Effects of obesity on insulin sensitivity and responsiveness in sheep

1989 ◽  
Vol 257 (5) ◽  
pp. E772-E781 ◽  
Author(s):  
E. N. Bergman ◽  
S. S. Reulein ◽  
R. E. Corlett
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Receptors ◽  
High Energy ◽  
Response Curves ◽  
Peripheral Tissues ◽  
Glucose Clamp Technique ◽  
Body Weights ◽  
Tissue Sensitivity ◽  
Free Body ◽  
The Right

To assess the mechanisms of insulin resistance in the ruminant, severe and adult-onset obesity was produced in Dorset ewes by overfeeding a high-energy ration over a 1- to 2-yr period. Body weights increased to 100 kg compared with 50 kg in lean control sheep; significant hyperinsulinemia (40 +/- 4 vs 10 +/- 1 microU/ml) also developed as did a moderate hyperglycemia (62 +/- 2 vs. 52 +/- 1 mg/100 ml). Tissue sensitivity and responsiveness to insulin were then determined in both obese and lean sheep by the euglycemic glucose-clamp technique. Insulin was infused at eight different rates from 0.2 to 50 mU.kg-1.min-1 and [6-3H]-glucose was infused for measurement of glucose kinetics. The mean dose-response curves for glucose utilization and clearance rates were displaced to the right in obese compared with lean sheep. As a result, the half-maximally effective insulin concentrations usually were elevated two- to fourfold, indicating decreased insulin sensitivity in obese sheep, and this is consistent with decreased insulin receptors in peripheral tissues. On the basis of fat-free body weight, the maximal glucose responses, however, were not significantly different between obese and lean sheep, indicating that postreceptor defects do not exist in muscle tissue. Furthermore, lean ruminants are more resistant to insulin than are humans, but this resistance seems only because of the sheep's decreased responsiveness to insulin and thus only because of postreceptor insulin effects in peripheral tissues.

Ridogrel Inhibits Systemic and Renal Formation of Thromboxane A2 and Antagonizes Platelet Thromboxane A2/Prostaglandin Endoperoxide Receptors upon Chronic Administration to Man

1992 ◽  
Vol 68 (02) ◽  
pp. 214-220 ◽  
Author(s):  
C Weber ◽  
J R Beetens ◽  
F Tegtmeier ◽  
P Van Rooy ◽  
E Vercammen ◽  
...  
Keyword(s):  
Uric Acid ◽  
Potent Inhibitor ◽  
Ex Vivo ◽  
Thromboxane A2 ◽  
Chronic Administration ◽  
Response Curves ◽  
Clinically Significant ◽  
Synthase Inhibitor ◽  
The Right ◽  
Steady State Plasma Level

SummaryThe effects of ridogrel, a dual thromboxane A2 (TXA2) synthase inhibitor and TXA2/prostaglandin (PG) endoperoxide receptor antagonist, on systemic and renal production of prostaglandins and on platelet TXA2/PG endoperoxide receptors was evaluated upon chronic administration (300 mg b. i. d. orally, for 8 and 29 days) to man. Such a medication with ridogrel inhibits the systemic as well as the renal production of TXA2 as measured by the urinary excretion of 2,3-dinor-TXB2 and TXB2 respectively without inducing significant changes in systemic or renal PGI2 production. Simultaneously with the latter effects, the production of TXB2 by spontaneously coagulated whole blood ex vivo is inhibited (>99%) while that of PGE2 and PGF2α is largely increased. Administration of ridogrel causes a three- to five-fold shift to the right of concentration-response curves for U46619 in eliciting platelet aggregation; no tachyphylaxis is observed after 29 days of treatment in this respect. Apart from a reduction of serum uric acid levels with a concomitant increase in urinary uric acid excretion during the first days of treatment, no clinically significant changes in hematological, biochemical, hemodynamic and coagulation parameters occur during the 8 days or 29 days study. The study demonstrates that ridogrel is a potent inhibitor of the systemic as well as renal TXA2 synthase and an antagonist of platelet TXA2/PG endoperoxide receptor in man, covering full activity during 24 h at steady-state plasma level conditions without tachyphylaxis during 29 days of medication. The compound is well tolerated, at least during 1 month of administration.

scholarly journals The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

2021 ◽  
Vol 46 (6) ◽  
pp. 1350-1358
Author(s):  
Fruzsina Bagaméry ◽  
Kamilla Varga ◽  
Kitti Kecsmár ◽  
István Vincze ◽  
Éva Szökő ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Metabolism ◽  
Relative Significance ◽  
Differentiated Cells ◽  
Mature Neuron ◽  
The Right ◽  
The Impact

