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Human obesity: lessons from experiments of nature
31
Faculty IPL1.31 RECENT
INSIGHTS INTO CONCERNS AND CONSEQUENCES OF ENDCYTHELIAL DYSFUNCTION IN RELATION TO VASCULAR DISEASE A CLINICIAN’S VIEW
C.D.A. Stehouwer. The Netherlands
l+rie Universiteit Medical Centre, 1081 HVAmsterdam,
Endothelial dysfunction is a central concept in current models of the pathogenesis of atherothrombosis. In accordance, several so-called ‘markers’ of endotbelial dysfunction have been shown to be associated with an adverse cardiovascular prognosis. This raises two questions for clinicians. Can the measurement of markers of endothelial dysfunction be used to estimate prognosis in individual patients, i.e. for risk stratification? And can findings from studies on the effects of interventions on endothelial function(s), in the absence of randomised trials with clinical endpoints, help clinicians decide whether or not to advise certain treatments to patients at high risk of cardiovascular disease? Endothelial function cannat be measured directly in humans. Estimates of different types of endothelial dysfunction may be obtained indirectly by measuring endothelium-dependent vasodilation, plasma levels of endotheliumderived regulatory proteins and, possibly, microalbumimnia (Table 1). Are these measurements valid estimates of endothelial dysfunction? The endothelium is an important locus of control of many vascular functions. Therefore, endothelial dysfunction is not a discrete entity, nor does a gold standard for its measurement exist. In addition, we have insufficient insight into the sensitivity, the specificity, the reproducibility and the interpretation of the estimates shown in the table. I shall argue that the variables shown in the table are plausible estimates of endothelial dysfunction, but that much more work is needed to establish the clinical validity of the use of such markers under different circumstances. Table I. Proposed estimates of end&&al dysfunction in humans [I] Measurement
Interpret&on of altered end&&xl functton
Impatred endothelium-dependent vascdilation Endothelin* Van Willebrand factor* sThmmbomodulin* Tissue-type plasminogen activator*, Plasminogen activator inhibitor-l l sE-selectin*, SCAM-l*
Decreasedproduction of vascdilators such as nitric oxide
Cellular fibronectu?, Type IV collagen fragments* Mtcmalbuminuria * = increased
Increased synthesis of vasoconstrictors Increased pmtbmmbotic and procoagulant actwity Decreased anticoagulant activity Decreased pmfibrinolytic activity Increased permeability to leukocytes; inflammatory activation Altered extracellular matrix synthesis Increased endothelial petmeabdity to macmmokules
plasma or serum level, s = soluble; VCAM = vascular cell adhesion molecule
References [I] Stehouwer CDA. Is measurement of enclothelial [editorial]. Eur J Clin Invest 1999;29:45961.
Cardiovascular Study have shown that these features of the insulin resistance syndrome are associated with a substantial increase in CHD risk. These atherogenic metabolic complications are even found in the pre-diabetic state or among individuals who may never develop type 2 diabetes. Recent results from our laboratory have suggested that the simultaneous measurement of simple variables such as waist circumference and fasting triglyceride concentrations could represent an inexpensive approach for the identification of asymptomatic individuals at high risk of CHD. It is proposed that “hypertriglyceridemic waist” is a new clinical phenotype describing a high risk form of abdominal obesity associated with the features of the insulin resistance syndrome.
IPL2.31 HUMAN OBESITY: LESSONS FROM EXPERIMENTS
OF
NATURE S. O’Rahilly. Departments of Medicine & Clinical Biochemistq Uniuersity of Cambridge, Addenbrookei Hospital, Cambridge CB2 2QR, UK Single gene disorders, although relatively uncommon, frequently provide important insights into the understanding of normal human endocrine physiology. Since 1997 a number of monogenic disorders having a major impact on fat mass have been described. In most cases, the particular gene’s candidacy has been established through previous studies in rodents. Several families with morbid obesity due to mutations in the leptin receptor gene have now been reported. A single family with homozygous mutations in the leptin receptor gene has also been described. The hyperphagia, extreme obesity and hypogonadotropic hypogonadism seen in these affected kindreds confirm the critical role of leptin in the regulation of human appetite and pubertal development. Although the major features of defective leptin signalling are shared between human and mice, there are considerable interspecies differences in the neuroendocrine consequences of leptin deficiency. Leptin is known to activate arcuate neurones expressing proopiomelanocortin (POMC) and is therefore of note that children born with homozygous or compound heterozygous mutations in the POMC gene show severe obesity along with defects in skin pigmentation and adrenal steroidogenesis. A single human has been described with compound heterozygous mutations in the prohormone convertase 1 gene. As no murine model of PC-I function is currently available, this patient provides the only available in vivo information regarding the role of PC-l in the integrated function of endocrine systems. Mice with melanocortin 4 receptor deleted by homologous recombination are severely obese and hyperphagic and there is an intermediate obesity phenotype in the heterozygous knockout mice. We and others have now shown that mutations in the MC4R gene are present in up to 5% of children with severe obesity, thus making it by far the commonest monogenic cause of human obesity so far described. Recently we have families with a recessive pattern of inheritance of MC4R mutations and have undertaken studies of genotype/phenotype correlation which appear to provide some explanation for these differences in inheritance.
