Medicine & Science in Sports & Exercise:
Roundtable Consensus Statement
Comorbidities of overweight and obesity: current evidence and research issues
PI-SUNYER, F. XAVIER
St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025
Address for correspondence: F. Xavier Pi-Sunyer, M.D., Obesity Research Center, St. Luke’s-Roosevelt Hospital Center, 1111 Amsterdam Ave., New York, NY 10025; E-mail: email@example.com.
Roundtable held February 4–7, 1999, Indianapolis, IN.
PI-SUNYER, F. X. Comorbidities of overweight and obesity; current evidence and research issues. Med. Sci. Sports Exerc., Vol. 31, No. 11, Suppl., pp. S602–S608, 1999.
Purpose: The evidence with regard to the relationship of obesity with medical comorbidities was assessed and priority research issues identified.
Methods: The existing literature in English was surveyed.
Results: The evidence is overwhelming on the association of obesity to a number of medical conditions. These include: insulin resistance, glucose intolerance, diabetes mellitus, hypertension, dyslipidemia, sleep apnea, arthritis, hyperuricemia, gall bladder disease, and certain types of cancer. The independent association of obesity seems also clearly established for coronary artery disease, heart failure, cardiac arrhythmia, stroke, and menstrual irregularities. The relationship between central (or upper body) obesity and the above conditions is positive for most of them but with a lesser number of studies. Most of the fat distribution studies have been done using anthropometric measurements rather than the more accurate magnetic resonance imaging or computer tomographic scans. Priority research issues include the following: more definitive data on the relation of central fat to comorbidities; the proportional importance of subcutaneous versus visceral fat in producing comorbidities; the relationship between obesity and psychiatric disease; the genetics of the relationship between obesity and each of the comorbidities; the independent contribution of diet and of sedentariness to the development of each of the comorbidities; the impact of gender, race, intensity, and duration on these associations.
Conclusions: The evidence for the relationship of obesity to a number of comorbidities is strong, though the strength of the relationship varies with the condition. Much more research is necessary on causation and on what other factors may play an interactive role.
There is a very large bibliography on the association of overweight and obesity with other medical conditions. The data include evidence for overweight and obesity and also for the distribution of body fat. The evidence that is available in English with regard to the former will be reviewed first and with regard to the latter second.
CURRENT STATUS OF KNOWLEDGE
Overweight and Obesity
Type II diabetes mellitus.
Although the relationship of obesity to Type II diabetes mellitus is not wholly clear, two facts are incontrovertible. Excess body fat leads to increasing insulin resistance (82), and insulin resistance predisposes to diabetes (82,116). Why, however, some individuals may be obese for years without developing diabetes, whereas others develop it readily, must depend on their genetic make-up. Until more is known about the genes responsible for insulin resistance and for Type II diabetes, the exact mechanisms involved will not be clarified.
Insulin resistance, impaired glucose tolerance, and diabetes mellitus have been strongly associated with overweight and obesity in many cross-sectional (68,100,115,120,149,150) (52,64,88,113,142,151,159) and longitudinal (17,20,57,81,92) studies.
The association between increased blood pressure and overweight and obesity has been shown repeatedly in both cross-sectional (2,3,7,14,34, 47,61,97,123,127,133,141,143,152,155) and longitudinal (66,69,103,140) studies. The independence of obesity as a risk factor for hypertension is underscored by observations of a much higher prevalence of hypertension in obese persons than in the general population. This has been reported both in populations with a high prevalence of hypertension, such as African-Americans (129), as well as in populations with a low prevalence of hypertension, such as Mexican-Americans (54). Weight gain leads to an increase in blood pressure, as has been reported in the Framingham study (72) among others. The mechanisms proposed for this relationship have been many (114) and until the genes responsible for this multi-etiological condition and the relationship of these genes to the genes that predispose to obesity have been identified, these mechanisms will not be clarified.
Obesity has been associated with two particular abnormalities: increased levels of triglycerides and decreased high-density lipoprotein cholesterol (high density lipoprotein (HDL)-C). Both of these are now recognized as independent risk factors for cardiovascular disease (8,9,48). Cross-sectional (128,143) as well as longitudinal (8,9) studies have shown the relationship of obesity to higher levels of triglycerides. Also, low HDL-C levels have been found in both cross-sectional (45,143) and longitudinal (48) studies. An increase in triglycerides has also been described longitudinally with an increase in weight (4). Total and low-density lipoprotein cholesterol (low density lipoprotein (LDL)-C) have been found to be either normal or elevated (8,37,128,142). In more recent years, there have been descriptions of a qualitative change in the size of LDL particles, with an increase in the number of small, dense ones that are more atherogenic (10). The relationship has been clearly shown for insulin resistance (11,98,117) and has thereby been extrapolated to obesity, which is an insulin resistant state (98). More research on the presence of this LDL-C phenotype (phenotype B) in obese populations is required.
