Silent myocardial ischemia: role of subclinical neuropathy in patients with and without diabetes.

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.

Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function.

Patients with diabetes are prone to silent myocardial infarction and silent exertional ischemia. Although the mechanism is not clear, it may reflect a specific impairment of the sensory innervation of the heart. To test this hypothesis, anginal perceptual threshold was measured in 32 diabetic patients and 36 nondiabetic control patients, all of whom had typical exertional angina. Anginal perceptual threshold was defined as the time from onset of 0.1 mV ST depression to the onset of chest pain during treadmill stress electrocardiography. Although ST depression occurred earlier in the diabetic than in the nondiabetic group (111 +/- 82 versus 216 +/- 162 s, p less than 0.005), the anginal perceptual threshold in the diabetic group was delayed by a mean of 86 s (149 +/- 76 versus 63 +/- 59 s, p less than 0.001), with 95% confidence intervals of 53 to 119 s. Autonomic function tests were abnormal in the diabetic group, and in both groups regression analyses (using a third order polynomial) showed marked prolongations of anginal perceptual threshold as the heart rate responses to the Valsalva maneuver decreased to below the normal range (r = 0.5, p less than 0.001). There was a similar though less pronounced relation between anginal perceptual threshold and the heart rate responses to deep breathing (r = 0.3, p less than 0.02). These data suggest that prolongation of the anginal perceptual threshold may be caused by autonomic neuropathy involving the sensory innervation of the heart. To test sensory function, median nerve conduction studies were performed in 19 patients (10 diabetic and 9 nondiabetic).(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged anginal perceptual threshold in diabetes: effects on exercise capacity and myocardial ischemia.

Anginal perceptual threshold (the time from onset of 0.1 mV of ST segment depression to onset of angina during treadmill exercise) is prolonged in diabetic patients with coronary artery disease. In the present study, the functional significance of this perceptual abnormality was evaluated by analysis of its effect on exercise capacity and the severity of myocardial ischemia. Treadmill exercise in 32 diabetic patients and 36 nondiabetic control patients showed a close linear correlation between the time to onset of electrical ischemia (ST segment depression) and exercise capacity in both groups (r = 0.8 and 0.9, respectively; p less than 0.001). However, the slope of the relation was flatter in the diabetic group because prolongation of the anginal perceptual threshold permitted continued exercise as ischemia intensified. The anginal perceptual threshold itself showed a close linear correlation with exercise capacity in the diabetic group (r = 0.8, p less than 0.001), although in the nondiabetic group these variables were unrelated. The permissive effect of a prolonged anginal perceptual threshold on exercise capacity is undesirable as reflected by its correlation with ischemia at peak exercise (r = 0.6, p less than 0.001): the longer the threshold, the greater the exercise capacity and the more severe the ischemia. Indeed, the inverse relation between the severity of ischemia at peak exercise and exercise capacity in the nondiabetic group (r = 0.4, p less than 0.02) was completely lost in the diabetic group. Thus, in diabetic patients with coronary artery disease, anginal perceptual threshold is a major determinant of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Reexamination of the role of endogenous opiates in silent myocardial ischemia.

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.

Apolipoprotein-D polymorphism: a genetic marker for obesity and hyperinsulinemia.

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.

An association between a Bc1I restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia in obese women.

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.

Acute gonococcal arthritis: an unusual host and pathogen combination.

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.

Brain-stem auditory evoked responses in diagnosis of central pontine myelinolysis.

Central pontine myelinolysis (CPM) developed in association with acute adrenocortical insufficiency during correction of severe hyponatraemia in a 58-year-old woman. Repeated CT scanning and NMR imaging were normal from the onset of the illness. Electroencephalography and brain-stem auditory evoked responses showed abnormalities consistent with a brain-stem lesion, which resolved as the patient made a gradual but incomplete recovery. Our observations illustrate the value of electrophysiological monitoring in CPM and support the proposed association between this condition and the rapid correction of an electrolyte imbalance.

trkA and trkC expression is increased in human diabetic skin.

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.

Options for the management of obesity.

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.

Genetic contribution of polymorphism of the GLUT1 and GLUT4 genes to the susceptibility to type 2 (non-insulin-dependent) diabetes mellitus in different populations.

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.

Relationship between retinopathy and glycaemic control in insulin-dependent and non-insulin-dependent diabetes.