AbstractRecently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

Evaluation of β-Adrenerglc Blocking Agents in Presence of Adrenergic Tone

1972 ◽  
Vol 50 (5) ◽  
pp. 381-388
Author(s):  
Victor Elharrar ◽  
Reginald A. Nadeau
Keyword(s):  
Dose Response ◽  
Sinus Node ◽  
Stellate Ganglion ◽  
Sodium Pentobarbital ◽  
Response Curves ◽  
Chronotropic Response ◽  
Blocking Agents ◽  
Sinus Node Artery ◽  
Anesthetized Dogs ◽  
The Right

The importance of the level of adrenergic tone in the determination of the dose–response curve to noradrenaline (NA) and in the evaluation of β-adrenergic blocking agents was studied in open-chest sodium pentobarbital anesthetized dogs by injecting drugs directly into the sinus node artery. Changes in the level of adrenergic tone by stimulating the right stellate ganglion resulted in variation of the observed chronotropic response to NA and of its ED50. The chronotropic responses were corrected by taking into account the underlying adrenergic tone. The negative chronotropic effect of dl-propranolol (1 and 10 μg) appeared to be related to its β-blocking properties and not to its quinidine-like effects as shown by the lack of effect of d-propranolol injected at the same doses. The magnitude of the negative chronotropic effects of 10 μg of propranolol and 100 μg of practolol, oxprenolol, and sotalol was shown to be related to the initial heart rate and consequently to the level of adrenergic tone. The comparison of these four β-blocking agents was carried out on corrected dose-response curves to NA. Their relative potencies were found to be: propranolol > oxprenolol > practolol > sotalol, corresponding to ratios of 1, [Formula: see text], [Formula: see text], and [Formula: see text]

EMPTY BODY WEIGHTS, CARCASS WEIGHTS AND OFFAL PROPORTIONS IN BULLS AND STEERS OF DIFFERENT MATURE SIZE

1984 ◽  
Vol 64 (1) ◽  
pp. 53-57 ◽  
Author(s):  
S. D. M. JONES ◽  
R. E. ROMPALA ◽  
J. W. WILTON ◽  
C. H. WATSON
Keyword(s):  
Body Weight ◽  
Small Animal ◽  
High Energy ◽  
Carcass Weight ◽  
Small Animals ◽  
Beef Steers ◽  
Body Weights ◽  
Breed Crosses ◽  
Large Animals ◽  
Animal Size

Empty body weights, carcass weights and offal proportions were compared in 33 young beef bulls and 33 beef steers of different mature body size (35 small or mainly British breed crosses, 31 large or Continental crosses). All cattle were fed a high energy diet based on corn silage and high moisture corn from weaning to slaughter. Slaughter was carried out once 6 mm of fat had been attained at the 11/12th ribs, determined ultrasonically. Feed was removed 24 h and water 16 h prior to slaughter. The offal components were all weighed fresh and the alimentary components emptied of digesta. Bulls weighed 8.0% heavier (P < 0.05) than steers at slaughter, while large animals were 38.7% heavier (P < 0.0001) than small animals. Bulls and large animals had carcasses that dressed out 1.5% heavier than steers and small animals. To eliminate the effect of gutfill, carcass weights and offal components were expressed as a proportion of empty body weight. Bulls had a higher proportion of warm carcass weight and lower proportions of liver, spleen, heart, lungs, rumen, abomasum, large intestine and front feet relative to empty body weight than steers. Large animals had a greater proportion of warm carcass weight and hind feet, and a lower proportion of head, hide, liver, kidneys, omasum and small intestine relative to empty body weight than small animals. All castration by size interactions for liveweight, carcass weight, empty body weight and offal proportions were not significant. Castration and small animal size both increased the proportion of noncarcass parts relative to empty body weight in animals slaughtered at similar finish. Key words: Body, carcass, offal, bull, steer, maturity

scholarly journals Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

2017 ◽  
Vol 114 (40) ◽  
pp. E8478-E8487 ◽  
Author(s):  
Masahiro Konishi ◽  
Masaji Sakaguchi ◽  
Samuel M. Lockhart ◽  
Weikang Cai ◽  
Mengyao Ella Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Food Intake ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Peripheral Tissues ◽  
Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

Antagonist properties of arylaminopyridazine GABA derivatives at the Ascaris muscle GABA receptor

1991 ◽  
Vol 159 (1) ◽  
pp. 149-164
Author(s):  
A. H. Duittoz ◽  
R. J. Martin
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Gaba Receptor ◽  
Dissociation Constants ◽  
Ascaris Suum ◽  
Antagonistic Activity ◽  
Maximal Response ◽  
Response Curves ◽  
Gaba Derivatives ◽  
The Right

