Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

OBJECTIVE: Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects. SUBJECTS AND MEASUREMENTS: Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin. RESULTS: Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed. CONCLUSIONS: Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.     

Effects of age and hypertension on cardiac responses to the α1-agonist phenylephrine in humans

Both aging and hypertension decrease the responsiveness of several receptor systems. The purpose of this study was to investigate the effect of aging versus hypertension on the blood pressure (BP), heart rate, and left ventricular (LV) responses to the α₁-agonist phenylephrine in humans. Fourteen young (age, 21–40 years; range, 30 ± 1 years; mean ± SEM), and 18 older (age, 50–73 years; range, 60 ± 1 years) healthy volunteers, as well as 10 young (age, 30–39 years; range, 36 ± 1 years) and 15 older (age, 50– 64 years; range, 58 ± 1 years) hypertensive subjects were studied. Phenylephrine was administered at four incremental rates for 8 min each. Cardiac responses were assessed by echocardiography. Phenylephrine caused twofold larger increases in systolic BP in young and older hypertensives and older normotensives, compared with young normotensives, but similar decreases in heart rate in all four groups. Younger normotensive subjects exhibited the largest decreases in stroke volume index, ejection fraction, and cardiac index in response to phenylephrine, despite similar increases in end-systolic stress for all groups. There is an age- and hypertension-related decrease in reflex vagal restraint in response to α₁-adrenoceptor stimulation in humans, which leads to significant attenuation of the decrease in heart rate as well as in LV function in response to a pressor stimulus, and presumably therefore to enhanced systolic BP responses relative to young normotensive subjects.     

Effects and relationship of intermittent hypoxia on serum lipid levels,hepatic low-density lipoprotein receptor-related protein 1, and hypoxia-inducible factor 1α

Objective

This study investigated the influence of intermittent hypoxia on serum lipid level, hepatic low-density lipoprotein receptor-related protein (LRP)1, and hepatic hypoxia-inducible factor (HIF)-1α and the underlying mechanisms of action.

Methods

Male Sprague Dawley rats were subjected to different levels of hypoxia. After 1–4 weeks hypoxemia, routine blood tests were performed and the levels of LRP1 and HIF-1α in liver were examined. Intermittent hypoxia (IH) was induced in HepG2 cells with or without HIF-1α inhibitor YC-1 pretreatment, and the levels of LRP1 and HIF-1α in cells were examined.

Results

IH caused elevated serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein in rats. IH caused elevated hepatic levels of LRP1 and HIF-1α. After pretreatment with YC-1, HIF-1α protein expression decreased but mRNA expression did not change in HepG2 cells.

Conclusions

IH caused dyslipidemia and elevated LRP1 and HIF-1α. Elevated LRP1 expression was caused by HIF-1α.

     

What is the contribution of differences in three measures of tumor necrosis factor-alpha activity to insulin resistance in healthy volunteers?

To address the potential role that tumor necrosis factor-alpha (TNF-alpha) might play in modulation of insulin resistance in healthy, nondiabetic individuals, we compared plasma TNF-alpha and soluble TNF-alpha receptor 2 (sTNF-R2) concentrations, as well as TNF-alpha polymorphisms, in 94 healthy individuals, stratified into insulin-resistant (IR) and insulin-sensitive (IS) groups based on their plasma insulin concentrations 120 minutes after oral glucose on 2 occasions (1993 and 2000). The IR group (n = 50; 29 men and 21 women) was in the upper quartile and the IS group (n = 44; 24 men and 20 women) in the lowest quartile of the distribution of post-glucose challenge insulin concentrations in a large unselected population (>50 v <23 microU/mL). The IR group had significantly higher values for body mass index, waist-to-hip girth, fasting and post-glucose challenge insulin concentrations, and fasting triglyceride concentrations, and lower high-density lipoprotein cholesterol concentrations as compared to the IS group. Despite the fact that they were relatively more obese, and insulin-resistant, plasma concentrations of TNF-alpha were similar in the IR (1.6 +/- 0.6 pg/mL) and IS (1.7 +/- 0.6 pg/mL) groups, as were the concentrations (5.4 +/- 1.4 v 5.8 +/- 2.0 pg/mL) of sTNF-R2. Furthermore, TNF-alpha polymorphisms (detected by polymerase chain reaction [PCR]) were similar in the 2 groups, with essentially identical allelic frequencies of the 238 (10.3% v 9.4%) and 308 polymorphisms (17.9% v 18.7%). In conclusion, plasma TNF-alpha and sTNF-R2 concentrations, as well as TNF-alpha gene polymorphisms, were not different in healthy volunteers stratified into IR and IS groups on the basis of their plasma insulin response to an oral glucose challenge. Given these data, it does not appear that differences in TNF-alpha activity contribute to the marked variations in insulin action that occur in healthy individuals.     