Coronary heart disease.
Coronary heart disease (CHD) is usually described epidemiologically as angina pectoris, nonfatal myocardial infarction, and sudden death. There have been differing opinions on the relationship of obesity to CHD. This is because, since the obesity enhances the risk of hypertension, dyslipidemia, and diabetes mellitus, all of which are risk factors for CHD, the independent effect of the obesity itself has been difficult to verify. However, recent studies have left little doubt of the relationship in both men and women (18,21,38,49,70,78,79,99,121,131). There is also an association between obesity and left ventricular hypertrophy and congestive heart failure (66,70,71,73,74). Arrhythmia and sudden death are also associated with obesity (31,66,73,101). The causative mechanisms between obesity and sudden death is not clear. Whether it is related to alterations in sympathetic and/or parasympathetic nervous activity has been debated (42,63,158).
Gall bladder disease.
Both cross-sectional (16,50,83,120) and longitudinal (41,75,96,109,130,138) studies have reported an association between gall bladder disease and overweight and obesity.
There is a gradually increasing impairment of respiratory function with increasing obesity. The sheer burden of the extra fat in the chest wall and the abdomen causes a decreased compliance of respiratory function and reduces lung volume (102,147). A ventilation-perfusion abnormality occurs (12) that initially causes hypoxia with normal pCO2 (30,65). Eventually, however, as the severity of obesity increases, hypercarbia also develops. Sleep apnea occurs as the severity and duration of the obesity exacerbates (119,146,157). This may be obstructive sleep apnea (118) or central (13) or a combination of the two. Eventually, the obesity-hypoventilation syndrome, with depression of hypercapnic and hypoxic respiratory drives, irregular breathing, frequent apneic periods with resultant hypoxia (84) and daytime sleepiness supervenes. Finally, cor pulmonale can occur (124).
The relationship of obesity to cancer has been a very difficult question to sort out and is still deeply mired in controversy. Part of the problem is that even though, in longitudinal studies, it is clear that obesity is associated with some cancers, it has been very difficult to separate the role of overweight and obesity per se from the effect of the macronutrient composition of the diet or of total calories (114). The American Cancer Society study, which was a longitudinal study that followed 750,000 men and women for 12 yr, found that the mortality ratio for cancer for men who were 40% or more overweight was 1.33 and for women it was 1.55 (43). These obese men had higher rates of colorectal and prostate cancers, whereas the women had higher rates of endometrial, gallbladder, cervical, ovarian, and breast cancers (43). With regard to breast cancer, other longitudinal studies have described a greater risk for obese postmenopausal women but not for obese premenopausal women (23,93,94,108,132,136,145,154). There have been a number of studies that have shown positive associations between weight and endometrial cancer (40,85,89,90,125,132,137). In men, some studies have shown increased colon cancer (91,112), but others have not (105,139,153,156).
Cross-sectional studies have reported an association between obesity and osteoarthritis of the knees (1,6,22,39,46,59,77,120). A twin study in which one twin weighed more than the other showed a strong association between obesity and osteoarthritis (58). This report concluded that every 5 kg of gain in weight increased the risk of knee arthritis by 35%. The evidence for the relationship of obesity to osteoarthritis of the hip is much less strong (59,77,144).
Association between Fat Distribution and Medical Conditions
A considerable literature is now available with regard to the association of central or upper body fat distribution and health risk. Most of the epidemiological studies that have been published have been done using anthropometric measurements as surrogates for fat distribution.
There have been a number of cross-sectional (29,53,68,110) and longitudinal (66) epidemiological studies that have reported an association between central fat distribution and hypertension.
Type II diabetes mellitus.
There are a number of studies, both cross-sectional (44,56,60,67) and longitudinal (55,57,76,95,106), that have shown an association between obesity and diabetes mellitus. The increased central fat distribution leads to insulin resistance and impaired glucose tolerance (28,35,36,80,111,126).