1. In a previous study, it was shown that the potency order for two arylamino-pyridazine derivatives, SR95531 and SR95103, was different in Ascaris suum when compared to vertebrate preparations. SR95531, the most potent analogue at the vertebrate GABAA receptor, was found to be very weak at antagonizing GABA responses in Ascaris, but SR95103, approximately 20 times less potent than SR95531 in vertebrate preparations, was more potent than SR95531 in Ascaris. These results suggested the existence of different accessory binding sites at the Ascaris GABA receptor. 2. To test this hypothesis, the effects of a series of arylaminopyridazine derivatives of GABA on the GABA response in Ascaris suum muscle were investigated using a two-microelectrode current-clamp technique. 3. The results showed that SR42627, a potent antagonist at the GABAA receptor, was one of the weakest analogues in Ascaris muscle. In contrast, SR95132, virtually inactive in vertebrate preparations, was equipotent to SR95103, the most potent analogue of the series in Ascaris muscle. 4. The three most potent analogues in Ascaris, SR95103, SR95132 and SR42666, displace GABA dose-response curves to the right without decreasing the maximal response. The modified Schild plots for these compounds are consistent with a competitive mechanism involving two molecules of GABA and only one molecule of antagonist interacting with the receptor. The estimated dissociation constants for SR95103, SR95132 and SR42666 are, respectively, 64, 65 and 105 mumol l-1. 5. Structure-activity relationships for this series of compounds were examined in Ascaris and compared to those in vertebrates. Substitution on the pyridazine ring in the 4-position, while detrimental for the antagonist potency at the vertebrate GABAA receptor, appears to be a prerequisite for antagonistic activity on the Ascaris muscle GABA receptor. These results are interpreted in terms of the accessory binding site theory of Ariens, and suggest the existence of different accessory binding sites on the Ascaris GABA receptor.

scholarly journals Surgical Treatment for Malunion of the Lateral Humeral Epicondyle with Posterior Subluxation of the Radial Head: A Case Report and Literature Review

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Koichi Yano ◽  
Yasunori Kaneshiro ◽  
Hideki Sakanaka
Keyword(s):  
Lateral Collateral Ligament ◽  
High Energy ◽  
Limited Range ◽  
Forearm Rotation ◽  
Collateral Ligament ◽  
Lateral Epicondyle ◽  
Limited Range Of Motion ◽  
Contracture Release ◽  
Normal Congruence ◽  
The Right

A 24-year-old right-handed man suffered right olecranon and lateral epicondylar fracture from high energy trauma. Fixation of olecranon was performed by a previous doctor. Three months after operation, he presented with limited range of motion (ROM) of the right elbow caused by malunion of the lateral epicondylar fracture and subluxation of the radiohumeral joint. Preoperative ROM of the right elbow was flexion 110° and extension −75°. Forearm rotation was pronation 85° and supination 65°. Fragment excision of the lateral epicondyle, which was 27 mm in length, and lateral collateral ligament repair using anchors were performed. Fourteen months postoperatively, contracture release of the elbow was performed. Twenty-four months postoperatively, radiograph of the elbow showed normal congruence without osteoarthritic changes and the ROM of the right elbow was flexion 120° and extension −35°. Forearm rotation was pronation 90° and supination 70°. In the surgical setting, in case of the size of the lateral epicondylar fragment is relatively large, the fragment should be fixed or lateral collateral ligament should be repaired when the instability of the elbow is found.

Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus

1982 ◽  
Vol 243 (1) ◽  
pp. E15-E30 ◽  
Author(s):  
J. M. Olefsky ◽  
O. G. Kolterman ◽  
J. A. Scarlett
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Tissue Level ◽  
Dependent Diabetes Mellitus ◽  
Target Tissue ◽  
Severe Insulin Resistance ◽  
Glucose Clamp Technique

Resistance to the action of insulin can result from a variety of causes, including the formation of abnormal insulin or proinsulin molecules, the presence of circulating antagonists to insulin or the insulin receptor, or defects in insulin action at the target tissue level. Defects of the latter type are characteristic of obesity and of noninsulin-dependent diabetes mellitus. Analysis of the nature of the insulin resistance in those disorders has been investigated in intact subjects with the use of the euglycemic glucose clamp technique, and both insulin receptors and insulin-mediated glucose metabolism have been studied in adipocytes and monocytes from affected individuals. In both conditions, the cause of insulin resistance is heterogeneous. In some, insulin resistance appears to be due to a defect in the insulin receptor, whereas others have a defect both in the receptor and at the postreceptor level. In both groups, more severe insulin resistance is due to the postreceptor lesion and is correctable with appropriate therapy.

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