Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia

<p>Abstract</p> <p>Background</p> <p>At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (<it>MC4R</it>) in the development of cancer cachexia. In humans, <it>MC4R </it>mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele.</p> <p>Methods</p> <p>BMI (body mass index in kg/m²) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (± SD) was 59.0 ± 14.5 (males: 58.8 ± 14.0, females 59.2 ± 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP.</p> <p>Results</p> <p>Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39).</p> <p>Conclusion</p> <p>Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele; possibly, Ile103 carriers might be more resistant to cancer cachexia in patients with solid tumors. Further studies of the melanocortinergic system in cachexia of patients with solid tumors are warranted.</p

Field trial on glucose-induced insulin and metabolite responses in Estonian Holstein and Estonian Red dairy cows in two herds

<p>Abstract</p> <p>Background</p> <p>Insulin secretion and tissue sensitivity to insulin is considered to be one of the factors controlling lipid metabolism <it>post partum</it>. The objective of this study was to compare glucose-induced blood insulin and metabolite responses in Estonian Holstein (EH, n = 14) and Estonian Red (ER, n = 14) cows.</p> <p>Methods</p> <p>The study was carried out using the glucose tolerance test (GTT) performed at 31 ± 1.9 days <it>post partum</it> during negative energy balance. Blood samples were obtained at -15, -5, 5, 10, 20, 30, 40, 50 and 60 min relative to infusion of 0.15 g/kg BW glucose and analysed for glucose, insulin, triglycerides (TG), non-esterified fatty acids (NEFA), cholesterol and β-hydroxybutyrate (BHB). Applying the MIXED Procedure with the SAS System the basal concentration of cholesterol, and basal concentration and concentrations at post-infusion time points for other metabolites, area under the curve (AUC) for glucose and insulin, clearance rate (CR) for glucose, and maximum increase from basal concentration for glucose and insulin were compared between breeds.</p> <p>Results</p> <p>There was a breed effect on blood NEFA (<it>P </it>< 0.05) and a time effect on all metabolites concentration (<it>P </it>< 0.01). The following differences were observed in EH compared to ER: lower blood insulin concentration 5 min after glucose infusion (<it>P </it>< 0.05), higher glucose concentration 20 (<it>P </it>< 0.01) and 30 min (<it>P </it>< 0.05) after infusion, and higher NEFA concentration before (<it>P </it>< 0.01) and 5 min after infusion (P < 0.05). Blood TG concentration in ER remained stable, while in EH there was a decrease from the basal level to the 40^thmin nadir (<it>P </it>< 0.01), followed by an increase to the 60^thmin postinfusion (<it>P </it>< 0.01).</p> <p>Conclusion</p> <p>Our results imply that glucose-induced changes in insulin concentration and metabolite responses to insulin differ between EH and ER dairy cows.</p

Effect of fasting and dexamethasone on binding characteristics of canine erythrocyte insulin receptors

Insulin binding characteristics of canine erythrocyte insulin receptors were studied before and after a 72-hour fast, and one and three days following glucocorticoid (dexamethasone) administration. The 72-hour fast tended to increase maximum insulin binding, but no significant differences were found. The administration of dexamethasone resulted in an increased maximum binding of insulin to its receptors which, at day 1, was due to an increase in receptor concentration, and at day 3, to an increased insulin binding affinity of the receptor. These data suggest that the erythrocyte insulin receptor may be useful in clinical and experimental studies in the dog

Effect of Insulin on Fever in Endotoxic Sheep

A study was conducted to determine the effect of intravenous (i.v.) administration of insulin on fever in sheep challenged with bacterial endotoxin, lipopolysaccharide (LPS). Six castrated male Suffolkcross wethers were randomly assigned to receive one of the following treatment combinations i.v: Saline control (SAL+SAL); SAL + LPS (0.06 &mu;g kg-l BW) or various doses of insulin (I) (2, 6, 12 or 20 mU kg-l BW) + LPS (0.06 &mu;g kg-1 BW). Serial blood samples were collected at hourly intervals for 10 h after the start of i.v injections. Glucose concentrations in the plasma were measured. Rectal temperature was monitored at the same time as for serial blood sampling. Temperatures for the saline control sheep (SAL+SAL) remained relatively constant throughout the study period ranging from 38.9 &plusmn; 0.1 to 39.1 &plusmn; 0.1&ordm;C. The SAL+LPS treated sheep had significantly (P&lt;0.05) elevated temperatures compared to the saline controls from 1 to 8 h post LPS injection. The sheep injected with 12mUI +LPS had significantly (P&lt;0.05) lower body temperature compared to the SAL +LPS treated sheep from 3 to 6 h post LPS injection. Within the insulin + LPS treatment combinations the 12mUI +LPS combination was found to significantly reduce (P&lt;0.05) body temperature in sheep to levels similar to the saline controls from 5 to 8 h after LPS injection. Sheep on the SAL+LPS or I+LPS treatments had reduced (P&lt;0.05) glucose levels than the saline control sheep from 5 to 8 h post LPS injection. This study demonstrates the ability of insulin to reduce fever in LPS challenged sheep

