International Textbook of Obesity - part 8 doc

(103) and Native Americans (104), although at least two studies in Europeans have failed to show the expected associations (105,106). A recent review of studies into associations be- tween fetal and/or infant growth and adult chronic disease concludes that the reported associations may be biased rather than causal, with possible selection bias due to loss to follow-up and con- founding by socioeconomic factors (107). New evi- dence for a genetic explanation of the link between fetal growth and adult diabetes comes from Dunger et al. (108), with the observation that variation in the expression of the insulin gene is associated with size at birth. Whatever the mechanism for the association of low birthweight with adult disease, and McCance et al. have suggested that the observations can be explained by more conventional genetic hypotheses (104), the association is strong in a number of ethni- cally varied populations and hence its effects may contribute to differences in risk of type 2 diabetes seen in people with similar levels of adult obesity. Leptin, Obesity and Type 2 Diabetes While it is now accepted that human obesity is generally associated with elevated circulating leptin levels (109), and in many studies leptin is correlated with insulin levels (110—114) or insulin resistance (115,116), it is not clear whether leptin has a role in glucose intolerance in humans. In the leptin defi- cient ob/ob mouse treatment with leptin lowered glucose and insulin concentrations in the blood independently of weight loss (117,118). The leptin treated animals also increased physical activity and metabolic rate to ‘normal’ levels (117) and this may have enhanced insulin sensitivity and glucose up- take via increased glycogen mobilization as dis- cussed above, or increased glucose uptake by some insulin-independent mechanism which would result in reduced insulin levels (118). Leptin may also in- fluence insulin secretion in ob/ob mice via neuro- peptide Y (NPY) (119) or by direct action on -cells (120,121). In humans, in contrast to rats and mice, insulin does not have an acute effect on leptin levels (111,113,122), although chronic hyperinsulinaemia appears to be associated with elevated leptin levels (111,123,124), perhaps due to adipocyte hyper- trophy (111). On the other hand, there is some evidence for leptin influencing insulin sensitivity. In isolated human liver cells leptin antagonizes insulin signalling (125), and in the Israeli sand rat (Psam- momys obesus), a polygenic animal model of type 2 diabetes, leptin has been reported to inhibit insulin binding to adipocyte insulin receptors (126). A number of studies have reported on leptin levels in diabetic versus non-diabetic individuals; after adjusting for obesity there is no consistent picture with no difference being found in Poly- nesians in Western Samoa (110), Mexican Ameri- cans (127), Finnish men (123), American men and women (128) and German men and women (129) who mostly appear to have type 2 diabetes. Cle´ ment et al. (130) have found lower leptin levels in morbid- ly obese, poorly controlled diabetes compared with controlled diabetes or non-diabetics with similar levels of obesity. The low leptin levels in poorly controlled subjects may have been associated with lower insulin levels in this group. Although the development of obesity in humans is unlikely to be linked to a defect in the OB gene as in the ob/ob mouse, in two related cases OB muta- tions in the homozygous form were reported to result in severe leptin deficiency and obesity (131). Recently, a rare mutation in exon 16 of OB-R was identified in humans. This alteration was found to result in morbid obesity and endocrine abnormali- ties in individuals homozygous for the mutation (132). Leptin resistance, as observed in the db/db mouse and fa/fa rat which have a single mutation in the leptin receptor gene, has not been demonstrated yet in humans (133) and it may be that leptin resistance is due to a defect in body mass regulation down- stream of leptin. It may also be that leptin is not important in preventing obesity in humans as it is in ob/ob mice, and merely reflects fat stores. In a small study of Pima Indians, low leptin levels predicted weight gain (134), but in a population-based study of Mauritians we were unable to find any associ- ation between high (leptin resistance) or low (leptin deficiency) leptin levels and weight gain over 5 years (135). Consistent with human evolutionary press- ure, it has been suggested that leptin may have a more important role in protecting against the effects of undernutrition (136—138), especially in relation to reproduction (139—141), rather than preventing overnutrition. In this case it may have little rele- vance to type 2 diabetes, but more research is 359OBESITY AND TYPE 2 DIABETES MELLITUS Figure 24.1 The complex relationship between obesity and type 2 diabetes