. The varying relationships observed between the state of insulin binding to membranes and the target tissue responsiveness to the hormone probably reflect the multiplicity of the factors operative in these processes and help us to understand why the over-all obese-hyperglycemic syndrome of ob/ob mice cannot be improved simply by decreasing endogenous hyperinsulinemia.

Adipose Tissue↗
PubMed1976

Secretory processes, carbohydrate and lipid metabolism in isolated mouse hepatocytes. Aspects of regulation by glucagon and insulin.

The procedure of Berry and Friend for isolation of intact hepatocytes has been adapted to mouse livers. The ultrastructure of these cells was satisfactorily preserved. Isolated mouse hepatocytes secreted proteins and triacylglycerols. These secretory processes were inhibited by colchicine, indicating a likely involvement of the microtubular system for their normal occurrence. Ultracentrifugation of medium incubated with hepatocytes, followed by electrophoresis and electron microscopic examination of the floating fraction (density less than 1.006) allowed to conclude that secreted triacylglycerols were very low density lipoproteins. Glycogenolysis and lipogenesis were stimulated or inhibited, respectively, by low concentrations of glucagon (10(-10) M). Other metabolic parameters were influenced by the hormone but were less sensitive to its action. Inhibition of lipogenesis by glucagon was associated with a decrease in acetyl CoA carboxylase activity. This decrease does not appear to be related to intracellular fatty acyl-CoA accumulation secondary to hepatic lipase activation by the hormone. Insulin was effective alone or counteracted glucagon effects on lipogenesis or glycogenolysis only when exposure of cells to collagenase was held minimal. This suggests that, during isolation of hepatocytes, insulin receptors may, for unknown reasons, be more fragile than those of glucagon.

Acetates↗
PubMed1976

Does hyperinsulinemia in ob/ob mice cause an insulin-stimulated adipose tissue?

After a 1-h preincubation to remove endogenous insulin, adipose tissue of obese mice (C57BL/L4 ob/ob) had a lower rate of glucose metabolism than tissue which was not preincubated. In contrast, preincubation did not change the metabolism of adipose tissue from lean mice (C57B1/6J +/+). The preincubation effect was abolished in obese mice which had had their serum insulin levels lowered toward normal by streptozotocin treatment. Injection of anti-insulin serum to obese mice caused adipose tissue removed 15 min after the injection to display a rate of glucose metabolsim lower than that of tissue removed before the injection. No such effect was seen in lean mice. These data are consistent with the hypothesis that hyperinsulinemia in the obese mice causes a chronic state of insulin stimulation of their adipose tissue, possibly contributing to their high rates of lipogenesis and their obesity. Several lipogenic enzymes were measured in adipose tissue of both lean and obese mice, and no single enzymatic abnormality was detected which might explain the hyperlipogenesis. Pyruvate dehydrogenase and acetyl-CoA carboxylase were both insulin-sensitive enzymes in lean and obese mice.

ATP Citrate (pro-S)-Lyase↗
PubMed1976

An anomaly of insulin removal in perfused livers of obese-hyperglycemic (ob/ob) mice.

Obese-hyperglycemic (ob/ob) mice have the interesting feature of being hyperinsulinemic, thus having some characteristics in common with human maturity-onset diabetics. As the cause of hyperinsulinemia in these mice is not established, and as the liver is known to play a role in determining the amount of hormone that reaches the periphery, it was hypothesized that an anomaly in the hepatic handling of insulin might prevail in obese-hyperglycemic mice. Immunoreactive insulin was therefore measured in the perfusate before and after a single passage through perfused livers of lean and ob/ob mice, permitting. It was found that the removal of insulin by livers of lean mice increased with increasing concentrations of the hormone in the portal vein. The removal process had a limited capacity, however, and as a consequence the percentage of hormone removed by the liver actually decreased when portal insulin concentrations increased. Insulin removal by livers of ob/ob mice had qualitatively the same characteristics but was considerably less efficient than in normal livers. Due to this, more insulin was found in the perfusate leaving the liver of ob/9b mice than in that of controls, at any insulin concentration tested. These observations suggest that in obese-hyperglycemic mice more of the hormone may reach the periphery and thus contribute to hyperinsulinemia. The present study further suggests that the anomaly of insulin removal observed in perfused livers of ob/ob mice might be secondary to hyperinsulinemia, since it was partly corrected upon artificially decreasing the circulating levels of insulin (e.g. via a fast, anti-insulin serum, or streptozotocin treatment) before perfusion. The characteristics of hepatic insulin removal reported in this study, as well as the differences observed between livers of lean and ob/ob mice, may reflect changes in membrane insulin receptors and/or in processes responsible for the degradation of the horomone.

Animals↗
PubMed1976

Decreased basal, noninsulin-stimulated glucose uptake and metabolism by skeletal soleus muscle isolated from obese-hyperglycemic (ob/ob) mice.

