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Biomedical subjects

M H Vickers

Publications and source records attributed to M H Vickers.

15 recordsLinked to original sources
PubMed2006

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat.

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg.kg(-1).day(-1)) in combination with acipimox (GH + acipimox, 20 mg.kg(-1).day(-1)) or fenofibrate (GH + fenofibrate, 30 mg.kg(-1).day(-1)) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effects.

Animals↗
PubMed2005

Neonatal leptin treatment reverses developmental programming.

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition.

Absorptiometry, Photon↗
PubMed2003

Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition.

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is now increasing evidence that alterations in the fetal environment have long-term consequences on metabolic and endocrine pathophysiology in adult life. This process has been termed "fetal programming," and we have shown that undernutrition of the mother during gestation leads to obesity, hypertension, hyperphagia, hyperinsulinemia, and hyperleptinemia in offspring. Using this model of maternal undernutrition throughout pregnancy, we investigated whether prenatal influences may lead to alterations in postnatal locomotor behavior, independent of postnatal nutrition. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (ad libitum group) or at 30% of ad libitum intake (undernourished group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [control or hypercaloric (30% fat)]. At ages of 35 days, 145 days, and 420 days, voluntary locomotor activity was assessed. At all ages studied, offspring from undernourished mothers were significantly less active than offspring born of normal birth weight for all parameters measured, independent of postnatal nutrition. Sedentary behavior in programmed offspring was exacerbated by postnatal hypercaloric nutrition. This work is the first to clearly separate prenatal from postnatal effects and shows that lifestyle choices themselves may have a prenatal origin. We have shown that predispositions to obesity, altered eating behavior, and sedentary activity are linked and occur independently of postnatal hypercaloric nutrition. Moreover, the prenatal influence may be permanent as offspring of undernourished mothers were still significantly less active compared with normal offspring at an advanced adult age, even in the presence of a healthy diet throughout postnatal life.

Animal Feed↗
PubMed2002

Adult growth hormone treatment reduces hypertension and obesity induced by an adverse prenatal environment.

The discovery of a link between an adverse in utero environment and the propensity to develop metabolic and cardiovascular disease in adult life is one of the most important advances in epidemiological research of recent Years. Increasing experimental evidence suggests that alterations in the fetal environment may have long-term consequences for the development of metabolic disorders in adult life. This process has been termed 'fetal programming' and we have shown that undernutrition of the mother during gestation leads to development of the metabolic syndrome X during adult life. Striking metabolic similarities exist between syndrome X and untreated GH deficiency (GHD). In the present study we have investigated the effects of GH treatment on blood pressure and metabolic parameters. Virgin Wistar rats (age 75+/-5 days, n=20 per group) were time-mated and randomly assigned to receive food either ad libitum (AD) or 30% of AD intake (UN) throughout pregnancy. At weaning, male offspring were assigned to one of two diets (control or hypercaloric (30% fat)). Systolic blood pressure was measured at day 100 and following twice daily treatment with recombinant bovine GH for 21 days. GH treatment increased body weights in all treated animals but significantly reduced retroperitoneal and gonadal fat pad weights. Following GH treatment, systolic blood pressure was markedly decreased in all UN offspring. Saline-treated animals showed no change in systolic blood pressure over the treatment period. GH treatment increased heart-to-body weight ratio in all GH-treated animals. Our data demonstrated that GH treatment reduces hypertension and improves cardiovascular function in animals exposed to adverse environmental conditions during fetal or postnatal life.

Analysis of Variance↗
PubMed2001

Fetal programming of appetite and obesity.

Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm is based on the observation that environmental changes can reset the developmental path during intrauterine development leading to obesity and cardiovascular and metabolic disorders later in life. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an adaptation to environmental changes during fetal development. While many endocrine systems can be affected by fetal programming recent experimental studies suggest that leptin and insulin resistance are critical endocrine defects in the pathogenesis of programming-induced obesity and metabolic disorders. However, it remains to be determined whether postnatal obesity is a consequence of programming of appetite regulation and whether hyperphagia is the main underlying cause of the increased adiposity and the development of metabolic disorders.

Animals↗
PubMed2001

IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming.