IPL3.21 HEART FAILURE 2001 dysfunction
clinically
useful?
N. Sharpe. Department
lPL2.11 INSULIN AS A MARKER OF CHD RISK J.-P. Despres. QuPbec Heart Institute, Lava1 Hospital, Sainte-Fey, Q&bec, GI V 4G5, Canada Under a positive energy balance resulting from a diet rich in fat and sugar combined with a reduced energy expenditure due to a sedentary lifestyle, genetically susceptible individuals may develop visceral obesity which has been shown to be a good marker of a cluster of metabolic abnormalities which are predictive of an increased risk of type 2 diabetes and premature coronary heart disease (CHD). Irrespective of the concomitant variation in the level of total body fat, excess visceral adipose tissue deposition has been associated with insulin resistance, hyperinsulinemia, glucose intolerance, hypertriglyceridemia, hypoalphalipoproteinemia, an elevated concentration of apo B-associated lipoproteins as well as with an increased concentration of small, dense LDL particles. We have proposed that this insulin resistancedyslipidemic syndrome resulting from visceral obesity is probably the most prevalent cause of CHD in affluent societies. Results from the Quebec
of Medicine,
Universiiy of Auckland, New Zealand
Heart failure is a common and increasing problem, particularly in the elderly. Morbidity and mortality are very high, as is the related healthcare expenditure. Diagnosis of heart failure is difficult, as symptoms and signs are relatively insensitive and nonspecific. Only about half of the patients with heart failure in the community are diagnosed and treated appropriately. Many patients on heart failure treatment do not have that condition. Echocardiography should be routine in assessment but is often not accessible. In the future, measurement of blood natriuretic peptides may be helpful in diagnosis. Heart failure is but part of a complete diagnosis and underlying remediable causes and precipitants should always be considered. Patients selected into heart failure clinical treatment trials are different from those with heart failure in the community generally. Trial patients are younger and predominantly male, with heart failure the principal diagnosis, LV systolic dysfunction documented, relatively little comorbidity and good compliance. Many patients with heart failure in the community (approximately 40% across several surveys) have normal or near normal systolic function. These
72nd EAS Congress
Faculty IPL1.31 RECENT
INSIGHTS INTO CONCERNS AND CONSEQUENCES OF ENDCYTHELIAL DYSFUNCTION IN RELATION TO VASCULAR DISEASE A CLINICIAN’S VIEW
C.D.A. Stehouwer. The Netherlands
l+rie Universiteit Medical Centre, 1081 HVAmsterdam,
Endothelial dysfunction is a central concept in current models of the pathogenesis of atherothrombosis. In accordance, several so-called ‘markers’ of endotbelial dysfunction have been shown to be associated with an adverse cardiovascular prognosis. This raises two questions for clinicians. Can the measurement of markers of endothelial dysfunction be used to estimate prognosis in individual patients, i.e. for risk stratification? And can findings from studies on the effects of interventions on endothelial function(s), in the absence of randomised trials with clinical endpoints, help clinicians decide whether or not to advise certain treatments to patients at high risk of cardiovascular disease? Endothelial function cannat be measured directly in humans. Estimates of different types of endothelial dysfunction may be obtained indirectly by measuring endothelium-dependent vasodilation, plasma levels of endotheliumderived regulatory proteins and, possibly, microalbumimnia (Table 1). Are these measurements valid estimates of endothelial dysfunction? The endothelium is an important locus of control of many vascular functions. Therefore, endothelial dysfunction is not a discrete entity, nor does a gold standard for its measurement exist. In addition, we have insufficient insight into the sensitivity, the specificity, the reproducibility and the interpretation of the estimates shown in the table. I shall argue that the variables shown in the table are plausible estimates of endothelial dysfunction, but that much more work is needed to establish the clinical validity of the use of such markers under different circumstances. Table I. Proposed estimates of end&&al dysfunction in humans [I] Measurement
Interpret&on of altered end&&xl functton
Impatred endothelium-dependent vascdilation Endothelin* Van Willebrand factor* sThmmbomodulin* Tissue-type plasminogen activator*, Plasminogen activator inhibitor-l l sE-selectin*, SCAM-l*
Decreasedproduction of vascdilators such as nitric oxide
Cellular fibronectu?, Type IV collagen fragments* Mtcmalbuminuria * = increased
Increased synthesis of vasoconstrictors Increased pmtbmmbotic and procoagulant actwity Decreased anticoagulant activity Decreased pmfibrinolytic activity Increased permeability to leukocytes; inflammatory activation Altered extracellular matrix synthesis Increased endothelial petmeabdity to macmmokules
plasma or serum level, s = soluble; VCAM = vascular cell adhesion molecule
References [I] Stehouwer CDA. Is measurement of enclothelial [editorial]. Eur J Clin Invest 1999;29:45961.
