Search PubMed⌕ Search

Biomedical subjects

G Williams

Publications and source records attributed to G Williams.

At least 955 records · Page 53Linked to original sources
PubMedDate not supplied

Insulin deficiency is a specific stimulus to hypothalamic neuropeptide Y: a comparison of the effects of insulin replacement and food restriction in streptozocin-diabetic rats.

Untreated insulin-deficient diabetes causes hyperphagia and neuroendocrine disturbances that may be partly mediated by increased hypothalamic activity of neuropeptide Y (NPY), a potent central appetite stimulant. The metabolic signal that stimulates hypothalamic NPY is unknown. This study aimed to determine whether insulin deficiency or hyperglycemia was responsible. Regional hypothalamic NPY concentrations were compared in streptozocin-diabetic (STZ-D) rats rendered nearly normoglycemic by either insulin replacement or food restriction. Untreated STZ-D rats were hyperphagic and showed significantly increased (p less than 0.01) hypothalamic NPY concentrations in the arcuate nucleus and lateral hypothalamic area. Once-daily ultralente insulin injections corrected hypoinsulinemia and hyperglycemia, abolished hyperphagia, and normalized NPY concentrations in all hypothalamic regions. By contrast, food restriction effectively lowered glycemia without raising insulin levels. In these underfed diabetic rats, NPY concentrations rose further and were significantly higher than nondiabetic and untreated diabetic levels in most hypothalamic regions. We conclude that insulin deficiency is a major stimulus to hypothalamic NPY in STZ-D, whereas hyperglycemia may exert an inhibitory influence. These findings support the hypothesis that hypothalamic NPY responds to specific metabolic cues and is involved in regulating energy balance and conserving body weight.

Animals↗
PubMedDate not supplied

Neuropeptide Y receptor numbers are reduced in the hypothalamus of streptozotocin-diabetic and food-deprived rats: further evidence of increased activity of hypothalamic NPY-containing pathways.

Neuropeptide Y (NPY) injected into the hypothalamus stimulates feeding and affects pituitary secretion. Insulin-deficient diabetes and food deprivation markedly increase hypothalamic NPY and NPY mRNA levels, suggesting increased activity of NPYergic pathways in the hypothalamus, which could account for hyperphagia and neuroendocrine changes in these conditions. To clarify these changes, NPY receptor characteristics were compared amongst rats with 3-weeks' untreated streptozotocin diabetes, insulin-treated normoglycemic diabetics, and non-diabetics, and also in food-deprived (72 h), food-deprived then refed, and in freely fed rats. Hypothalamic tissue homogenates (pooled from 3 rats; n = 9 per group) in Tris/HCl buffer were incubated with 30 pM [125I]porcine NPY and unlabeled NPY (range, 1 pM to 1 microM) for 1 h. Bound and free fractions were separated by vacuum filtration. Scatchard analysis revealed both high-affinity (Kd 0.3-0.8 nM) and low-affinity (Kd 14-40 nM) NPY receptor populations. Compared with nondiabetics, diabetic rats showed significantly reduced numbers (Bmax) of both high-affinity receptors (10 +/- 2 vs. 57 +/- 2 pmol/mg protein; p < 0.001) and low-affinity receptors (113 +/- 25 vs. 544 +/- 48 pmol/mg protein; p < 0.001). Insulin treatment partially restored Bmax of both high- and low-affinity receptors (24 +/- 1 and 334 +/- 60 pmol/mg protein, respectively; p < 0.01 vs. both other groups). Food deprivation also reduced Bmax of high-affinity (36 +/- 2 vs. 56 +/- 7 pmol/mg protein in freely fed; p < 0.05) and low-affinity receptors (288 +/- 6 vs. 457 +/- 17 pmol/mg protein; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Increased neuropeptide Y concentrations in specific hypothalamic nuclei of the rat following treatment with methysergide: evidence that NPY may mediate serotonin's effects on food intake.

