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Obesity treatment remains a 'Cinderella' of all clinical management programmes, but generally without a happy ending. The great expectation for new therapeutic agents has not been fulfilled in clinical practice, whilst the restriction of eating through surgical division of the upper bowel seems strange in an age of advanced and sophisticated technology. The better understanding of the neuro-regulation of appetite, and its application as part of evidence-based clinical interventions, could lead to a more coherent approach to obesity treatment. Nevertheless, investigation of potential neuroendocrine targets for appetite suppression suggests redundancy in the systems, which make development of effective agents against single receptors impractical. Importantly, the progressive rise in the prevalence of obesity will inevitably mean that only a small proportion of afflicted patients will actually be treated by long-term drugs and surgery. Drugs and surgery are not currently the answer for the majority of obese individuals. What is required is a better way of identifying patients who may particularly benefit from such approaches. However, the major emphasis must be the development of effective population-wide interventions that halt the increase in fatness and ensure that future generations maintain and enjoy a healthy body weight. [ABSTRACT FROM AUTHOR]

BACKGROUND: The success rate of long-term maintenance of weight loss in obese patients is usually low. To improve the success rate, determinants of long-term weight maintenance must be identified. OBJECTIVE: The objective of the study was to identify determinants of long-term success in weight maintenance in obese subjects who completed the Sibutramine Trial on Obesity Reduction and Maintenance (n = 261), a multicenter European study of weight loss and weight maintenance in obesity that combines sibutramine treatment with dietary restriction and advice on exercise and behavior. DESIGN: We studied weight maintenance over 18 mo in subjects who had completed a 6-mo weight-loss phase. Factors included in the analysis were initial body weight, the percentage of initial body weight lost, dietary intake, various components of physical activity (measured with the Baecke questionnaire), the type of treatment (sibutramine or placebo), age, and sex. RESULTS: Multiple regression analysis identified treatment group (sibutramine or placebo), the percentage of the initial body weight that was lost during the 6-mo weight-loss phase, and the leisure-time physical activity index as significant determinants of weight maintenance. Together, these 3 factors explained 20% of the variation in weight maintenance (P < 0.001). Dietary factors, age, and sex were not significant predictors of weight-maintenance success in this study. CONCLUSIONS: Weight-maintenance success after weight loss is positively influenced by sibutramine treatment during weight maintenance, by a greater initial weight loss, and by a higher leisure-time physical activity index, which reflects higher levels of activities such as walking and cycling and lower levels of television viewing. [ABSTRACT FROM AUTHOR]

Primary intervention in the medical management of obesity is dietary restriction and physical activity with additional benefit gained from behaviour therapy. Subsequent use of anti-obesity drugs depends on unsatisfactory weight loss in a patient at medical risk from obesity. All treatment programmes must include long-term follow up.

The obese are subject to health problems directly relating to the carriage of excess adipose tissue. These problems range from arthritis, aches and pains, sleep disturbance, dyspnea on mild exertion, and excessive sweating to social stigmatization and discrimination, all of which may contribute to low quality of life and depression (Table 1). The most serious medical consequences of obesity are a result of endocrine and metabolic changes, most notably type 2 diabetes mellitus, cardiovascular disease, and increased risk of cancer. Not all obesity comorbidities are fully reversed by weight loss. The degree and duration of weight loss required may not be achievable by an individual patient. Furthermore, "weight cycling" may be more detrimental to both physical and mental health than failure to achieve weight loss targets with medical and lifestyle advice.

A randomized, double-blind, placebo-controlled study of brain-derived neurotrophic factor (rhBDNF) was conducted in 30 patients with insulin-treated diabetes mellitus, with obligatory abnormalities of sural nerve conduction studies and vibration perception threshold (VPT) at the great toe on recruitment. Nine patients received placebo, 11 rhBDNF (25 microg/ kg) and 10 rhBDNF (100 microg/kg) s.c. daily for 3 months, and were assessed at days 0, 8, 15, 29, 43, 57 and 85 with nerve conduction and quantitative sensory and autonomic tests including VPT, thermal and light touch thresholds, and cutaneous axon-reflexes. No statistically significant differences were found among the 3 treatment groups between baseline and day 85 values. To examine possible reasons for lack of effect, post hoc analysis was performed. In the subset of patients with abnormal but detectable cool detection threshold (CDT) at baseline, there was improvement of CDT at day 85 when compared to baseline in the treated (p < 0.02) but not placebo group. Further, from days 43 to 85, in the treated group but not the placebo group, CDT was indistinguishable from a group of matched normal subjects (p > 0.05). Skin biopsies failed to show evidence of structural change; assessment of innervation of hair follicles, which is partly dependent on BDNF, was not possible because of the marked loss of this end-organ in diabetic neuropathic skin. The only side effects of rhBDNF were infrequent non-painful injection-site skin reactions and increased gut motility at the higher dose. We conclude that further preclinical studies are warranted before any future clinical trials to see if rhBDNF improves CDT and constipation in diabetics.