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is increasing evidence that alterations in the fetal environment may have long-term consequences on cardiovascular, metabolic, and endocrine pathophysiology in adult life. This process has been termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia in the offspring. Using this model of maternal undernutrition throughout pregnancy combined with postnatal hypercaloric nutrition of the offspring, we examined the effects of IGF-I therapy. Virgin Wistar rats (age 75 +/- 5 d, n = 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libitum intake (UN) throughout pregnancy. At weaning, female offspring were assigned to one of two diets (control or hypercaloric [30% fat]). Systolic blood pressure was measured at day 175 and following infusion with 3 microg/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatment, UN offspring were hyperinsulinemic, hyperleptinemic, hyperphagic, obese, and hypertensive on both diets, compared with ad libitum offspring and this was exacerbated by hypercaloric nutrition. IGF-I treatment increased body weight in all treated animals. However, systolic blood pressure, food intake, retroperitoneal and gonadal fat pad weights, and plasma leptin and insulin concentrations were markedly reduced with IGF-I treatment. IGF-I treatment resulted in a 3- to 5-fold increase in 38--44 kDa and 28--30 kDa IGF binding proteins, although in UN animals, there was an impaired and differential up-regulation of these insulin-like growth factor binding proteins following IGF-I treatment. The 24-kDa IGF binding protein representing IGF binding protein-4 was down-regulated in all IGF-I-treated animals, but the decrease was more marked in UN animals. Our data suggest that IGF-I treatment alleviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypertension in rats programmed to develop the metabolic syndrome X.

Animals↗
PubMed2001

Dysregulation of the adipoinsular axis -- a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming.

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.

Adipose Tissue↗
PubMed2000

The effects of bovine recombinant growth hormone administration on insulin-like growth factor-I and the haemopoietic system in thoroughbred geldings.

The effect of intramuscularly administered recombinant bovine growth hormone (rbGH) on insulin-like growth factor-I (IGF-I) and white and red blood cell indices was studied in Thoroughbred geldings. An insulin-like growth factor binding protein (IGFBP)-blocked radioimmunoassay was modified and validated for the measurement of IGF-I in equine blood plasma. Baseline values of IGF-I and blood indices were determined over a 48 h period and then a single dose of 5 microg/kg, 10 microg/kg or 50 microg/kg of rbGH was administered. Insulin-like growth factor-I levels increased in a dose-dependent manner, with the highest values between 12 h and 24 h. The highest dose (50 microg/kg) yielded the greatest IGF-I response with a 90.2+/-10.8% increase at 24 h. White blood cell count increased following the three doses of rbGH with the highest white blood cell count at 12 h after the 50 microg/kg dose. Haemoglobin was significantly increased at 24 h (P< 0.05), when values following doses of 10 microg/kg and 50 microg/kg were significantly greater than after the vehicle or the dose of 5 microg/kg. Red blood cell count was not affected by any of the rbGH doses. These results indicated that rbGH is biologically active in the horse and that rbGH at a dose rate of 10 microg/kg or more could be used therapeutically.

Animals↗
PubMed2000

Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition.

Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [a control diet or a hypercaloric (30% fat) diet]. Food intake in offspring from UN mothers was significantly elevated at an early postnatal age. It increased further with advancing age and was amplified by hypercaloric nutrition. UN offspring also showed elevated systolic blood pressure and markedly increased fasting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.

Animal Nutritional Physiological Phenomena↗
PubMed1999

IGF-I treatment increases motility and improves morphology of immature spermatozoa in the GH-deficient dwarf (dw/dw) rat.

It has recently been shown that short-term growth hormone (GH) treatment can increase the motility of spermatozoa in the GH-deficient dw/dw rat. To examine whether the effects of GH on motility of immature spermatozoa are mediated by an increase in plasma concentrations of IGF-I, we treated GH-deficient dw/dw rats with 2 microg/g/day of IGF-I using osmotic minipumps. Body weight (saline 227+/-5 g, IGF-I 253+/-4 g) and IGF-I concentrations in blood plasma (saline 472+/-19.9 ng/ml, IGF-I 986+/-43.6 ng/ml) and seminal vesicle fluid (saline 30.9+/-1.7 ng/ml, IGF-I 47.9+/-2.9 ng/ml) were significantly increased with IGF-I treatment (P<0.001), similar to the observed responses to GH therapy in our earlier study. While epididymal fluid IGF-I concentrations were not changed, IGF-I treatment significantly increased the number of immature motile spermatozoa (saline 14.4+/-3.5%, IGF-I 28.3+/-4.1%, P<0.05) and the number of spermatozoa with normal morphology (control 65.7+/-3.3%, IGF-I 75+/-1.9%, P<0.05). These data suggest that increasing the circulating concentrations of IGF-I in the GH-deficient rat can improve the motility and morphology of immature spermatozoa and thus mimic, at least in part, the effects of GH.

Animals↗
PubMed1999

Effects of maternal captopril treatment on growth, blood glucose and plasma insulin in the fetal spontaneously hypertensive rat.