Neuropeptide Y (NPY) is a potent central appetite stimulant found in hypothalamic neurons that have close anatomical associations with neurons containing serotonin, a powerful anorectic agent. To determine whether the two neurotransmitters interact functionally, we have studied the effects on regional hypothalamic NPY concentrations of acute and chronic administration of methysergide, a 5-HT1BC/serotonin receptor antagonist. Chronic methysergide treatment (10 mg/kg/day) was given by subcutaneously implanted osmotic minipumps (n = 8). Acute effects of methysergide were determined 4 h after a single injection (10 mg/kg) in a separate group (n = 8). Controls (n = 8) had implanted minipumps delivering saline, and also received a saline injection 4 h before sacrifice. Food intake was significantly increased (p < 0.01) by both acute and chronic methysergide treatment. In the chronically treated rats, NPY levels were significantly increased over controls in the arcuate nucleus (ARC; by 41%, p = 0.02) and paraventricular nucleus (PVN; by 40%, p < 0.01). Acute methysergide treatment also increased NPY concentrations in the ARC (by 81%, p < 0.01) and PVN (by 30%, p < 0.01). Methysergide administration, which stimulated feeding, therefore raised NPY concentrations in the ARC, where NPY is synthesized, and in the PVN, a major site of NPY release where NPY injection induces hyperphagia. These findings suggest that NPYergic and serotoninergic innervations in the hypothalamus interact to regulate food intake, and raise the possibility that increased NPY release may mediate the hyperphagic effect of serotoninergic 5-HT1BC/receptor blockade.

Animals↗
PubMedDate not supplied

The hypothalamus and the control of energy homeostasis: different circuits, different purposes.

The hypothalamus regulates many aspects of energy homeostasis, adjusting both the drive to eat and the expenditure of energy in response to a wide range of nutritional and other signals. It is becoming clear that various neural circuits operate to different degrees and probably serve specific functions under particular conditions of altered feeding behaviour. This review will discuss this functional diversity by illustrating hypothalamic neurones that express neuropeptide Y (NPY), the melanocortin-4 receptor (MC4-R) and the orexins. NPY neurones in the arcuate nucleus (ARC) release NPY, a powerful inducer of feeding and obesity, in the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA). ARC-NPY neurones are inhibited by leptin and insulin and become overactive when levels of these hormones fall during undernutrition. They may function physiologically to protect against starvation. With disruption of the inhibitory leptin signals due to gene mutations, the NPY neurones are overactive, which contributes to hyperphagia and obesity in the ob/ob and db/db mice and fa/fa Zucker rat. The MC4-R is activated by alpha-melanocyte-stimulating hormone [alpha-MSH; a cleavage product of pro-opiomelanocortin (POMC), which is expressed in the other ARC neurones] and inhibits feeding. This effect is antagonised by agouti gene-related peptide (AGRP), which is coexpressed by the ARC-NPY neurones only. Activation of MC4-R, possibly mediated by blockade of AGRP release, appears to restrain overeating of a palatable diet. This response may be programmed by a transient rise in leptin soon after presentation of palatable food, and rats that fail to do this will overeat and become obese. Orexin-A and -B (corresponding to hypocretins 1 and 2) are expressed in specific LHA neurones. These have extensive reciprocal connections with many areas involved in appetite control, including the nucleus of the solitary tracts (NTS), which relays vagal afferent satiety signals from the viscera. Orexin neurones also have close anatomical connections with LHA glucose-sensitive neurones. Orexin-A induces acute feeding but does not cause obesity. Orexin neurones are stimulated by hypoglycaemia partly via the NTS and inhibited by food ingestion. These neurones may therefore be involved in the severe hyperphagia of hypoglycaemia and short-term control of feeding.

Animals↗
PubMedDate not supplied

Smoking habits and painful diabetic neuropathy.

In order to assess the relationship between chronic painful diabetic neuropathy and current--or lifetime--smoking habits, the smoking history of 49 diabetic patients was investigated and compared with that of 23 diabetic patients without chronic pain (age 51.0 +/- 1.9 years, mean +/- SEM). Current level of nicotine intake was measured using urinary cotinine (a nicotine metabolite), and expressed as cotinine/creatinine ratio (COT/Cr), and lifetime smoking load by pack years (20 cigarettes per day for 1 year equals 1 pack year). Current pain intensity was evaluated using a visual analogue scale (VAS). The presence of chronic painful diabetic neuropathy was based on clinical history and examination. Of those patients with painful neuropathy, 26% were current smokers (age 54.2 +/- 3.2 years, mean +/- SEM), 31% ex-smokers (age 57.0 +/- 2.9 years), and 43% lifelong nonsmokers (age 58.0 +/- 2.9 years). Pain duration and intensity were similar in all three groups. COT/Cr levels were similar in current diabetic smokers with pain [5.0 (0.2-10.6) micrograms/mg] and the diabetic control group of smokers without pain [6.8 (1.8-13.3) micrograms/mg, NS]. There was no relationship between VAS and either COT/Cr levels or pack years in current smokers, or between duration of pain and pack years in diabetic current or ex-smokers. In conclusion, we found no relationship between current or previous levels of smoking and severity or duration of chronic painful diabetic neuropathy.