Aims/hypothesis: Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (-55 c-->t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations., Methods: The -55 c-->t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes., Results: In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the -55 c-->t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039)., Conclusion/interpretation: The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females.

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Aims: This study set out to establish a novel procedure for the measurement of human nerve growth factor (NGF) messenger ribonucleic acid (mRNA) and to use this method to measure NGF expression in skin biopsies from control subjects and from patients with early neuropathies. NGF mRNA levels were related to functional measures of the competence of NGF-responsive nerves., Methods: mRNA levels were measured by competitive reverse transcription with polymerase chain reaction amplification (cRT-PCR). Functional correlates of this observation were assessed by indices of thermal sensitivity--mediated by C-fibres, whose phenotype is regulated by NGF., Results: NGF mRNA was increased in skin biopsies from 19 diabetic patients (5.12+/-3.88 (SD)) compared with samples from eight controls (1.57+/-0.95; P=0.001). Diabetic patients showed significantly (P < 0.001) diminished detection of cool and warm stimuli compared to age matched control group (n=24), but there were no differences in detection of heat as pain, or correlation with NGF mRNA levels., Conclusions: These findings suggest abnormally increased expression of NGF in diabetic neuropathy, which may represent a compensatory mechanism for impaired phenotype in NGF-responsive neurones.

Management strategies for obesity, which include drug therapy, are emerging as a consequence of the increasing recognition of the medical seriousness of obesity. Obesity requires appropriate and effective management by suitably trained members of a multidisciplinary team, with treatment programmes putting equal importance on weight reduction and its maintenance. Such programmes must also take into account the reduction in risk from co-morbid conditions after modest weight loss (5-10% of initial body weight). The use of an anti-obesity drug may be justified for patients at risk from obesity where dietary methods, including exercise and behaviour modification, have failed to achieve a 10% reduction in initial body weight after at least three months from the start of the episode of managed care. Anti-obesity drugs must be prescribed in an appropriate setting, with patients being reviewed on a regular basis. Essential elements for managed weight loss include, a printed management programme, appropriate equipment, specified and realistic weight-loss goals, documentation of individual patient's health risks, and clearly defined follow-up procedures with explicit guidelines for the use of drugs and notification of other doctors involved in the patient's care. The process of drug treatment necessitates a system of regular medical audit. Many health-care professionals and lay persons remain sceptical about the scientific value of anti-obesity drugs. The emergence of increasingly specific and effective agents underlines the importance of ensuring appropriate use for patients at risk from obesity.

Background: Leptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects., Subjects and Design: We have studied the effect of food and fasting on circulating leptin levels in 20 subjects of normal body mass index (BMI range 18-25) and in a group of 12 moderately-severely obese subjects (BMI range 34-61). We also studied the effect of food and fasting in a patient both before and after the successful removal of a pancreatic insulinoma as a model of excess insulin secretion., Results: Mean leptin levels were significantly higher in the obese than in the lean group (42.7 +/- 3.41 vs 5.35 +/- 1.55 micrograms/l, mean +/- SEM; P < 0.001), and showed a positive correlation with body mass index (r = +0.71; P < 0.001). Frequent (every 20 minutes) sampling for 3 hours after food did not show any acute changes in circulating leptin levels. On the fasting day we observed a small but significant fall in circulating leptin levels in the last 4 hours of a 20-hour fast in our subjects as a group (92 +/- 0.03% of basal, P = 0.03); however, in the lean subjects the fall was greater (86 +/- 0.04% of basal, P = 0.02) than in the obese, where it did not reach statistical significance (96 +/- 0.05% of basal). Pre-meal and peak insulin levels showed a positive correlation with circulating mean leptin levels (r = +0.65; P < 0.001 and r = +0.78; P < 0.001, respectively) in all subjects, while pre-meal and peak serum cortisol levels showed an inverse relation with leptin levels (r = -0.53; P = 0.002 and r = -0.41; P = 0.02, respectively); this effect was independent of BMI in the obese subjects. In the patient with the insulinoma the markedly elevated insulin and leptin levels measured before the operation returned to normal after removal of the tumour, in accord with reports of experimental animal data that long-term insulin excess per se is associated with increased circulating leptin concentrations., Conclusion: Leptin is a robust indicator of BMI and insulin levels, both basal and stimulated, but does not change acutely following food. Fasting causes a proportionately greater decline in leptin levels in lean subjects than in obese subjects. Circulating leptin is inversely correlated with the activity of the hypothalamo-pituitary-adrenal axis: whether this is a direct influence of leptin on hypothalamo-pituitary-adrenal activity, or whether both are indirect indicators of body fat stores, requires further investigation.