Effects of aging on male fertility?

The increase in male life expectancy has raised issues concerning the impact of aging on the endocrine system and male fertility. This review focuses on the relationship of spermatogenesis to changes with age in androgen production and testicular morphology, the influence of age on semen parameters and chromosomal quality, and the impact of paternal age and pregnancy outcome.While age-related endocrine changes are well documented, those concerning semen parameters and consequent fertility are based on cross-sectional studies alone. Nevertheless, characteristic age-related morphological testicular alternations have been described, such as decreased numbers of Leydig cells paralleling decreased testosterone production, arteriosclerotic lesions, thickening and hernia-like protrusions of the basal membrane of the seminiferi tubules, and fibrotic thickening of the tunica albuginea. Surprisingly, these alterations do not lead to significant differences in sperm-morphology, time of spermatozoa development or sperm function between young and elderly males. Reports on decreased sperm motility, semen volume and changes in sperm count are contradictory. Although numerical chromosomal abnormalities of spermatozoa are not higher in aging males, an increase in structural aberrations can be observed. Consequently, children of elderly fathers show a 20% higher risk for autosomal dominant diseases, presumably due to increasing numbers of germ cell meioses and mitoses. Thus, the American Fertility Society recommends an age limit for semen donors of 50 years or less.     

Effect of dark chocolate on arterial function in healthy individuals: Cocoa instead of ambrosia?

Cocoa has been consumed for at least 2500 years, and for long time it has been regarded as a medicine. Arterial function is of paramount importance for the proper function and integrity of the cardiovascular system. Dark chocolate and flavonoid-rich cocoa have beneficial acute and shortterm effects on endothelial function and wave reflections in normal individuals, in adults with cardiovascular risk factors, and in patients with coronary artery disease. Furthermore, dark chocolate and flavonoid-rich cocoa may have a blood pressure-lowering effect. These effects can be attributed to flavonoids and are mainly mediated through increased nitric oxide bioavailability. Further research is needed to demonstrate whether these effects of chocolate on arterial function are translated into clinical benefit.     

Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophills and regulation by interleukin 10 during intestinal inflammation

Ｉｎｃｒｅａｓｅｄｓｅｃｒｅｔｉｏｎｏｆｐｒｏｉｎｆｌａｍｍａｔｏｒｙｃｙｔｏｋｉｎｅｓｂｙｃｉｒｃｕｌａｔｉｎｇｐｏｌｙｍｏｒｐｈｏｎｕｃｌｅａｒｎｅｕｔｒｏｐｈｉｌｓａｎｄｒｅｇｕｌａｔｉｏｎｂｙｉｎｔｅｒｌｅｕｋｉｎ１０ｄｕｒｉｎｇｉｎｔｅｓ...     

Effects of a novel glucagon receptor antagonist (Bay 27–9955) on glucagon-stimulated glucose production in humans

AIMS/HYPOTHESIS: To study the effects of a specific glucagon receptor antagonist (Bay 27-9955), on plasma glucose concentrations and rates of glucose production in response to hyperglucagonaemia in humans. METHODS: The study was conducted as a two-dose [Low Dose Bay 27-9955 70 mg, (n = 6), High Dose Bay 27-9955 200 mg, (n = 8)], double blind, placebo controlled, crossover study. Basal glucose production was measured after an overnight fast with [6,6-2H]. At 0 min Bay 27-9955 or placebo was administered and at 120 min an infusion of somatostatin [0.1 microg x (kg x min)(-1)], insulin [24 pmol x (m2 x min)(-1)] and glucagon [3 ng x (kg x min)(-1)] was initiated. RESULTS: Basal plasma glucose concentrations were about 5 mmol/l and basal rates of glucose production were about 13 micromol x (kg x min)(-1). During the hyperglucagonaemic period, plasma glucagon concentrations doubled to 100 pg/ml, plasma glucose concentration increased by 75 % to a peak of about 10 mmol/l and glucose production doubled to about 23 micromol x (kg x min)(-1) (p < 0.0001 vs basal). In the High Dose Group these effects of glucagon were markedly blunted, plasma glucose concentrations were 7.6 +/- 1.1 mmol/l (p = 0.012 vs placebo) and rates of glucose production increased minimally to 15.3 +/- 1.9 micromol x (kg-min)(-1) (p < 0.0003 vs placebo]. In the Low Dose Group, there was a proportional decrease in the effects of Bay 27-9955 on these parameters. CONCLUSION/INTERPRETATION: Bay 27-9955 is an effective and safe glucagon antagonist in humans. Given the potentially important role of glucagon in increasing glucose production and gluconeogenesis in patients with Type II (non-insulin-dependent) diabetes mellitus this agent could represent an innovative class of therapeutic agents for the disease.     