Diabetes Mellitus, Type 1↗
PubMedDate not supplied

Lack of relationship between sympathetic nervous system activity, measured by two circulating markers, and blood pressure in diabetic and nondiabetic subjects.

Two putative sympathetic nervous system (SNS) markers, noradrenaline and neuropeptide Y (NPY) were related to 24-h ambulatory blood pressure (BP) in 59 normotensive subjects, 34 non-insulin-dependent diabetics, and 25 controls. Plasma NPY levels were not significantly different between the two groups [non-insulin-dependent (NIDDM) diabetes mellitus 4.33 (3.25-5.78), controls 5.68 (3.39-6.97) p=0.26] as were those of noradrenaline (1.51+/-0.69 versus 1.78+/-0.55; p=0.053). There were correlations, controlled for age and obesity, of plasma NPY with clinic and night time diastolic BP in the control group only (r=0.49 [p=0.013] and r=0.48 [p=0.023] respectively). No similar correlation was found in the NIDDM group, or between plasma noradrenaline and blood pressure in either group. No correlation was found between plasma insulin and NPY or noradrenaline levels. There is a weak independent relationship between NPY and blood pressure in normotensive nondiabetics but not in NIDDM subjects. We found no evidence for the hypothesis that insulin modulates blood pressure through activity of the SNS.

Adult↗
PubMedDate not supplied

Effects of ambient particle pollution on daily mortality in Melbourne, 1991-1996.

This paper presents the results of a study in Melbourne, Australia, of the short-term effects of ambient fine particle pollution on daily mortality occurring between 1991 and 1996. The methodological approach used Poisson regression and Generalized Additive Models (GAM) with LOESS smoothing to control for temporal and meteorological effects. The association between particles and increases in daily mortality was examined using nephelometry data (bsp, mean 24 h average = 0.26 x 10(-4) m(-1), mean 1 h maximum = 0.60 x 10(-4) m(-1)), PM2.5 (24 h mean = 9.42 microg/m3) and PM10 (24 h mean = 19 microg/m3). Both the PM10 and PM2.5 data were estimated from nephelometry data using previously derived relationships for the Melbourne airshed. Significant positive associations between the particle measures considered and all cause and respiratory mortality were found in the warm season (November-March). A 1 x 10(-4) m(-1) increase in maximum 1-h bsp levels was associated with a 2.19% (95% CI = 0.01-4.43%) increase in risk of death for all cause mortality and a 10.40% (95% CI = 2.44-18.97%) increase in risk for respiratory mortality in the warm season. A 1 microg/m3 increase in 24-h PM2.5 in the warm season was associated with a 0.38% (95% CI = 0.06-0.70%) increase in risk of death for all cause mortality and a 1.18% (95% CI = 0.05-2.32%) increase in risk for respiratory mortality. For PM10, a 1 microg/m3 increase was associated with an increased risk of 0.18% (95% CI = 0.03-0.33%) for all cause mortality and 0.59% (95% CI = 0.06-1.13%) for respiratory mortality. Significant associations were also found in the 65+ age group in the warm season. However, for these warm periods, the effects of ozone (average 1 h maximum = 127 ppb) and nitrogen dioxide (average 1 h maximum = 70.7 ppb) were also significant and, due to high correlations between these pollutants, it was not possible to separate the particle effects from those of O3 and NO2. Sulfur dioxide was not examined as concentrations of this pollutant in Melbourne are very low (max 1 h = 15-24 ppb, annual average 0.8 ppb). Comparison with other Australian studies in Sydney and Brisbane indicates different results for particle pollution.

Adult↗
PubMedDate not supplied

Weight loss in tumour-bearing mice is not associated with changes in resistin gene expression in white adipose tissue.

Resistin, a product of white adipose tissue, is postulated to induce insulin resistance in obesity and regulate adipocyte differentiation. The aim of this study was to examine resistin gene expression in adipose tissue from mice bearing the MAC16 adenocarcinoma, which induces cancer cachexia with marked wasting of adipose tissue and skeletal muscle mass. MAC16-bearing mice lost weight progressively over the period following tumour transplantation, while the weight of control mice remained stable. Leptin mRNA in gonadal fat was 50 % lower in MAC16 mice than in controls (p < 0.05). Plasma insulin concentrations were also significantly lower in the MAC16 group (p < 0.05). However, resistin mRNA level in gonadal fat in MAC16 mice was similar to controls (94 % of controls). Thus, despite severe weight loss and significant falls in leptin expression and insulin concentration, resistin gene expression appears unchanged in white adipose tissue of mice with MAC16 tumour. Maintenance of resistin production may help inhibit the formation of new adipocytes in cancer cachexia.