Nerve growth factor (NGF) is reduced in epidermal keratinocytes in human diabetic skin, and this decrease has been related to dysfunction of cutaneous sensory fibres. In vitro studies show that keratinocytes express both NGF and its high-affinity receptor, trkA, and that NGF may increase keratinocyte proliferation and its own expression via an autocrine loop. However, the level of trkA expression in vivo by keratinocytes in normal and diabetic skin is unknown. We have therefore measured trkA expression in calf skin biopsies from patients with early subclinical diabetic neuropathy and control subjects, using in situ hybridisation combined with image analysis quantification. Expression of trkC was also studied, as its endogenous ligand neurotrophin-3 (NT-3) is related to NGF, and is present in human epidermis. Hybridisation signal was seen for both trkA and trkC localised throughout the epidermal layer of control skin, with a higher density of silver grain deposition observed for trkA mRNA. However, in diabetic epidermis there was a significant increase (P < 0.001) for both trk A (control, 0.178 +/- 0.013; diabetic, 0.304 +/- 0.032; mean silver grain counts/microm2 +/- SEM) and trkC expression (controls, 0.059 +/- 0.004; diabetics, 0.191 +/- 0.010). The up-regulation of epidermal trk receptors may result from decreased autocrine neurotrophin action, and could represent a compensatory mechanism.

Obesity is characterised by alterations in metabolic function which result from a combination of increasing total body fatness and the regional distribution of adipose tissue. Abdominal visceral obesity is particularly associated with hyperinsulinaemia, increased portal vein free fatty acid concentration, hepatic gluconeogenesis, altered adrenocortical activity and androgen secretion and reduced plasma sex hormone binding globulin levels. These alterations, which are accompanied by changes in visceral adipocyte sensitivity to plasma catecholamine stimulation, enhance further visceral fat deposition and the perpetuation of the metabolic derangements. The characteristic dyslipidaemia associated with upper body obesity and the frequent development of NIDDM are predictable consequences. In contrast to the considerable knowledge about the biochemical background to these alterations, relatively little is understood about the mechanisms through which an individual's ethnic background influences the changes. This chapter reviews these important issues.

Background: It has been previously shown that food intake elevates circulating ACTH and cortisol levels, but no report has been published regarding the changes in circulating dehydroepiandrosterone (DHEA). DHEA was originally described as a weak androgen, but more recently it has been associated with a wide range of metabolic functions. In addition, previous studies have described a hyper-responsive hypothalamo-pituitary-adrenal axis in obese subjects in response to various stimuli, but the specific response to food has not been studied., Subjects and Design: We studied the effect of food on the hypothalamo-pituitary-adrenal axis in 20 subjects of normal body mass index (BMI range 18-25) and also in a group of 12 obese subjects (BMI range 34-61). Levels of glucose, insulin, ACTH, cortisol and dehydroepiandrosterone were measured every 20 minutes., Results: A small rise in DHEA accompanies the rise in circulating ACTH and cortisol in response to food in both lean and obese subjects, but DHEA rose independently of cortisol and ACTH on the fasting day. In the obese subjects, food induced a significantly greater change in serum cortisol (peak cortisol rise (mean +/- SEM); normal-weight group, 169 +/- 14%; obese group, 294 +/- 23%) and in the cortisol/DHEA ratio (area under the curve; normal-weight group, 202 +/- 15%; obese group, 292 +/- 29%) than in the normal-weight subjects. This difference was particularly notable in those with central-type obesity (waist/hip ratio > 0.80). A group of the normal, jean female subjects showed no cortisol rise after food intake., Conclusion: Our results suggest that DHEA may vary independently of circulating cortisol, and that the cortisol response to food is enhanced in obese subjects, particularly in those with central obesity. We speculate that there may be a caused connection between the cortisol response to food in normal subjects, and the subsequent distribution of fat if such subjects overeat sufficiently to become obese.