mellitus, illustrating the roles of other risk factors. IGT, impaired glucose tolerance needed to determine whether leptin has a role in the development of diabetes. CONCLUSION Obesity, and central obesity in particular, are known to be important risk factors for development of type 2 diabetes. As discussed in this review, the association between obesity and type 2 diabetes may be modified by diet, physical activity, duration of obesity and other factors (Figure 24.1). Obesity and diabetes are interlinked through sev- eral mechanisms, and some of the relations are com- plicated by methodological issues surrounding as- sessment of obesity and study design. In a multi- factonal setting comprising environmental (includ- ing behavioural) and genetic factors, where risk fac- tors and outcome can both influence each other, data derived from epidemiological studies descri- bing average effects can only provide a rough esti- mate of an individual’s risk of developing type 2 diabetes. 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Nat Genet 1996; 12: 318—320 (Letter). 364 INTERNATIONAL TEXTBOOK OF OBESITY 25 Cardiovascular Disease Antonio Tiengo and Angelo Avogaro University of Padova, Padova, Italy INTRODUCTION Morbid obesity is linked to a higher mortality rate but the association between more modest over- weight and mortality appears less clear (Figure 25.1) (1,2). Although data from more than four million subjects initially suggested a direct positive associ- ation between body weight and overall mortality, subsequent studies showed an increased mortality only above a certain threshold, but described J- or even U-shaped associations between weight and mortality (3,4). The relationship of indicators of obesity to all-cause mortality has been extensively analysed: univariate analysis concerning the body mass index (BMI) for various age groups, the two sexes, and variable periods of follow-up has almost invariably shown minimum levels of risk for BMI values of 27—29 (5,6). However, the quantification of the excess mortal- ity from all causes associated with obesity remains controversial. It has been recently shown in a large cohort of obese persons that morbid obesity (BMI P 40 kg/m) was a strong predictor of premature death while moderate degrees of obesity (BMI 25—32 kg/m) were not significantly associated with excess mortality (7). Much of the obesity-associated mortality is linked to the negative effect of excessive fat distribu- tion on myocardial function and perfusion. As we will outline later in the chapter, much of the infor- mation on the relationship between obesity and heart disease derives from autopsy studies of mass- ively obese patients dying of congestive heart failure without clinical evidence of hypertension or cardiac disease. In obesity major haemodynamic changes take place affecting cardiac output, cardiac index and left ventricular stroke work; this increased car- diac output is determined by a major increase in total body fat mass which requires increased blood flow to support metabolism (Table 25.1). It has been estimated that 2—3 mL of blood is necessary to per- fuse every 100 g of adipose tissue at rest: in a patient with 100 kg of fat this would require up to a 3 L/min increase in blood flow. This increased workload leads to an increased ventricular mass and hyper- trophy which predispose to an important imbal- ance between perfusion and metabolic demand (8). In the light of these observations obesity deter- mines, at heart levels, structural alterations which make the myocardium and coronary vessels more prone to the atherosclerotic damage independently from the classic risk factors which are usually pres- ent in overweight people. Undoubtedly, the negative effects of obesity ap- pear closely linked to fat distribution. Central fat distribution is closely linked with a state of insulin resistance and the metabolic abnormalities asso- ciated with this syndrome; they all represent power- ful risk factors for atherosclerotic cardiovascular disease (ACVD) (9). Nonetheless obesity irrespec- tively from fat distribution is associated with dia- betes mellitus, hypertension and dyslipidaemia, which all predispose to ACVD (10). ACVD is closely associated with adiposity as measured by either weight, BMI, or measures of central fat accumulation. This relationship is in part mediated by the other risk factors which co-segre- gate with obesity, in part by obesity itself. The rela- International Textbook of Obesity. Edited by Per Bjo¨ rntorp. © 2001 John Wiley & Sons, Ltd. International Textbook of Obesity. Edited by Per Bjorntorp. Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic) Figure 25.1 Relative risk from all-cause mortality according to BMI in three studies that minimized confounding by smoking and underlying diseases. (a) Harvard Alumni Study; (b) The Nurses Health Study population; (c) The Seventh Day Adventist Study. From Solomon and Manson (4) Table 25.1 Ventricular dysfunction reported in severely obese patients 1. Impaired ventricular function 2. Abnormal response to exercise 3. Depressed contractility related to ventricular mass 4. Reduced atrial dimension 5. Reduced ventricular wall and septal size Adapted from Benotti et al. (8) tionship between obesity and ACVD appears to be consistent for both coronary artery disease (CHD) and stroke (CVA), but doubtful for peripheral ar- tery disease. RISK FACTORS FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE IN OBESITY Although obesity has been established as an inde- pendent risk factor for the development of atheros- clerotic cardiovascular disease (ACVD), obese people often present well-recognized coronary risk factors such as hypertension, lipid abnormalities, and type 2 diabetes (Table 25.2). There is now evi- dence that fat distribution rather than excess fatness is more commonly associated with these risk factors for ACVD. Abdominal fat deposition, which is prin- cipally observed in males and in postmenopausal females, is not only independently associated with ischaemic heart disease, but is a clinical condition in which the traditional risk factors for atherosclerosis are determined by the presence of insulin resistance which has likewise been associated with increased cardiovascular risk (11). The clinical aggregation of all these risk factors is also called the ‘(pluri)meta- bolic syndrome or syndrome X’. Regardless of these linguistic bagatelles, these patients will be exposed throughout their life to an excess risk for ACVD. Obese people not only have an excess of tradi- tional risk factors, they also have an excess presence of emerging risk factors such as a altered en- dothelial function and inappropriate production of cytokines, which are believed to play an important role in the development and progression of ACVD. Lipid Abnormalities Lipid and lipoprotein abnormalities are commonly present in obese patients. Population studies have shown a linear relationship between body weight and lipoprotein levels in blood plasma (12). In pa- tients of both sexes between the ages of 20 and 50 years there is a linear relationship between body weight, triglyceride and cholesterol concentrations. In people older than 50 years this relationship is no longer observed (13). Moreover, there is an inverse correlation between body weight and high density lipoprotein (HDL) cholesterol; this reciprocity is observed at all ages and in both sexes. Reduction in 366 INTERNATIONAL TEXTBOOK OF OBESITY Table 25.2 Atherogenic risk factors in obesity Lipid and lipoprotein abnormalities !Triglycerides !Cholesterol !Small dense LDL HDL cholesterol HDL  /HDL  cholesterol !Postprandial free fatty acids Hypertension Impaired glucose tolerance/type 2 diabetes Abnormalities of coagulation and fibrinolysis !von Willebrand !Fibrinogen !PAI-1 antigen/activity tPA !Factor VII Abnormalities in acute phase reaction proteins !C-reactive protein !TNF !Interleukin-6 Endothelial dysfunction Endothelium-dependent vasodilation Effect of insulin to augment endothelium-dependent vasodilation LDL, low density lipoprotein; HDL, high density lipoprotein; PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; TNF, tumour necrosis factor . HDL cholesterol is a consistent finding in over- weight patients (14). On the other hand, most pa- tients with hypertriglyceridaemia and decreased HDL cholesterol are overweight. Although the relationship between body weight and lipid abnormalities is weak and appreciable only in long-term prospective studies, the effects of obesity on lipoprotein metabolism are more profound than those predicted by the determina- tion of their plasma levels. This concept is sup- ported by kinetic studies which demonstrate that in obese people there is an increase of both production and clearance of very low density lipoprotein (VLDL) without significant alterations in their pre- vailing plasma concentrations (15). In obese patients there is an increased hepatic synthesis of VLDL. However, a substantial fraction of these lipoproteins are removed from the circula- tion without being converted to LDL which are themselves removed faster than in non-obese sub- jects (16). The reduction of HDL-cholesterol in obese subjects is partly determined by the increased mass of triglyceride-rich lipoproteins (17). More recently it has been shown that lipoprotein abnormalities are more profound in visceral than in subcutaneous adiposity (18). While excess fat does not appear to be significantly associated with lipid abnormalities, abdominal obesity is a better indi- cator of the lipoprotein abnormalities commonly used to quantify the risk for ACVD, particularly the LDL to HDL ratio (19). In the general population, waist-to-hip ratio (WHR), an index of abdominal fat accumulation, correlates with VLDL triglyceride concentration and with HDL cholesterol. Furthermore, WHR has been reported to be