Adenocarcinoma↗
PubMedDate not supplied

Leptin and the adaptations of lactation in rodents and ruminants.

Lactation markedly increases nutrient requirements in both rodents and ruminants. This is met mostly by increased food intake, but there are also adaptations to increase metabolic efficiency. Despite such changes, lactating animals usually experience periods of negative energy balance. This is not due to a physical constraint on food intake, at least in the rat. Leptin, a hormone secreted by adipocytes, plays an important role in the regulation of appetite and energy balance. During lactation, serum leptin concentration is decreased in both rodents and ruminants, and the nocturnal rise in concentration is lost in rats. Hypoleptinaemia in lactation is primarily a result of negative energy balance. There is also increased clearance of serum leptin, and the attenuation of the nocturnal rise in leptin in rats is at least partly due to the suckling stimulus. Hypoleptinaemia is not the major factor driving hyperphagia in lactating rats, but it probably facilitates the increased food intake. Leptin may play a more important role in this respect in lactating ruminants. Leptin is probably involved in other adaptations that increase metabolic efficiency during lactation. The ability of hypothalamic neuropeptides to respond to leptin does not appear to be altered by lactation in either rodents or ruminants. The reason why lactating animals do not respond to hypoleptinaemia with a further increase in appetite, thereby achieving energy balance, appears to be due to a failure to respond to changes in neuropeptides which mediate the effects of leptin.

Adaptation, Physiological↗
PubMedDate not supplied

Associations between outdoor air pollution and daily mortality in Brisbane, Australia.

The results of several studies have indicated significant associations between daily mortality and air pollution, with little evidence of a threshold. In the current study, the authors examined daily mortality during the period 1987-1993 for the Brisbane region, which is the fastest-growing urban region in Australia (annual average concentration of particulate matter less than 10 microm in diameter = 27 microg/m3, maximum hourly sulfur dioxide level = 60 ppb, and maximum daily ozone hourly level = 118 ppb). The authors conducted a general estimating equation analysis, and they used autoregressive Poisson models for daily mortality to examine associations with air pollution variables. The authors used research methods developed in the Air Pollution on Health, European Approach (APHEA), project to control confounding effects of weather and temporal trends. The air pollutants examined included particulate pollution (measured by nephelometry [bsp data]), sulfur dioxide, ozone, and nitrogen dioxide. The results indicated that the associations between total daily mortality and particulate levels found in studies in the United States and other countries may be applicable in Brisbane, Australia. Ozone levels were also associated significantly with total daily mortality. There was little evidence of interaction between the ozone effects (mainly in summer) and particulates or with sulfur dioxide and nitrogen dioxide. The associations between pollutants (ozone, bsp) and daily mortality were significant only for individuals who were older than 65 y of age; positive associations were also found with cardiovascular disease categories, and the regression coefficients--when significant--were higher than those for total mortality. The results indicated a possible threshold for ozone levels, but a similar result for particulate levels was not apparent.

Age Factors↗
PubMedDate not supplied

Guar sprinkled on food: effect on glycaemic control, plasma lipids and gut hormones in non-insulin dependent diabetic patients.

The effects of guar granules sprinkled over food on carbohydrate and lipid metabolism were studied in a double-blind cross-over trial in 18 patients with non-insulin-dependent diabetes mellitus (mean +/- SEM age 61.3 +/- 2.5 years). Five-gram guar granules (Guarem, Rybar Laboratories, Amersham, Bucks) were sprinkled over food at each main meal for 4 weeks, and during a 4-week placebo period (separated by a 2-week 'wash-out' period), 5 g wheat bran was taken in the same way. Diabetic treatment was not changed during the study. Mean fasting plasma glucose (FPG) concentration and glycosylated haemoglobin (HbA1) concentration after treatment were significantly lower than after the placebo period (FPG 8.29 +/- 0.47 vs 8.78 +/- 0.53 mmol/l, p less than 0.05; HbA1: 8.70 +/- 0.39 vs 9.09 +/- 0.39%, p less than 0.05). There was a 50% reduction in the incremental area under the postprandial glycaemic curve when guar was eaten with a standardized test meal. Total plasma cholesterol decreased from 5.79 +/- 0.29 to 5.19 +/- 0.22 mmol/l (p less than 0.05) after the guar treatment period. Guar ingestion reduced postprandial insulin and enteroglucagon responses, the latter significantly so, but had no apparent effect on gastric inhibitory polypeptide, pancreatic glucagon, gastrin, and pancreatic polypeptide.