The St Vincent Declaration includes a commitment to continuous quality improvement in diabetes care. This necessitates the collection of appropriate information to ensure that diabetes services are efficient, effective and equitable. The quantity of information, and the need for rapid access, means that this must be computer-based. The choice of architecture and the design of a database for diabetes care must take into account available equipment and operational requirements. Hardware topology may be determined by the operating system and/or netware software. An effective database system will include: user-friendliness, rapid but secure access to data, a facility for multiple selections for analysis and audit, the ability to be used as part of the patient consultation process, the ability to interface or integrate with other applications, and cost efficiency. An example of a clinical information database for diabetes care, Diamond, is described.

This review highlights the considerable advances in the understanding of the inheritance of fatness and the possible genetic mechanisms. The investigation of animal models confirms the fundamental importance of genes in determining fatness and demonstrates a genetic link between adipocyte function, derangements of steroid metabolism, insulin secretion and hypothalamic regulation. The heterogeneous nature of human obesity makes it unwise to extrapolate directly from the findings in animals but these findings do provide important clues to the situation in man. It is crucial that advances in the knowledge of genes involved in human obesity are paralleled by an understanding of gene-gene interactions and the influence of environmental factors. The rapidly increasing prevalence of obesity in society underlines the paramount influence of the environment.

Polymorphic variation of genes encoding the glucose transporters glycoproteins (GLUT) may contribute to the genetic susceptibility to type 2 (non-insulin-dependent) diabetes. In this study we evaluated the allele and genotype frequencies of GLUT1 and GLUT4 restriction fragment length polymorphism (RFLP), revealed by digestion with XbaI for GLUT1 and KpnI for GLUT4, in Caucasian, Chinese, Japanese, Asian Indian and American black populations. No differences of the KpnI GLUT 4 RFLP were found between control and diabetic subjects in any ethnic group or when all data are combined. In contrast, positive results were found for the XbaI RFLP: (1) most ethnic groups showed an association of allele 1 with type 2 diabetes, and this association was maintained when all groups were analysed together; (2) after stratifying for sex and obesity, this association was significant only for overweight/obese women. This joint analysis suggests that GLUT1 polymorphism may contribute to susceptibility to type 2 diabetes in some populations, and especially in overweight/obese women.

Synthesis of postulated hydroxylated metabolites of gliclazide is described together with their detailed structural analysis using 1H-NMR, two-dimensional 1H-NMR, and MS to characterize the products. Metabolism of gliclazide has been investigated in the urine of nine patients of different ethnic origins receiving gliclazide therapy for the treatment of diabetes. Urine extracts were analyzed by GC/MS to quantify and identify the metabolites excreted in urine and the metabolites compared with the synthesized products. Metabolic profiles in all diabetic patients were very similar and comparable with those reported for healthy human volunteers. In addition to the expected metabolites arising from oxidation of the 4-methylphenyl ring, four isomeric hydroxylated products of the azabicyclooctyl ring were identified and the structure of a fifth isomer postulated.

A computerized diabetic clinic management system, DIAMOND, has been developed with the collaboration of local general practitioners (GPs) to assist communication about diabetic patients across the district. DIAMOND is written in a Windows format using Microsoft Access and its dataset is in line with BDA and Diabcare recommendations. DIAMOND is user-friendly and includes displays and help messages throughout and does not require advanced computer knowledge. The main index contains two primary tables: a patient registration table with demographic data and an episode table with clinically important physical and biochemical measures. All entered data are coded to facilitate audit and an audit function, which automatically presents data, either numerically or graphically, is included in the report facility. DIAMOND also incorporates a system for patient education and training (PEATS) which may be operated by a health professional or the patient. Over 4500 patients in Newham are presently registered on DIAMOND with in excess of 15,000 episodes. Evaluation of this information is providing important clinical information both within individual GP practices and district-wide to assist future plans for health care provision.