There have been a number of studies that have described dyslipidemia in patients with central fat distribution. The syndrome is similar to that seen for obesity per se, with hypertriglyceridemia, low HDL-cholesterol, and an increased number of small dense LDL particles, which are very atherogenic (24–27,107,135). In addition, increased apoB lipoprotein levels have been described (89).
Cross-sectional studies have shown a relationship between central fatness and CHD (89). Longitudinal studies have reported similar findings (19,29,32,33,62,86,87,121,134).
There is also a report of enhanced risk for stroke with central obesity (148).
Other medical conditions.
Gall bladder disease has been reported to be associated with central fat distribution (56).
There are many unanswered questions on the association of obesity and central fat distribution with health risks. Research priorities with regard to these associations are numerous. Most important is the fact that all of the above cited studies show an association or correlation between obesity, central fat distribution, and morbidity, but correlation does not necessarily indicate causality (5). Three studies have suggested that obesity and cardiovascular risk factors are not pleiotropic (51,104,122). In addition, within person changes in fatness lead to changes in morbidity (71,103,140). Also, there is a report of a negative relationship between baseline cardiovascular risk factors and future fatness, suggesting that these risk factors are not elevated before weight gain (15). Clear confounders are physical activity, composition of the diet, caloric intake, and smoking. The role of each of these confounders on comorbid conditions needs to be investigated.
More investigation is also needed on the following:
1. The relation of central fat to comorbidities, with better characterization of the central fat so as to be able to sort out the contribution of central versus subcutaneous fat tissue to each comorbidity.
2. The genetics of the relationship between obesity, fat distribution, and each of the comorbidities.
3. The impact of gender, race, intensity, and duration of obesity and fat distribution on each of the comorbidities.
4. The interaction between obesity and central fat distribution and other potential associated factors responsible for particular comorbidities.
5. The relationship between obesity and psychiatric disease.
6. The independent contribution of diet and of sedentariness to the development of each of the comorbidities.
The evidence for the relationship of obesity to a number of comorbidities is strong, but much more research is necessary on causation and on what other factors play a role.
1. Acheson, R. M., and A. B. Collart. New Haven survey of joint diseases. XVII. Relationship between some systemic characteristics and osteoarthrosis in a general population. Ann. Rheum. Dis. 34: 379–387, 1975.
2. Adams-Campbell, L. L., R. Wing, F. A. Ukoli, C. A. Janney, and M. U. Nwankwo. Obesity, body fat distribution, and blood pressure in Nigerian and African-American men and women. J. Natl. Med. Assoc. 86: 60–64, 1994.
3. Agarwal, A. K., M. Yunus, A. Khan, and J. Ahmad. A clinical-epidemiological study of hypertension in a rural population of Jawan Block, Dist. Aligarh (UP) India. J. R. Soc. Health 114: 17–19, 1994.
4. Allbrink, M. J., J. W. Meigs, and M. A. Granoff. Weight gain and serum triglycerides in normal men. N. Engl. J. Med.: 484–489, 1962.
5. Allison, D. B., and F. X. Pi-Sunyer. Obesity treatment: examining the premises. Endocr. Prac. 1: 353–364, 1995.
6. Anderson, J. J., and D. T. Felson. Factors associated with osteoarthritis of the knee in the first National Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am. J. Epidemiol. 128: 179–189, 1988.
7. Armellini, F., F. A. Rossi, R. Ostuzzi, G. Crivellenti, and C. Bosello. Studies of blood pressure in obese women. In: Medical Complications of Obesity: Proceedings of the Serono Symposia, M. Mancini, B. Lewis, and F. Contaldo (Eds.). New York: Academic Press, 1979, pp. 253–257.
8. Assmann, G., and H. Schulte. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Munster Study. Am. J. Cardiol. 70: 10H–13H, 1992.
9. Austin, M. A. Plasma triglyceride and coronary heart disease (Review). Arterioscler. Thromb. 11: 2–14, 1991.
10. Austin, M. A., J. L. Breslow, C. H. Hennekens, et al. LDL subclass patterns and risk of myocardial infarction. JAMA 260: 1917–1921, 1988.
11. Austin, M. A., M. C. King, K. M. Vranizan, and R. M. Krauss. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease. Circulation 82: 495–506, 1990.
12. Barrera, F., P. Hillyer, G. Ascanio, and J. Bechtel. The distribution of ventilation, diffusion, and blood flow in obese patients with normal and abnormal blood gases. Am. Rev. Respirat. Dis. 108: 819–830, 1973.