Effects of metoclopramide on gastrointestinal myoelectric activity in rats

ＥｆｅｃｔｓｏｆｍｅｔｏｃｌｏｐｒａｍｉｄｅｏｎｇａｓｔｒｏｉｎｔｅｓｔｉｎａｌｍｙｏｅｌｅｃｔｒｉｃａｃｔｉｖｉｔｙｉｎｒａｔｓＱＩＮＸｉａｏＭｉｎ１，ＬＩＨｏｎｇＦａｎｇ１ａｎｄＷＡＮＧＬｏｎｇＤｅ２Ｓｕｂｊｅｃｔｈｅａｄｉｎｇｓｍｅｔｏ...     

Effects of octreotide on acute necrotizing pancreatitis in rabbits

AIM:To assess the role of oxygen-derived free radicals andcytokines in the pathogenesis of taurocholic acid-inducedacute pancreatitis,and to evaluate the preventive effectsof octreotide towards the development of acutepancreatitis.METHODS:Acute pancreatitis was induced in male New Zealandwhite rabbits by retrograde injection of 0.8 mL/kg·b.m,of50 g/L sodium taurocholate (NaTC) in the pancreatic duct.Sham-operated animals served as control.Octreotide i mg/kg·b.m.was administered subcutaneously before the induction ofpancreatitis.Blood was taken from the jugular vein beforeand at 1,3,6,12 and 24 h after pancreatitis induction.Serum activities of amylase,IL-6 and TNF-α and levels ofmalonyl dialdehyde (MDA),glutathione (GSH),glutathioneperoxidase (GPx),catalase and superoxide dismutase (Mn-,Cu-,and Zn-SOD) in pancreatic tissue were measured.RESULTS:Serum TNF-α and IL-6 levels increasedsignificantly 3 h after the onset of pancreatitis,and thenreturned to control level.The tissue concentration of MDAwas significantly elevated at 24 h,while the GSH level andGP-x,catalase,Mn-SOD,Cu-,Zn-SOD activities were allsignificantly decreased in animals with pancreatitis ascompared to the control.Octreotide pretreatmnent significantlyreversed the changes in cytokines and reactive oxygenmetabolites.Octreotide treatment did not alter the serumamylase activity and did not have any beneficial effects onthe development of histopathological changes.CONCLUSION:Oxygen-derived free radicals andproinflammatory cytokines are generated at an early stageof NaTc-induced acute pancreatitis in rabbits.Prophylacticoctreotide treatment can prevent release of cytokines andgeneration of reactive oxygen metabolites,but does nothave any beneficial effects on the development of necrotizingpancreatitis.     

Five days of antibacterial therapy for bacterial meningitis in children?

Summary We evaluated the effectiveness of 5-day antibacterial therapy for bacterial meningitis in children. The study group included 26 children from 2 months to 15 years of age, admitted with microbiologically confirmed bacterial meningitis in 1990–1993 and treated for 5 days. A historical comparison group of 49 patients treated for 8 to 15 days was used. Penicillin monotherapy (300 mg/kg body weight) was used for meningococcal and pneumococcal meningitis and ampicillin (300 mg/kg body weight) forHaemophilus influenzae b meningitis. On day 5 of therapy the activity of aspartate aminotransferase (AST), lactic dehydrogenase (LDH), creatine phosphokinase (CPK) and gamma-glutamyl-transpeptidase (GT) in the CSF was determined by photocolorimetric assay and the concentration of creatine kinase BB (CK-BB) by ELISA. IL-6 was analysed using EIA technique and a cerebral ultrasound was performed at the time of the termination of the antibacterial therapy. The mean follow-up time was 1.3 years for children in the study group and 3.2 in the control group. The time of hospitalisation was shorter in children treated for 5 days (p<0.005). Complete clinical recovery was 81% in the study group and 66% in the comparison group at the time of the termination of antibacterial therapy. No relapses occurred. The activity of AST, CPK, LDH, and GT in the CSF had returned to normal by the 5th day of therapy, but almost a 7-fold higher concentration of CK-BB was registered. The concentration of IL-6 in the CSF decreased with the therapy from 1,800 pg/ml to 685 pg/ml but still remained high. Long term follow-up did not differ between the two groups. We conclude that 5 days of antibacterial therapy is adequate for the treatment of meningococcal meningitis in children.

---

5-Tages-Therapie für die antimikrobielle Behandlung der bakteriellen Meningitis im Kindesalter?