A 76 year old man was admitted for evaluation and treatment of acute oligoarticular arthritis having recently returned from India. He was diabetic on admission. Neisseria gonorrhoeae was isolated from pus collected by arthrocentesis of his right knee and was subsequently found to be chromosomally resistant to penicillin. The isolate required proline for growth and expressed the protein 1B-1 serovar. These characteristics of host and pathogen are atypical in that gonococcal arthritis usually occurs in young women and is usually caused by N gonorrhoeae isolates exhibiting hypersusceptibility to penicillin, the arginine, hypoxanthine and uracil requiring auxotype, and the protein 1A serotype. The patient responded well to therapy with oral ciprofloxacin and initial high dose penicillin.

Obesity frequently clusters with hypertension, hyperlipidemia, non-insulin-dependent diabetes mellitus, and ischemic heart disease with hyperinsulinemia as syndrome X. Although central obesity has been recognized to have a strong genetic component, few candidate genes have been studied in this disorder. After a recently described association between the apolipoprotein-D (Apo-D) gene polymorphism and non-insulin-dependent diabetes mellitus by our group, we have now looked at a TaqI polymorphism of the Apo-D gene in two other components of syndrome X, namely obesity and hyperinsulinemia. Apo-D genotype differences were found between obese subjects (n = 57) and slim controls (n = 57; P = 0.006). Furthermore, in the obese group an association was found between the Apo-D genotype and fasting insulin (P < 0.001). Preliminary evidence, therefore, suggests that the TaqI Apo-D polymorphism can be used as a genetic marker for obesity and several components of syndrome X.

This chapter has reviewed the evidence for obesity being characterized by distinct patterns of hormonal changes related to both the degree of obesity and the distribution of fat tissue. Many of these changes are also seen in subjects with Cushing's and polycystic ovary syndromes, in particular hyperinsulinaemia, alterations in adrenocortical activity and sex steroid secretion and binding. Animal models of obesity provide evidence to suggest the possibility of a primary abnormality of hypothalamic-pituitary function as a basis to corpulence and this cannot be excluded in the human situation. Nevertheless, abdominal distribution of adiposity plays a significant role in establishing a vicious cycle of metabolic events which may perpetuate both the obese state and PCOS. It is of interest that the additive genetic effect for total body fat is about 25% whereas the heritability of subcutaneous truncal-abdominal fat is about 30-35%, and may possibly be higher (Bouchard et al, 1993). Upper body obesity is characterized by large adipose cells with higher LPL activity, elevated basal and stimulated lipolysis but a low antilipolytic effect of insulin. The results from preliminary investigations of potential candidate genes suggest a possible genetic basis to hyperinsulinaemia/insulin resistance found in upper body obesity but further studies of greater numbers are required for confirmation. It is hoped that the findings from such molecular studies will shed additional light on both the genetic background to obesity and the complex hormonal alterations seen at the tissue level. This should provide the confirmation of a unifying theory for the causal factors associated with obesity and related conditions.

Objectives: This study was designed to examine the role of beta-endorphin and met-enkephalin in the pathophysiology of silent myocardial ischemia, with emphasis on their role in the physiologic response to stress., Background: Silent myocardial ischemia is more common in patients whose perception of pain is reduced. Whether endogenous opiates can contribute to this process remains uncertain largely because of the conflicting findings of previous studies., Methods: Forty-three patients with coronary artery disease and ischemia on treadmill stress testing underwent electrical pain tests and exercise treadmill tests during naloxone and placebo infusion in a randomized, double-blind crossover study. Thirty-one patients developed angina during both treadmill tests (group A), and 12 had silent ischemia (group B). Plasma beta-endorphin, metenkephalin, epinephrine, norepinephrine and cortisol were measured before and after exercise in a subgroup of 17 patients., Results: Naloxone reduced electrical pain tolerance (1.40 +/- 0.10 [mean +/- SEM] vs. 1.72 +/- 0.19 mA, p = 0.04) but did not affect the time to angina in group A (260 +/- 20 vs. 248 +/- 20 s, p = 0.72) or induce angina in group B patients. Beta-endorphin and met-enkephalin levels during placebo infusion were not significantly different in groups A and B at baseline and after exercise, although beta-endorphin levels were significantly increased during naloxone infusion, confirming effective opiate receptor blockade. Norepinephrine and cortisol increased with exercise, but catecholamines and cortisol were similar in both groups and were unaffected by naloxone., Conclusions: Beta-endorphin and met-enkephalin were similar in patients with painful and silent ischemia, and naloxone infusion did not influence anginal symptoms despite effective opiate receptor blockade and a reduction in somatic pain tolerance. These findings suggest that endogenous opiates do not play an important role in modulating symptoms in myocardial ischemia. The increase in beta-endorphin with exercise that coincided with an increase in plasma cortisol is most likely due to its release from the anterior pituitary gland as part of the physiologic stress response.