13. Barrocas, M., S. Chokroverty, G. L. Baum, A. Schwartz, and J. T. Sharp. Hypoventilation-obesity syndrome: central origin of a ventilatory dysrythmia (Abstract). Chest 68:(Suppl.) 401, 1975.
14. Boe, J., S. Humerfelt, and G. Wedervang. The blood pressure in a population: blood pressure readings and height and weight determinations in the adult population of the city of Bergen. Acta Med. Scand. Suppl. 321: 1–336, 1957.
15. Burack, R. C. Cardiovascular risk factors and obesity: are baseline levels of blood pressure, glucose, cholesterol and uric acid elevated prior to weight gain? J. Chronic Dis. 38: 865–872, 1985.
16. Burnett, W. The epidemiology of gall stones. Tijdschr. Gastroenterol. 14: 79–89, 1971.
17. Chan, J. M., E. B. Rimm, G. A. Colditz, M. J. Stampfer, and W. C. Willett. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17: 961–969, 1994.
18. Chapman, J. M., A. H. Coulson, V. A. Clark, and E. R. Borun. The differential effect of serum cholesterol, blood pressure and weight on the incidence of myocardial infarction and angina pectoris. J. Chronic Dis. 23: 631–645, 1971.
19. Clark, L. T., M. M. Karve, K. T. Rones, et al. Obesity, distribution of body fat and coronary artery disease in black women. Am. J. Cardiol. 73: 895–896, 1994.
20. Colditz, G. A., W. C. Willett, M. J. Stampfer, et al. Weight as a risk factor for clinical diabetes in women. Am. J. Epidemiol. 132: 501–513, 1990.
21. Coleman, M. P., T. J. Key, D. Y. Wang, et al. A prospective study of obesity, lipids, apolipoproteins and ischemic heart disease in women. Atherosclerosis 92: 177–185, 1992.
22. Davis, M. A., W. H. Ettinger, J. M. Neuhaus, S. A. Cho, and W. W. Hauck. The association of knee injury and obesity with unilateral and bilateral osteoarthritis of the knee. Am. J. Epidemiol. 130: 278–288, 1989.
23. de Waard, F. Breast cancer incidence and nutritional status with particular reference to body weight and height. Cancer Res. 35: 3351–3356, 1975.
24. Després, J. P., C. Allard, A. Tremblay, J. Talbot, and C. Bouchard. Evidence for a regional component of body fatness in the association with serum lipids in men and women. Metabolism 34: 967–973, 1985.
25. Després, J. P., M. Ferland, S. Moorjani, et al. Role of hepatic-triglyceride lipase activity in the association between intra-abdominal fat and plasma HDL cholesterol in obese women. Arteriosclerosis 9: 485–492, 1989.
26. Després, J. P., S. Moorjani, M. Ferland, et al. Adipose tissue distribution and plasma lipoprotein levels in obese women: importance of intra-abdominal fat. Arteriosclerosis 9: 203–210, 1989.
27. Després, J. P., S. Moorjani, A. Tremblay, et al. Relation of high plasma triglyceride levels associated with obesity and regional adipose tissue distribution to plasma lipoprotein-lipid composition in premenopausal women. Clin. Invest. Med. 12: 374–380, 1989.
28. Després, J. P., A. Tremblay, J. Talbot, and C. Bouchard. Regional adipose tissue distribution and plasma lipoproteins. In: Fat Distribution during Growth and Later Health Outcomes, C. Bouchard and F. E. Johnson (Eds.). New York: Alan R. Liss, Inc., 1988, pp. 221–242.
29. Donahue, R. P., R. D. Abbott, E. Bloom, D. M. Reed, and K. Yano. Central obesity and coronary heart disease in men. Lancet 1: 821–824, 1987.
30. Douglas, F. G., and P. Y. Chong. Influence of obesity on peripheral airways patency. J. Appl. Physiol. 33: 559–563, 1972.
31. Drenick, E. J., G. S. Bale, F. Seltzer, and D. G. Johnson. Excessive mortality and causes of death in morbidly obese men. JAMA 243: 443–445, 1980.
32. Ducimetiere, P., and J. L. Richard. The relationship between subsets of anthropometric upper versus lower body measurements and coronary heart disease risk in middle-aged men: the Paris Prospective Study. Int. J. Obes. 13: 111–122, 1989.
33. Ducimetiere, P., J. L. Richard, and F. Cambien. The pattern of subcutaneous fat distribution in middle-aged men and the risk of coronary heart disease: the Paris Prospective Study. Int. J. Obes. 10: 229–240, 1986.