negatively correlated with HDL  cholesterol, and positively with both the ‘small dense’ LDL and with the ‘intermediate den- sity lipoprotein’ (20). In the light of these findings fat localization rather than total fat mass plays a major role in determining an atherogenic lipid profile. There exists much evidence suggesting a major role for the oxidized low density lipoprotein (LDL) and VLDL particles in the pathogenesis of atherosclero- sis (21). In obese subjects there are not only quanti- tative but also qualitative alterations in circulating lipoproteins. Van Gaal et al. measured the oxidiza- bility in vitro of lipoproteins in 21 obese premeno- pausal women and compared them to 18 age- matched non-obese controls (22). They found that TBARS, an index of lipid oxidation, measured every 30 minutes, increased in non-obese controls up to a maximum of 59.6 at 180 minutes in contrast to a maximum of 77.1 at 180 minutes (P : 0.001) in obese, but healthy, normocholesterolaemic sub- jects. At each measurement the TBARS were signifi- cantly higher (P : 0.01—0.001) in obese subjects. Also the lag-time (period from zero to the start of the particle oxidation process) was significantly lower in obese subjects, when compared to lean 367CARDIOVASCULAR DISEASE Figure 25.2 Potential mechanisms leading to the increased formation of small dense LDL and decreased levels of HDL. TG, triglyceride controls. BMI correlates significantly with TBARS formation. Thus in vitro oxidizability of non-HDL lipoproteins is significantly increased in obese, non- diabetic subjects and related to increased body weight (23). Thus patients present five main lipid abnormalities: (1) high triglycerides; (2) low HDL cholesterol; (3) reduced HDL  cholesterol; (4) in- creased proportion of small dense LDL; (5) in- creased susceptibility to oxidation of non-HDL lipoproteins. Obesity and particularly abdominal obesity is associated with lipid and lipoprotein abnormalities not only in the fasting but also in postprandial state. In patients with visceral obesity there is an exag- gerated postprandial free fatty acid (FFA) response which suggests that abdominal distribution of fat may contribute to both fasting and postprandial hypertrygliceridaemia by altering FFA metabolism in the postprandial state (16). The negative effect of obesity on FFA metab- olism appears to be determined by different compo- nents. First, insulin appears to have a blunted anti- lipolytic effect and this favours the delivery of FFA to the liver. Second, in viscerally obese women re- duced post-heparin lipoprotein lipase activity has been observed. In viscerally obese patients, in- creased activity in another lipase, the hepatic lipase which operates on small triglyceride-rich lipop- roteins, has also been observed (Figure 25.2) (24). This leads to an enrichment of LDL and HDL with triglycerides while VLDL become filled up with cholesterol esters. This process is the result of the action of plasma lipid transfer proteins which leads to increased levels of small dense LDL, a reduced HDL cholesterol (25,26). Fasting hypertriglyceridaemia is a common fea- ture of visceral obesity (27,28). This metabolic alter- ation is the result of an increased inflow of FFA to the liver. Several studies have shown that in obese subjects the lipolytic action of catecholamines in subcutaneous fat is reduced. This defect is caused by decreased expression and function of   -adrenocep- tors, increased antilipolytic action of   -adrenocep- tors and impaired ability of cyclic AMP to activate lipolysis (29). In contrast, visceral adipocytes show an enhanced lipolytic response to catecholamines due to an increased lipolytic activity of the   - adrenoceptors and to decreased antilipolytic activ- ity of the   -adrenoceptors. Moreover, visceral adi- pocytes show an inappropriately elevated lipolytic activity which is poorly inhibited by insulin. This metabolic abnormality results in increased FFA levels in both peripheral and portal circulation which leads to higher esterification of these substra- tes, to reduced degradation of apolipoprotein B, and to an increased synthesis and secretion of VLDL particles (15). The association between abdominal obesity, hy- pertriglyceridaemia and small dense LDLs, which are more susceptible to oxidation, appears to be the most robust cluster in term of cardiovascular risk. However, this aggregation is liable to correction since it was shown that weight loss normalizes the physico-chemical properties of LDL. A hypocaloric diet and modest weight reduction induce a signifi- cant reduction of triglyceride concentrations within a few weeks (30). However, a longer period is necess- ary to bring about a reduction in total cholesterol and LDL cholesterol, and an increase in HDL cho- lesterol. When weight loss is achieved by a combi- nation of diet and physical exercise, the improve- ment in lipid profile appears to be more consistent and stable (31). Hypertension The association between obesity and hypertension has been extensively documented by several studies and specifically from the Framingham Study and the National Health and Nutrition Examination 368 INTERNATIONAL TEXTBOOK OF OBESITY [...]