The need to treat obesity successfully can be measured by the medical penalty paid by the obese individual and the financial price paid by society in general. The management of obesity has 2 objectives: first, to produce significant weight reduction (10% of pretreatment bodyweight) and, second, to maintain this weight reduction. For the purpose of this paper, we have defined successful treatment as that maintaining significant weight loss for at least 5 years. A review of the literature confirms that there is no single outstanding treatment for obesity, and that clinicians must consider an individual's needs before selecting a particular method of weight reduction. The main determinants of suitability of any specific treatment are degree of obesity, concomitant medical disorders, urgency of treatment, and the individual's willingness to undergo the programme prescribed.

Objectives: Silent myocardial ischemia is common in patients with diabetes. This study was designed to assess the role of subclinical autonomic impairment in diabetic patients with silent ischemia., Background: Studies have suggested that silent ischemia is more common in diabetic patients with microvascular complications, but this has not been a consistent finding., Methods: Twenty-two diabetic and 30 nondiabetic patients with proved coronary artery disease and a history of angina and ischemia on treadmill stress testing underwent clinical tests of autonomic function and measurement of 24-h heart rate variability. Diabetic patients with a history of microvascular complications were excluded., Results: Although all 52 patients manifested ischemia during treadmill testing, only 36 patients experienced angina (angina group), whereas 16 did not (silent ischemia group). Diabetic and nondiabetic patients were similar in age (59 +/- 1 vs. 61 +/- 2 years, p = 0.56) and extent of coronary artery disease. However, clinical tests showed reduced parasympathetic function in the diabetic patients (Valsalva ratio 1.38 +/- 0.07 vs. 1.60 +/- 0.06; p = 0.007). Patients in the silent ischemia group were more often diabetic (33% vs. 63%, p = 0.05) and had prolonged time to ischemia on treadmill testing (200 +/- 20 vs. 271 +/- 20 s, p = 0.03). In addition, autonomic function was impaired in the silent group (supine/standing heart rate ratio 1.15 +/- 0.02 vs. 1.05 +/- 0.02, p = 0.002). Subgroup analysis showed that abnormalities of autonomic function were confined to the diabetic patients in the silent group., Conclusions: Despite the absence of overt microvascular complications, diabetic patients with silent exertional ischemia have evidence of significant autonomic impairment compared with findings in symptomatic patients. This difference is not seen in nondiabetic patients and indicates that subclinical neuropathy is an important cause of silent ischemia in patients with diabetes.

Objective: The purpose of this study was to determine whether alterations in the hypothalamo-pituitary-adrenal axis and arginine vasopressin secretion, which have been associated with animal obesity, also occur in man., Design: Cross-sectional analysis of extremely obese women and normal weight controls., Patients: Thirty-three obese premenopausal, non-diabetic women (mean age 31 years, mean body mass index (BMI) 41), and 15 normal weight controls (mean age 24 years, mean BMI 22)., Measurements and Results: Arginine vasopressin (AVP), ACTH, beta-lipotrophin and cortisol responses to insulin-induced hypoglycaemia (0.2 units Actrapid/kg body weight for obese; 0.15 unit/kg for controls) were measured. The obese women were further characterized by anthropometric measurements (weight, body mass index, fat distribution) and indices of insulin secretion/resistance: fasting insulin, insulin secretion during 75-g oral glucose tolerance test area under curve, insulin-stimulated glucose disposal and an index of insulin resistance. No significant differences were found in the basal levels of ACTH, AVP, beta-lipotrophin or cortisol. An augmented peak beta-LPH (n = 16, P < 0.02, the difference of the mean 3.65, 95% confidence interval 1.33-10) and ACTH (n = 16, P = 0.05, the difference of the mean 2.12, 95% CI 1.0-4.5) response were found in obese as compared with normal weight controls. Both ACTH and AVP areas under the curve were similar in both groups studied. There was additionally a direct positive association between the integrated ACTH response (area under the curve) and the weight of the obese subjects (P < 0.05, r2 = 0.265). The cortisol response was negatively correlated with insulin-stimulated glucose disposal (P < 0.01, r2 = 0.23), but not with other indices of insulin secretion/resistance (fasting insulin, oral glucose tolerance test area under the curve, index of insulin resistance) or fat distribution. Comparable responses to hypoglycaemia were seen for AVP and cortisol. There was no correlation between the ACTH, AVP or cortisol responses., Conclusion: Obesity is associated with increased activity of the hypothalamo-pituitary-adrenal axis as supported by augmented ACTH and beta-lipotrophin secretion in response to insulin-induced hypoglycaemia and the positive association between the ACTH response and the body weight of obese women studied.