The possible relationship between antecedent diabetic control, as determined by serial glycosylated haemoglobin (HbA1) measurements, and diabetic retinopathy was examined in 40 insulin-dependent and 41 non-insulin-dependent diabetics selected consecutively from our clinic population. Multiple logistic regression analysis demonstrated a significant association between mean HbA1 and prevalence of retinopathy in both groups of patients. This association was independent of duration of diabetes which was also significantly associated with retinopathy prevalence. Hypertension and smoking were not obvious risk factors in this group of patients; an apparent association of hypertension and diabetes was entirely accounted for by a positive relationship between the presence of hypertension and duration of diabetes.

The effects of weight loss treatments on upper and lower body fat.

The intra-abdominal visceral deposition of adipose tissue, which characterises upper body obesity, is a major contributor to the development of hypertension, glucose intolerance and hyperlipidaemia. Conversely, individuals with lower body obesity may have comparable amounts of adipose tissue but remain relatively free from the metabolic consequences of obesity. This raises an obvious question-are there particular weight reducing treatments which specifically target intra-abdominal fat? In theory, surgical removal of upper body fat should be effective. In reality, neither liposuction nor apronectomy ('tummy tuck') have any beneficial metabolic effects, they simply remove subcutaneous adipose tissue which is often rapidly replaced. Vertical banded gastroplasty and gastric bypass operations may be dramatically effective in improving blood pressure, insulin sensitivity and glucose tolerance. However, these benefits result from a parallel reduction in visceral and total body fat. Studies of body fat distribution in postmenopausal women confirm that the marked decrease in adiposity, following a programme of very low calorie diet and exercise, reflects a comparable reduction in visceral and thigh fat. The reduction in waist circumference after a low fat/exercise programme suggests a similar situation in men. Exercise has an important role in treatment but, once again, the fat loss is generalised. Nevertheless, the improved metabolic parameters seen in exercising obese subjects, independent of weight loss, suggest other beneficial actions. Growth hormone (GH) has a marked lipolytic action. GH replacement treatment for GH deficient adults with pronounced abdominal fat deposition, has been shown to reduce intra-abdominal fat by 47% compared to 27% decrease in abdominal subcutaneous fat. Similar beneficial actions on abdominal fat have been reported following treatment with testosterone in obese men. The potential hazards of such treatments make them unsuitable therapy for obesity. Dexfenfluramine is effective in reducing total body fat but the results from a six month randomised controlled trial indicates that it does not specifically influence changes in waist circumference associated with weight loss. In conclusion, any treatment which reduces total body fat will, by its nature, reduce intra-abdominal visceral fat. There are presently no specific treatments which can be recommended for intra-abdominal fat but increasing knowledge of the biochemical aberrations associated with visceral adiposity may lead to more specific therapies for the future.

Clinical complications of obesity.

The development of important respiratory disorders and significant hypertension in association with increasing body weight is not widely recognized. Altered respiratory function results from a combination of mechanical impedance to breathing exerted by thoracic and abdominal fat and a ventilation-perfusion mismatch. Sleep-disordered breathing with periods of hypoventilation, with or without apnoeic episodes, may commonly occur in patients with extreme obesity. Nocturnal hypercapnia and hypoxia in such patients may lead to a decrease in ventilatory drive, abnormal central respiratory control and possibly, in time, the development of the obese-hypoventilation syndrome. Respiratory abnormalities should be suspected in obese patients with a history of restlessness at night, loud snoring and daytime somnolence. Treatment is substantial weight reduction, but short-term measures include the use of compressed air via nasal cannulae for obstructive apnoea, and drugs which alter sleep pattern or stimulate respiration. The alterations in endocrine function, which accompany weight gain, may contribute to an increase in blood pressure and there appears to be a relationship between plasma insulin and catecholamine concentrations, fat cell size and the development of hypertension. The confirmation of a raised blood pressure requires that readings be taken with an adequately sized arm-cuff. In many instances endocrine function becomes normal with weight loss, and there is a corresponding decrease in blood pressure. The ideal management for an obese hypertensive patient is the combination of a suitable calorie-restricted diet with a programme of physical exercise.

Emerging management strategies for obesity.

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.

Obesity as a medical problem.

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.

Hormones and obesity.

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.