Cardiovascular Study have shown that these features of the insulin resistance syndrome are associated with a substantial increase in CHD risk. These atherogenic metabolic complications are even found in the pre-diabetic state or among individuals who may never develop type 2 diabetes. Recent results from our laboratory have suggested that the simultaneous measurement of simple variables such as waist circumference and fasting triglyceride concentrations could represent an inexpensive approach for the identification of asymptomatic individuals at high risk of CHD. It is proposed that “hypertriglyceridemic waist” is a new clinical phenotype describing a high risk form of abdominal obesity associated with the features of the insulin resistance syndrome.
IPL2.31 HUMAN OBESITY: LESSONS FROM EXPERIMENTS
OF
NATURE S. O’Rahilly. Departments of Medicine & Clinical Biochemistq Uniuersity of Cambridge, Addenbrookei Hospital, Cambridge CB2 2QR, UK Single gene disorders, although relatively uncommon, frequently provide important insights into the understanding of normal human endocrine physiology. Since 1997 a number of monogenic disorders having a major impact on fat mass have been described. In most cases, the particular gene’s candidacy has been established through previous studies in rodents. Several families with morbid obesity due to mutations in the leptin receptor gene have now been reported. A single family with homozygous mutations in the leptin receptor gene has also been described. The hyperphagia, extreme obesity and hypogonadotropic hypogonadism seen in these affected kindreds confirm the critical role of leptin in the regulation of human appetite and pubertal development. Although the major features of defective leptin signalling are shared between human and mice, there are considerable interspecies differences in the neuroendocrine consequences of leptin deficiency. Leptin is known to activate arcuate neurones expressing proopiomelanocortin (POMC) and is therefore of note that children born with homozygous or compound heterozygous mutations in the POMC gene show severe obesity along with defects in skin pigmentation and adrenal steroidogenesis. A single human has been described with compound heterozygous mutations in the prohormone convertase 1 gene. As no murine model of PC-I function is currently available, this patient provides the only available in vivo information regarding the role of PC-l in the integrated function of endocrine systems. Mice with melanocortin 4 receptor deleted by homologous recombination are severely obese and hyperphagic and there is an intermediate obesity phenotype in the heterozygous knockout mice. We and others have now shown that mutations in the MC4R gene are present in up to 5% of children with severe obesity, thus making it by far the commonest monogenic cause of human obesity so far described. Recently we have families with a recessive pattern of inheritance of MC4R mutations and have undertaken studies of genotype/phenotype correlation which appear to provide some explanation for these differences in inheritance.
IPL3.21 HEART FAILURE 2001 dysfunction
clinically
useful?
N. Sharpe. Department
lPL2.11 INSULIN AS A MARKER OF CHD RISK J.-P. Despres. QuPbec Heart Institute, Lava1 Hospital, Sainte-Fey, Q&bec, GI V 4G5, Canada Under a positive energy balance resulting from a diet rich in fat and sugar combined with a reduced energy expenditure due to a sedentary lifestyle, genetically susceptible individuals may develop visceral obesity which has been shown to be a good marker of a cluster of metabolic abnormalities which are predictive of an increased risk of type 2 diabetes and premature coronary heart disease (CHD). Irrespective of the concomitant variation in the level of total body fat, excess visceral adipose tissue deposition has been associated with insulin resistance, hyperinsulinemia, glucose intolerance, hypertriglyceridemia, hypoalphalipoproteinemia, an elevated concentration of apo B-associated lipoproteins as well as with an increased concentration of small, dense LDL particles. We have proposed that this insulin resistancedyslipidemic syndrome resulting from visceral obesity is probably the most prevalent cause of CHD in affluent societies. Results from the Quebec
of Medicine,
Universiiy of Auckland, New Zealand
Heart failure is a common and increasing problem, particularly in the elderly. Morbidity and mortality are very high, as is the related healthcare expenditure. Diagnosis of heart failure is difficult, as symptoms and signs are relatively insensitive and nonspecific. Only about half of the patients with heart failure in the community are diagnosed and treated appropriately. Many patients on heart failure treatment do not have that condition. Echocardiography should be routine in assessment but is often not accessible. In the future, measurement of blood natriuretic peptides may be helpful in diagnosis. Heart failure is but part of a complete diagnosis and underlying remediable causes and precipitants should always be considered. Patients selected into heart failure clinical treatment trials are different from those with heart failure in the community generally. Trial patients are younger and predominantly male, with heart failure the principal diagnosis, LV systolic dysfunction documented, relatively little comorbidity and good compliance. Many patients with heart failure in the community (approximately 40% across several surveys) have normal or near normal systolic function. These
72nd EAS Congress