Obesity is likely to be a multifactorial disease with an important genetic component. Animal models of genetic and experimentally induced obesity suggest that glucocorticoid receptor (GR) activity plays a role in the aetiology and maintenance of the obese state. Glucocorticoid activity appears to be essential for the development of hyperinsulinaemia and subsequent fat deposition. In humans, glucocorticoid excess is associated with central fat distribution. We have therefore investigated the restriction fragment length polymorphisms of the human GR gene locus (GRL) and have sought associations of specific alleles with anthropometric measurements and indices of insulin secretion and resistance in obesity. Fifty-six extremely obese, unrelated, nondiabetic premenopausal British Caucasian females and 43 age-matched, normal weight controls were studied. The obese subjects were characterized by fat distribution (waist to hip ratio), insulin secretion and insulin resistance (fasting insulin (FI)), an index of insulin resistance (HOMA), stimulated insulin secretion during an oral glucose tolerance test and insulin-mediated glucose disposal, steady-state plasma glucose). A Bc1I polymorphism (fragments of 4.5 and 2.3 kb) demonstrated significant association with indices of glucose metabolism in obesity; those subjects homozygous for the 4.5 kb fragment had elevated FI (Pc = 0.012) and HOMA (Pc = 0.012) values. The genotypic and allelic frequencies of the GRL Bc1I polymorphism were otherwise similar in obese and normal weight subjects. We postulate that the GRL Bc1I polymorphism may directly affect GR gene expression, or be in linkage disequilibrium with a possible mutation within one of three exons of the GR gene, and thereby modulate GR transcriptional activity on target genes involved in glucose and insulin homeostasis.

Disordered nocturnal breathing with significant arterial oxygen desaturation and sleep apnoea is a feature of extreme obesity which is often difficult to manage in the short term. We have evaluated the effect of fluoxetine, a centrally acting 5-HT re-uptake inhibitor, on sleep-breathing patterns in asymptomatic extremely obese subjects. A double-blind cross-over study was used to compare fluoxetine (60 mg for three days) to placebo. Eleven obese subjects (ten males, one female, mean weight +/- s.d. 131 +/- 2 kg) slept overnight in a sleep laboratory with the polysomnographic study recorded after an initial acclimatization night. The obese subjects had normal respiratory function and normal fully awake arterial oxygen saturation (%SaO2 97 +/- 1). Marked O2 desaturation was seen in all the subjects during sleep but the average asleep %SaO2 did not differ between the two treatment phases (placebo 90 +/- 5; fluoxetine 92 + 2%). However, fluoxetine significantly increased the minimum %SaO2 recorded during the study night either by abolishing or reducing REM sleep (placebo 73 +/- 2%; fluoxetine 81 +/- 8%; P < 0.05, 95% CI -12.3 to -2.03). Frequent hypopnoea was observed in all subjects in both REM and non-REM sleep whereas apnoea was uncommon. The total apnoea/hypopnoea index fell in six subjects during the fluoxetine night, the largest reduction being seen in the most severely affected. In five of the six the improvement was associated with the abolition of REM sleep. Total sleep time did not differ between the placebo and fluoxetine nights nor did a qualitative assessment of sleep using a visual analogue score.(ABSTRACT TRUNCATED AT 250 WORDS)