34. Epstein, F. H., T. Francis, N. S. Fayner, B. C. Johnson, M. O. Kjelsberg, and J. A. Napier. Prevalence of chronic diseases and distribution of selected physiologic variables in a total community, Tecumseh, Michigan. Am. J. Epidemiol. 81: 301–322, 1965.
35. Evans, D. J., R. G. Hoffmann, R. K. Kalkhoff, and A. H. Kissebah. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metab. Clin. Exp. 33: 68–75, 1984.
36. Evans, D. J., R. Murray, and A. H. Kissebah. Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography. J. Clin. Invest. 74: 1515–1525, 1984.
37. Farinaro, E., C. Cortese, P. Rubba, L. Dimarino, and M. Mancini. Overweight and plasma lipoprotein abnormalities in a random sample of the Neapolitan population. In: Medical Complications of Obesity, M. Mancini, B. Lewis, and R. Contaldo (Eds.). London: Academic Press, 1979, pp. 13–150.
38. Fitzgerald, A. P., and R. J. Jarrett. Body weight and coronary heart disease mortality: an analysis in relation to age and smoking habit. 15 years follow-up data from the Whitehall Study. Int. J. Obes. 16: 119–129, 1992.
39. Fletcher, E., and E. Lewis-Faning. Chronic rheumatic diseases with special reference to chronic arthritis: a survey based on 1000 cases. Postgrad. Med. J. 21: 51–56, 1945.
40. Folsom, A. R., S. A. Kaye, J. D. Potter, and R. J. Prineas. Association of incident carcinoma of the endometrium with body weight and fat distribution in older women: early findings of the Iowa Women’s Health Study. Cancer Res. 49: 6828–6831, 1989.
41. Friedman, G. D., W. B. Kannel, and T. R. Dawber. The epidemiology of gallbladder disease: observations in the Framingham Study. J. Chronic Dis. 19: 273–292, 1966.
42. Gao, Y. Y., J. C. Lovejoy, A. Sparti, G. A. Bray, L. K. Keys, and C. Partington. Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women. Obes. Res. 4: 55–63, 1996.
43. Garfinkel, L. Overweight and cancer. Ann. Intern. Med. 103: 1034–1036, 1985.
44. Gillum, R. F. The association of body fat distribution with hypertension, hypertensive heart disease, coronary heart disease, diabetes and cardiovascular risk factors in men and women aged 18–79 years. J. Chronic Dis. 40: 421–428, 1987.
45. Glueck, C. J., H. L. Taylor, D. Jacobs, J. A. Morrison, R. Beaglehole, and O. D. Williams. Plasma high-density lipoprotein cholesterol: association with measurements of body mass. Circulation 62: 62–69, 1980.
46. Goldin, R. H., L. McAdam, J. S. Louie, R. Gold, and R. Bluestone. Clinical and radiological survey of the incidence of osteoarthritis among obese patients. Ann. Rheum. Dis. 35: 349–353, 1976.
47. Gopinath, N., S. L. Chadha, A. K. Sood, S. Shekhawat, S. P. Bindra, and R. Tandon. Epidemiological study of hypertension in young (15–24 yr) Delhi urban population. Indian J. Med. Res. (Sect. A) 99: 32–37, 1994.
48. Gordon, T., W. P. Castelli, M. C. Hjortland, W. B. Kannel, and T. R. Dawber. HDL as a protective factor against coronary heart disease: the Framingham Study. Am. J. Med. 62: 707–714, 1977.
49. Gordon, T., and J. T. Doyle. Weight and mortality in men: the Albany Study. Int. J. Epidemiol. 17: 77–81, 1988.
50. GREPCO. The epidemiology of gallstone disease in Rome, Italy. Part 1: prevalence data in men. Hepatology 8: 904–906, 1988.
51. Grim, C. E., T. W. Wilson, G. D. Nicholson, et al. Blood pressure in blacks: twin studies in Barbados. Hypertension 15: 803–809, 1990.
52. Haas, T., S. Svacina, J. Pav, R. Hovorka, P. Sucharda, and J. Sonka. Risk calculation of type 2 diabetes. Comp. Meth. Prog. Biomed. 41: 297–303, 1994.
53. Haffner, S. M. Excess androgenicity only partially explains the relationship between obesity and bone density in premenopausal women. Int. J. Obes. Relat. Metab. Disord. 16: 869–874, 1992.