Insulin resistance of diaphragms of ob/ob mice has been repeatedly demonstrated previously both in vitro and in vivo. In the present study, transport and metabolism of glucose with and without insulin stimulation were compared in a skeletal muscle more likely than diaphragm or heart to be representative of the overall striated muscle mass, i.e. isolated soleus muscle. Compared with soleus muscle from lean controls, unstimulated lactate release in the presence of exogenous glucose was depressed from 16.2 to 12.3 nmol/60 min per mg wet wt in soleus from ob/ob mutants; glycolysis was decreased from 6.6 to 3.7 and [14C]glucose oxidation to 14CO2 from 0.90 to 0.33 nmol glucose/60 min per mg wet wt. Uptake of 2-deoxyglucose (2-DOG), both with and without insulin, was very much less for soleus from ob/ob than from lean mice, at 2-DOG concentrations ranging from 0.1 to 10 mM, and in mice of 6-15 wk. When 2-DOG concentration was 1 mM, its basal uptake was 0.53 nmol/30 min per mg wet wt for soleus of ob/ob as against 0.96 for soleus of lean mice. The absolute increment due to 1 mU/ml insulin was 0.49 in muscle of ob/ob as against 1.21 in that of lean mice. When the resistance to insulin action was decreased by pretreatment in vivo by either streptozotocin injection or fasting, the decreased basal 2-DOG uptake of subsequently isolated soleus muscle was not improved. Inhibition of endogenous oxidation of fatty acids by 2-bromostearate, while greatly increasing 14CO2 production from [14C]glucose, did not affect basal [5-3H]glucose metabolism or 2-DOG uptake. It is suggested that transport and/or phosphorylation of glucose under basal, unstimulated conditions are depressed in soleus muscle of ob/ob mice, whether or not resistance to insulin and hyperinsulinemia are also present. Although the origin of the decreased basal glucose uptake remains unknown it might be related to a similar decrease in basal glucose uptake by ventromedial hypothalamic cells, an event presumably resulting in a tendency to hyperphagia. Decreased basal glucose uptake by soleus muscle of ob/ob mice might explain the hyperglycemia, and hence partly the hyperinsulinemia and excessive fat deposition of those animals.

Acetates↗
PubMed1975

Colchicine administration to mice: a metabolic and ultrastructural study.

A single injection of colchicine has been administered to normal albino mice, and the metabolic effects as well as the hepatic ultrastructural changes resulting from this treatment have been studied at various time intervals. A marked decrease in circulating triglyceride levels was evident 4 hours after colchicine injection and was maximum after 11 hours. It coincided with a marked increase in hepatic triglyceride content. Twenty hours after colchicine administration, plasma triglyceride levels and hepatic triglyceride content had returned to normal values. Similar changes in the levels of circulating proteins were observed although their magnitude was less than that observed for triglycerides. Ultrastructurally, colchicine treatment resulted in the virtual disappearance of the microtubules from the hepatocytes, and in the appearance of many clusters of vesicles containing very low density lipoprotein-like particles which eventually transformed into lipid droplets. These ultrastructural alterations were also completely reversible, the reversibility coinciding with the morphological reappearance of microtubules. Finally, colchicine treatment resulted in marked metabolic changes that are interpreted as representing an attempt, by the organism, to keep adequate energy sources during the period of lack of circulating triglycerides.

Amino Acids↗
PubMed1975

Colchicine-binding protein of the liver. Its characterization and relation to microtubules.

Colchicine-binding activity of mouse liver high-speed supernate has been investigated. It has been found to be time and temperature dependent. Two binding activities with different affinities for colchicine seem to be present in this high-speed supernate, of which only the high-affinity binding site (half maximal binding at 5 x 10(-6) M colchicine) can be attributed to microtubular protein by comparison with purified tubulin. Vinblastine interacted with this binding activity by precipitating it when used at high concentrations (2 x 10(-3) M), and by stabilizing it at low concentrations (10(-5) M). Lumicolchicine was found not to compete with colchicine. The colchicine-binding activity was purified from liver and compared with that of microtubular protein from brain. The specific binding activity of the resulting preparation, its electrophoretic behavior, and the electron microscope appearance of the paracrystals obtained upon its precipitation with vinblastine permitted its identification as microtubular protein (tubulin). Electrophoretic analysis of the proteins from liver supernate that were precipitated by vinblastine indicated that this drug was not specific for liver tubulin. Preincubation of liver supernate with 5 mM EGTA resulted in a time-dependent decrease of colchicine-binding activity, which was partly reversed by the addition of Ca++. However, an in vitro formation of microtubules upon lowering the Ca++ concentration could not be detected. Finally, a method was developed enabling that portion of microtubular protein which was present as free tubulin to be measured and to be compared with the total amount of this protein in the tissue. This procedure permitted demonstration of the fact that, under normal conditions, only about 40% of the tubulin of the liver was assemled as microtubules. It is suggested that, in the liver, rapid polymerization and depolymerization of microtubules occur and may be an important facet of the functional role of the microtubular system.

Animals↗