Modulation of Growth Hormone-Releasing Factor Stimulated Growth Hormone Secretion by Plasma Glucose and Free Fatty Acid Concentrations in Sheep

Effects of plasma glucose and free fatty acid (FFA) concentrations on bovine growth hormone-releasing factor (bGRF)-induced release of growth hormone (GH) were examined in ovariohysterectomized sheep. In experiment 1, the effects of an infusion of insulin (0.025 U/kg BW·h⁻¹), glucose (40 mg/kg BW·h⁻¹), insulin plus glucose or saline on the subsequent effects of bGRF on plasma GH concentrations were determined. Insulin-induced hypoglycemia inhibited GRF effects on plasma GH concentrations while glucose infusion enhanced bGRF actions. Infusing a higher glucose dose (120 mg/kg BW·h⁻¹) had no effect on GRF actions. Subsequently, infusion of FFA (0.25 g/kg/·h⁻¹), nicotinic acid (50 mg/kg BW) or saline for 1 h prior to bGRF injection demonstrated that FFA inhibited GRF actions but FFA depletion by nicotinic acid infusion had no effect on GRF actions. Nicotinic acid (40 mg/kg BW·h⁻¹) infused for 2 h prior to bGRF injection significantly enhanced bGRF-stimulated GH secretion. Finally, to determine whether central nervous system glucopenia produced similar effects to insulin-induced hypoglycemia, 2-deoxyglucose (500 mg) was injected into the lateral ventricle followed in 1 h by the i.v. injection of bGRF. The central glucopenia produced by 2-DG inhibited GRF-stimulated GH release. These data demonstrate that decreased peripheral or central nervous system glucose availability and exogenous administration of FFA antagonized GRF-induced release of GH. And, pharmacologic depletion of circulating FFA for at least 2 h facilitated GRF-induced release of GH

Effects of acute insulin deficiency on catecholamine and indoleamine content and catecholamine turnover in microdissected hypothalamic nuclei in streptozotocin-diabetic rats

The effects of streptozotocin-induced diabetes on catecholamine and indoleamine concentrations and catecholamine turnover rates in individual microdissected hypothalamic nuclei known, or believed, to be involved in the control of neuroendocrine function, were examined in control, insulin-treated diabetic and acutely insulin-withdrawn diabetic female rats. Streptozotocin-induced diabetes and acute insulin deficiency were demonstrated to result in increased concentrations of epinephrine in the suprachiasmatic nucleus, decreased turnover of epinephrine in the arcuate nucleus and decreased turnover of dopamine in the ventromedial nucleus was found to be increased in the insulin-treated diabetic animals. These data indicate that experimental diabetes and acute insulin deficiency result in the rapid onset of detectable alterations in epinephrine and dopamine activity in specific hypothalamic nuclei. These diabetes-induced changes may cause, or contribute to, the development of secondary neuroendocrine abnormalities known to occur in the diabetic condition

Effects of parachlorophenylalanine, quipazine and cyproheptadine on growth hormone and adrenocorticotropin secretion in steers

Adrenergic and perhaps dopaminergic neurons provide inhibitory regulation of growth hormone (GH) secretion in ruminants. This suggests that either serotonergic or other neurons regulate the stimulatory release of GH. The nature of neurotransmitter control of adrenocorticotropin (ACTH) secretion in ruminants has not been determined. Parachlorophenylalanine (PCPA; serotonin synthesis inhibitor), quipazine (serotonin receptor agonist) and cyproheptadine (serotonin receptor antagonist) were utilized in Holstein steers to determine whether serotonin receptors mediate stimulatory actions on GH and ACTH secretion. PCPA (100 mg/kg BW) administered each day at 1900 hr for three successive days did not alter mean GH concentrations, amplitude of GH peaks, nor the number of GH peaks. Likewise, PCPA altered none of these parameters for ACTH. Quipazine injected iv at .1 or .5 mg/kg BW increased plasma GH (

Binding characteristics of swine erythrocyte insulin receptors

Crossbred gilts (controls; n = 7) had 8.8 ± 1.1% (mean ± SEM) maximum binding of [ 125I]insulin to insulin receptors on erythrocytes. The number of insulin-binding sites per cell was 137 ± 19, with a binding affinity ranging from 7.4 x 107M⁻¹ to 11.2 x 107M⁻¹ and mean of 8.8 x 107M⁻¹. Pregnant sows (n = 5) had a significant increase (