Adult↗
PubMedDate not supplied

Elevated neuropeptide Y concentrations in the central hypothalamus of the spontaneously diabetic BB/E Wistar rat.

Insulin-deficient diabetes causes hypothalamic and pituitary dysfunction. The possible role of hypothalamic regulatory peptides in mediating these disturbances was investigated in spontaneously diabetic BB/E Wistar rats. Concentrations of 10 regulatory peptides were measured in the central (nucleus-rich) and lateral parts of the hypothalamus in 18 diabetic and 5 non-diabetic BB/E rats. Diabetic rats were treated with either intensified or low-dose insulin schedules to achieve moderate or severe hyperglycaemia (mean blood glucose concentrations, 8 and 20 mmol l-1 respectively). Neuropeptide Y concentration and content in the central hypothalamus were increased by 30-40% in both moderately and severely hyperglycaemic diabetic groups (p less than 0.01). Lateral hypothalamic neuropeptide Y levels did not differ significantly between the groups. The only other peptide to show any significant difference between diabetic and control rats was calcitonin gene-related peptide, whose central hypothalamic concentrations were significantly increased in the severely hyperglycaemic animals. Alterations of hypothalamic neuropeptide Y, which has potent experimental effects on hypothalamo-pituitary function, may contribute to certain neuroendocrine disturbances in insulin-deficient diabetes.

Animals↗
PubMedDate not supplied

Increased hypothalamic neuropeptide Y messenger RNA levels in two rat models of diabetes.

Elevated levels of immunoreactive hypothalamic neuropeptide Y have recently been reported both in streptozotocin-induced diabetic rats and in the spontaneously diabetic BB rat. We have measured the levels of neuropeptide Y encoding messenger ribonucleic acid (mRNA) in both of these rat models to determine whether an increase in neuropeptide Y gene expression is a contributory factor to the increases in hypothalamic neuropeptide Y immunoreactive peptide content. In the hypothalami of both the spontaneously diabetic BB/E and the streptozotocin-diabetic animals, neuropeptide Y mRNA showed significant elevations (to 204 +/- 13% (+/- SE) and 387 +/- 48% of control values, respectively, p less than 0.01 for both). Our results demonstrate that two models of insulin-deficient diabetes in the rat are associated with increased hypothalamic neuropeptide Y mRNA. Taken with the known effects of neuropeptide Y on food intake these results suggest that increased neuropeptide Y synthesis in the hypothalamus may be related to the hyperphagia seen in the diabetic condition.

Animals↗
PubMedDate not supplied

A prospective study of painful symptoms, small-fibre function and peripheral vascular disease in chronic painful diabetic neuropathy.

Fifty diabetic patients with chronic painful sensorimotor neuropathy were studied prospectively to clarify the natural history of this condition and the roles of small-fibre damage and concomitant peripheral vascular disease (PVD). Initially, 30 patients had no significant PVD (ankle:brachial Doppler ratio > 1.0). Pain was assessed using a visual analogue scale (0-10 cm), and small-fibre function by thermal limen (TL), heat-pain threshold (HPT), and weighted pinprick threshold (PPT). At follow-up, on average 3.6 years later (range 3.0-4.1), 11 patients had died (6 with PVD) and contact had been lost with 6. Pain scores fell in subjects without PVD (n = 24; median (range), from 4.8 (0.5-10.0) to 2.0 (0.0-9.2) cm, p < 0.001) and also in those with PVD (n = 9; from 5.1 (2.0-8.2) to 2.1 (0.0-8.0) cm, p < 0.05). Seven patients (5 without PVD) became painfree; at presentation, these 7 patients had experienced pain for a shorter period of time. Despite this symptomatic improvement, small-fibre function generally deteriorated in both groups, with significant worsening (p < 0.05) of HPT and PPT in patients without PVD, and in HPT and TL in patients with PVD. Neuropathic pain therefore tends to improve with time and can resolve completely. By contrast, small-fibre function continues to deteriorate, indicating that these peripheral measures do not predict the evolution of painful symptoms. The presence or absence of PVD does not appear to affect the natural history of neuropathic pain or its symptomatology.

Adult↗