... feature of non-insulin-dependent diabetes mellitus, appears to play a major role in the development and progression of ACVD in obese people with diabetes (81 ,82 ) This subject is described in detail in Chapter 24 372 INTERNATIONAL TEXTBOOK OF OBESITY CARDIOVASCULAR DISEASE Coronary Artery Disease The Framingham Study showed in 2005 men and 2521 women that the 2 8- year age-adjusted rates (per 100) of CHD... follow-up Diabetologia 1992; 35: 464—4 68 82 Casassus P, Fontbonne A, Thibult N, Ducimetiere P, Richard JL, Claude JR, Warnet JM, Rosselin G, Eschwege CARDIOVASCULAR DISEASE 83 84 85 86 87 88 89 90 91 92 93 94 E Upper-body fat distribution: a hyperinsulinemia-independent predictor of coronary heart disease mortality The Paris Prospective Study Arterioscler Thromb 1992; 12: 1 387 —1392 Higgins M, Kannel W, Garrison... 19 98; 7: 177—194 International Textbook of Obesity Edited by Per Bjorntorp Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-4 7 1-9 88 707 (Hardback); 0-4 7 0 -8 46739 (Electronic) 27 Pulmonary Diseases (Including Sleep Apnoea and Pickwickian Syndrome) Tracey D Robinson and Ronald R Grunstein Royal Prince Alfred Hospital, Sydney, New South Wales, Australia INTRODUCTION PULMONARY FUNCTION IN OBESITY Obesity... Insulin levels, blood pressure and sleep apnea Sleep 1994; 17: 614—6 18 Brooks D, Horner RL, Kozar LF, et al Obstructive sleep apnoea as a cause of systemic hypertension Evidence from a canine model J Clin Invest 1997; 99(1); 106—109 Chin K, Shimizu K, Nakamura T, et al Changes in intra- 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 abdominal visceral fat and leptin levels in patients with OSA... sleep apnea, and the pathogenesis of obesity hypoventilation Am Rev Resp Dis 1 982 ; 126: 640—645 9 Leech J, Onal E, Baer P, Lopata M Determinant of hypercapnia in occlusive sleep apnea syndrome Chest 1 987 ; 100: 1334—13 38 10 Kress JP, Pohlman AS, Alverdy J, Hall JB The impact of morbid obesity on oxygen cost of breathing at rest Am J Respir Crit Care Med 1999; 160: 88 3 88 6 11 Barrera F, Hillyer P, Ascanio... study of body mass index, weight change and risk of adult-onset asthma in women Arch Intern Med 1999; 159: 2 582 —2 588 28 Schachter LM, Salome CM, Peat JK, Woolcock AJ Obesity is a risk factor for asthma and wheeze but not for airway responsiveness Thorax 2001; 56: 4 8 29 Dixon JB, Chapman L, O’Brien P Marked improvement in asthma after lap-band surgery for morbid obesity Obes Surg 1999; 9: 385 — 389 30... number of types of study There have been large-scale population studies that have investigated the relationship between overweight and cancer at a range of sites In addition, there have been studies of various types (cohort, case-control etc.) into the role of overInternational Textbook of Obesity Edited by Per Bjorntorp ¨ © 2001 John Wiley & Sons, Ltd One of the early population cohort studies of note... of OSA (81 ) Data from the Wisconsin Sleep Cohort suggests that smoking history may be a dose-dependent risk factor for OSA (82 ) A number of endocrine and metabolic disorders apart from obesity are associated with an increased prevalence of OSA Hypothyroidism may lead to sleep apnoea by reducing chemosensitivity, myxoedematous infiltration of the upper airway and upper airway myopathy (83 ) Over 50% of. .. Hotamisligil GS Mechanisms of TNF-alpha-induced insulin resistance [see comments] Exp Clin Endocrinol Dia- betes 1999; 107: 119—125 67 Hotamisligil GS The role of TNFalpha and TNF receptors in obesity and insulin resistance J Intern Med 1999; 245: 621—625 68 Le Marchand-Brustel Y Molecular mechanisms of insulin action in normal and insulin-resistant states [see comments] Exp Clin Endocrinol Diabetes 1999;... as one of the most prominent in the metabolic syndrome It has been recently shown that the adipose tissue is a site of active PAI-1 production which is a function of cell size and of their lipid content ( 58) Overproduction of PAI-1 is determined by an increased PAI-1 gene expression Visceral rather than subcutaneous adipose tissue is a site of inappropriate PAI-1 production This excessive PAI-1 production . accumulation. This relationship is in part mediated by the other risk factors which co-segre- gate with obesity, in part by obesity itself. The rela- International Textbook of Obesity. Edited by Per Bjo¨. Wiley & Sons, Ltd. International Textbook of Obesity. Edited by Per Bjorntorp. Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-4 7 1-9 88 707 (Hardback); 0-4 7 0 -8 46739 (Electronic) Figure. incidence of diabetes mel- litus. 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 1 985 ; 35: 1055—10 58. 22. Haffner SM, Stern MP, Mitchell BD, Hazuda HP, Patter- son