Obesity is a multifactorial disease with a marked genetic component. The situation is further complicated by the heterogeneity of obesity demonstrated by the topographical distribution of body fat, e.g. upper body (central) and lower body (gluteal) obesity. Furthermore, the distribution of fat shows a stronger heritable tendency compared with total body fat. Central obesity is characterized by hyperinsulinaemia and insulin resistance, a feature in common with non-insulin dependent diabetes mellitus, hypertension and atherosclerosis. In order to study the molecular genetics of central obesity we have examined 56 severely obese (mean body mass index 40), unrelated British Caucasoid young non-diabetic women for associations of restriction fragment length polymorphism of candidate genes with anthropometric measurements and indices of insulin secretion and resistance. The candidate genes examined were insulin receptor, insulin sensitive glucose transporter and insulin. An association of the class 3 allele of the hypervariable region in the 5' flanking region of the insulin gene was found with upper segment obesity (P = 0.005). Furthermore, the class 3 allele was also associated with fasting hyperinsulinaemia (P = 0.01), stimulated insulin secretion (P = 0.01) and insulin resistance as calculated from the homeostatic model of assessment (HOMA; P = 0.008). No such associations were found with the other candidate genes studied. This data suggests that polymorphisms in the 5' flanking region of the insulin gene may affect expression of the gene and thereby modulate insulin production in severely obese female subjects.

Objective: To determine the effects of age and autonomic function on the perception of angina., Design: Prospective evaluation of the relations between anginal perceptual threshold, autonomic function, and systolic blood pressure in patients with symptomatic coronary artery disease. Statistical analysis was by non-parametric techniques., Setting: Cardiology departments of a district general hospital and a post-graduate teaching centre., Subjects: 82 non-diabetic men with typical exertional angina and coronary artery disease confirmed by arteriography (n = 64) or a history of Q wave infarction (n = 18)., Main Outcome Measures: Age, anginal perceptual threshold, autonomic function, and blood pressure. Anginal perceptual threshold was defined as the time from onset of 0.1 mV ST depression to the onset of angina during treadmill stress testing. Autonomic function was measured as the ratio of peak heart rate during the Valsalva manoeuvre to the minimum rate after release., Results: Anginal perceptual threshold showed a weak but significant correlation with age, with older patients tending to have a longer interval between the onset of ST depression and the onset of angina. Comparison of patients in the upper and lower quartile age ranges showed a difference of 50 seconds between median threshold measurements. Blood pressure and heart rate responses to the Valsalva manoeuvre also correlated with age, but neither variable correlated with the anginal perceptual threshold., Conclusions: In non-diabetic men with coronary artery disease the perception of angina tends to deteriorate with advancing age. The mechanism is unclear but is not attributable solely to alterations in blood pressure or autonomic function.

Objective: The aim was to investigate a possible relationship between measures of insulin secretion and glucose disposal and hypothalamic-pituitary function in extreme obesity., Design: A cross-sectional analysis of obese subjects attending the Obesity Clinic at the Royal London Hospital and normal weight volunteers was undertaken. Investigations were performed on separate occasions and in random order., Patients: The subjects were 34 extremely obese women, menstruating and with normal glucose tolerance (mean Body Mass Index, BMI = 42) and 15 normal weight female controls (mean BMI = 22)., Measurements: The following were measured: fasting insulin, relative insulin resistance calculated using fasting insulin and plasma glucose by the homeostatic model of assessment, insulin release during a 75-g oral glucose tolerance test (insulin area under the curve), steady-state plasma glucose level achieved during a simultaneous intravenous infusion of dextrose, insulin and somatostatin, and the prolactin and growth hormone (GH) responses to insulin-induced hypoglycaemia., Results: In the obese group an impaired prolactin response to hypoglycaemia (mean area under the curve obese 54 U/l min, controls 155 U/l min; P = 0.0001) was inversely correlated to fasting insulin, r2 = 0.142, P = 0.03; relative insulin resistance, r2 = 0.134, P = 0.03 and steady-state plasma glucose level, r2 = 0.345, P = 0.0004 whereas the impaired GH response (mean GH area under the curve obese 1.9 U/l min, controls 65.7 U/l min; P = 0.0001) was inversely correlated to steady-state plasma glucose level, r2 = 0.196, P = 0.01. Backward procedure for stepwise regression analysis confirmed the steady-state plasma glucose level to be the most important variable associated with the prolactin and growth hormone response among the remaining indices of insulin secretion/resistance., Conclusion: We conclude from these findings that hyperinsulinaemia in obesity is an important association with altered hypothalamic-pituitary function indicated by impaired prolactin and growth hormone secretion to insulin-induced hypoglycaemia.