Zusammenfassung Die Wirksamkeit einer 5tägigen antibakteriellen Therapie wurde bei bakterieller Meningitis im Kindesalter geprüft. Die Studiengruppe umfaßte 26 Kinder im Alter von 2 Monaten bis 15 Jahren, die 1990–1993 mit mikrobiologisch gesicherter bakterieller Meningitis aufgenommen und 5 Tage lang behandelt wurden. 49 Patienten, die 8–15 Tage lang behandelt wurden, dienten als historische Vergleichsgruppe. Bei Meningokokken- und Pneumokokken-Meningitis wurde eine Monotherapie mit Penicillin (300 mg/kg KG) durchgeführt, dieHaemophilus influenzae-Meningitis wurde mit Ampicillin (300 mg/kg KG) behandelt. Am Behandlungstag 5 wurden die Aktivitäten von Aspartataminotransferase (AST), Laktatdehydrogenase (LDH), Kreatinphosphokinase (CPK) und gamma-Glutamyl-Transpeptidase (GT) im Liquor fotokolorimetrisch bestimmt. Die Kreatinkinase BB-Konzentration (CK-BB) wurde mittels ELISA gemessen. IL-6 wurde mit einer EIA Technik bestimmt und zum Zeitpunkt des Therapieendes mit Antibiotika wurde eine zerebrale Ultraschalluntersuchung vorgenommen. Die mittlere Verlaufsbeobachtung betrug bei den Kindern der Studiengruppe 1,3 Jahre, bei der Kontrollgruppe 3,2 Jahre. Kinder, die die 5-Tages-Therapie erhielten, blieben kürzer in stationärer Behandlung (p<0,005). Eine vollständige klinische Wiederherstellung war bei Kindern der Studiengruppe bei Therapieende in 81% und bei der Vergleichsgruppe in 66% der Fälle eingetreten. Rezidive ereigneten sich nicht. Am 5. Therapietag hatten sich AST, CPK, LDH und GT im Liquor normalisiert, die Konzentration von CK-BB war noch fast 7fach erhöht. Die IL-6 Konzentration im Liquor nahm mit der Therapie von 1,800 pg/ml auf 685 pg/ml ab, blieb jedoch noch erhöht. Die Langzeit-Verlaufsbeobachtung zeigte keine Unterschiede zwischen den Gruppen. Wir folgern, daß eine antibakterielle 5-Tages-Therapie für die Behandlung der Meningokokkenmeningitis bei Kindern adäquat ist.

     

The effect of age on vascular compliance in man: which are the appropriate measures?

Vascular compliance declines rapidly with age and measures of arterial compliance may help understanding of the aging process. Of the different measures of vascular compliance, those more closely related to chronological age need to be identified. These measures may help in the estimation of 'biological age'. We measured pulse wave velocity as the carotid-finger interval, carotid-toe interval and QKD interval (time between the Q wave and the arrival of the diastolic Korotkoff sound (K) over the brachial artery in diastoly (D)); central aortic compliance (CAC) and SV/PP (the stroke volume divided by pulse pressure in the brachial artery). Thirty-six volunteers were studied (30 men), ages 20 to 84, mean 49 years, to give the relationship of these measurements with age. CAC, the QKD interval and the carotid-toe interval were most closely related to age (r = - 0.51, -0.60 and -0.58 respectively). After adjustment for age, the only measure related to blood pressure was the carotid-finger interval; b for diastolic blood pressure = -0.83 (P = 0.01), the higher the pressure the shorter the interval. Measurements of CAC, QKD interval and carotid-toe interval may be employed to assess the impact of age on vascular compliance. Measures of peripheral vascular compliance, such as the carotid-finger interval, may prove useful in assessing the relationship between blood pressure and vascular compliance.     

The effect of balneotherapy on osteoarthritis. Is an intermittent regimen effective?

Background: Balneotherapy is used as a treatment modality for various musculoskeletal disorders. The aim of this study was to evaluate the effectiveness of intermittent balneotherapy in patients with knee osteoarthritis (OA). Methods: Seventy-two patients with knee OA were included in the study. Patients were divided into two groups: group A (48 patients) was given intermittent once weekly treatment for 6 weeks; group B (24 patients) served as a control group. Evaluation was done prior to study entry, at weeks 4 and 6, and 4 weeks following completion of treatment (week 10). Assessment included global pain score (VAS), WOMAC index, Lequesne's functional index, patients' and physician's disease severity score, and NSAID/analgesic consumption. Results: Following balneotherapy, a statistically significant improvement, determined by the reduction in the mean changes of most outcome parameters (VAS, WOMAC, and Lequesne's index), was noted in group A at weeks 4 and 6 and was sustained 4 weeks after cessation of treatment (week 10). Significant improvement in both physician's and patients' disease severity scores, as well as a reduction in analgesic and NSAID consumption, were also noted in group A. No improvement was found in the control group in any of the tested parameters. Conclusions: Intermittent balneotherapy appears to be effective in the treatment of knee OA.