In the spontaneously hypertensive rat (SHR) fetal growth and metabolism are abnormal. It has been speculated that maternal hypertension may be the cause of these abnormalities. Captopril treatment, which reduces maternal blood pressure, during pregnancy and lactation, is reported to have a beneficial effect postnatally, normalizing the blood pressure of offspring in the SHR. In the present study, the effects of maternal captopril treatment on fetal growth and plasma metabolites were investigated in the fetuses of two rat strains (SHR and Wistar-Kyoto (WKY)), in order to determine whether normalizing maternal blood pressure also normalized abnormalities in fetal growth and metabolism. On fetal Day 20, SHR fetuses were lighter and placentae were heavier than for the corresponding WKY. Captopril had no effect on fetal weight in the SHR, but decreased it in the WKY. There was no effect of captopril on placental weight. Fetal plasma insulin levels were higher in the SHR than in the WKY and were decreased by captopril treatment in both strains. Fetal blood glucose was elevated and fetal blood lactate was decreased in captopril-treated litters from both strains. Captopril had no effect on fetal plasma IGF-1 but fetal plasma IGF-2 levels were lower in the captopril-treated SHR than in the captopril-treated WKY. These findings suggest that maternal captopril treatment decreases insulin secretion in the fetal rat. High levels of fetal plasma insulin suggest that the SHR fetus is insulin resistant. Fetal insulin levels may contribute to the adverse consequences of gestational captopril treatment observed in many species. The differences in the effect of captopril on the two strains suggest that there are underlying endocrine differences in the SHR.

Animals↗
PubMed1997

Impaired sperm characteristics in postpubertal growth-hormone-deficient dwarf (dw/dw) rats.

The objective of the current study was to determine if sperm function is compromised in rats deficient in growth hormone (dw/dw) since a deficiency in this hormone has been implicated as a cause of lowered fertility and spermatogenic cessation in some biological models. Spermatozoa were recovered from the cauda epididymides of adult dwarf and Wistar control male rats. Spermatozoa were diluted in Medium 199 and analysed for motility. Aliquots were then fixed in phosphate buffered formalin, sperm concentration determined and morphology assessed. The mean measurements for percent motile and normal morphology were compared by Student's t-test. Sperm concentrations were compared by Mann-Whitney two sample test. The mean percentage of motile spermatozoa was significantly greater in the Wistar control group than in the dwarf group (75 +/- 1.44 vs 28 +/- 3.71%, P < 0.001). The percentage of normal sperm morphology was also greater in the Wistar control group (88 +/- 1.00 vs 75 +/- 6.9%, P < 0.001). The concentration of spermatozoa in the cauda epididymis was also significantly higher in the Wistar group. These results indicate that sperm function parameters are diminished in growth-hormone-deficient dw/dw rats. The effects of growth hormone deficiency in rats appears to be associated with compromised spermatogenesis as well as impaired sperm motility. The GH-deficient rat appears to be a suitable model for the study of the effects of GH on sperm characteristics.

Animals↗
PubMed1996

Growth hormone (GH) therapy markedly increases the motility of spermatozoa and the concentration of insulin-like growth factor-I in seminal vesicle fluid in the male GH-deficient dwarf rat.

There is increasing evidence for an important role of the somatotropic axis in male reproductive function. We investigated the effect of recombinant bovine GH (rbGH) treatment for 21 days on semen characteristics in post-pubertal GH-deficient dwarf (dw/dw) rats. Male dw/dw rats at an age of 75-80 days were divided into two groups (n = 10 per group) and injected twice per day with either rbGH (2 micrograms/g/day) or saline. While the concentration (96.4 +/- 51.3 x 10(6) per ml) and morphology of spermatozoa (spermatozoa with normal morphology 73.5 +/- 6.3%) in the dw/dw rat were within the normal range, the motility of spermatozoa was very low (27.5 +/- 11.7%), establishing a state of sub-fertility. The rbGH treatment markedly increased (p < 0.01) motility of spermatozoa (44.5 +/- 10.7%) but did not change the concentration (144 +/- 80.3 x 10(6) per ml) and morphology (spermatozoa with normal morphology 79.5 +/- 6.0%). The rbGH treatment also significantly increased the concentration of insulin-like growth factor-I (IGF-I) in blood plasma (control 389.1 +/- 65 ng/ml, rbGH 813.9 ng/ml, p < 0.001) and in seminal vesicle fluid (control 11.3 +/- 3.0 ng/ml, rbGH 16.1 +/- 5.4 ng/ml, p < 0.05). We conclude that rbGH therapy markedly increases motility of spermatozoa in sub-fertile male GH-deficient dw/dw rats. Thus, GH therapy may offer considerable potential for the treatment of impaired male reproductive performance.

Animals↗
PubMed1993

Recurrent pseudomonas septic arthritis.

Episodes of septic arthritis caused by Pseudomonas aeruginosa occurred in a patient with an infected vascular graft. He responded well to antibiotic therapy and removal of the graft was not required. The aetiology of this unusual cause of septic arthritis is discussed.

Aged↗