54. Haffner, S. M., E. Ferrannini, H. P. Hazuda, and M. P. Stern. Clustering of cardiovascular risk factors in confirmed prehypertensive individuals. Hypertension 20: 38–45, 1992.
55. Haffner, S. M., B. D. Mitchell, H. P. Hazuda, and M. P. Stern. Greater influence of central distribution of adipose tissue on incidence of non-insulin-dependent diabetes in women than men. Am. J. Clin. Nutr. 53: 1312–1317, 1991.
56. Haffner, S. M., M. P. Stern, H. P. Hazuda, M. Rosenthal, J. A. Knapp, and R. M. Malina. Role of obesity and fat distribution in non-insulin-dependent diabetes mellitus in Mexican Americans and non-Hispanic whites. Diabetes Care 9: 153–161, 1986.
57. Haffner, S. M., M. P. Stern, B. D. Mitchell, H. P. Hazuda, and J. K. Patterson. Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution. Diabetes 39: 283–288, 1990.
58. Hart, D. J., and T. D. Spector. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J. Rheumatol. 20: 331–335, 1993.
59. Hartz, A. J., M. E. Fischer, G. Bril, et al. The association of obesity with joint pain and osteoarthritis in a general population. J. Chronic Dis. 39: 311–319, 1986.
60. Hartz, A. J., D. C. Rupley Jr., R. D. Kalkhoff, and A. A. Rimm. Relationship of obesity to diabetes: influence of obesity level and body fat distribution. Prev. Med. 12: 351–357, 1983.
61. Havlik, R. J., H. B. Hubert, R. R. Fabsitz, and M. Feinlab. Weight and hypertension. Ann. Intern. Med. 98: 855–859, 1983.
62. Higgins, M., W. Kannel, R. Garrison, J. Pinsky, and J. Stokes, 3rd. Hazards of obesity: the Framingham experience. Acta Med. Scand. Suppl. 723: 23–36, 1988.
63. Hirsch, J., R. L. Leibel, R. Mackintosh, and A. Aguirre. Heart rate variability as a measure of autonomic function during weight change in humans. Am. J. Physiol. 261: R1418–R1423, 1991.
64. Holbrook, T. L., E. Barrett-Connor, and D. L. Wingard. The association of lifetime weight and weight control patterns with diabetes among men and women in an adult community. Int. J. Obes. 13: 723–729,.
65. Holley, H. S., J. Milic-Emili, M. R. Becklake, and D. V. Bates. Regional distribution of pulmonary ventilation and perfusion in obesity. J. Clin. Invest. 46: 475–481, 1967.
66. Hubert, H. B., M. Feinlieb, P. M. McNamara, and W. P. Castelli. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67: 968–977, 1983.
67. Joos, S. K., W. H. Mueller, C. L. Hanis, and W. J. Schull. Diabetes alert study: weight history and upper body obesity in diabetic and non-diabetic Mexican American adults. Ann. Hum. Biol. 11: 167–171, 1984.
68. Kalkhoff, R. K., A. H. Hartz, D. Rupley, A. H. Kissebah, and S. Kelber. Relationship of body fat distribution to blood pressure, carbohydrate tolerance, and plasma lipids in healthy obese women. J. Lab Clin. Med. 102: 621–627, 1983.
69. Kannel, W. B., N. Brand, J. J. Skinner Jr., T. R. Dawber, and P. M. McNamara. The relation of adiposity to blood pressure and development of hypertension: the Framingham Study. Ann. Intern. Med. 67: 48–49, 1967.
70. Kannel, W. B., R. B. D’agostino, and J. L. Cobb. Effect of weight on cardiovascular disease (Review). Am. J. Clin. Nutr. 63: 419S–422S, 1996.
71. Kannel, W. B., and T. Gordon. Obesity and cardiovascular disease. In: Obesity Symposium: Proceedings of a Servier Research Institute Symposium, December 1973, W.L. Burland, P.D. Samuel and J. Yudkin (Eds.). New York: Churchill Livingstone, 1974.
72. Kannel, W. B., T. Gordon, and D. Offutt. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence, and mortality in the Framingham study. Ann. Intern. Med. 71: 89–105, 1969.
73. Kannel, W. B., J. F. Plehn, and L. A. Cupples. Cardiac failure and sudden death in the Framingham Study. Am. Heart J. 115: 869–875, 1988.
74. Kasper, E. K., R. H. Hruban, and K. L. Baughman. Cardiomyopathy of obesity: a clinicopathologic evaluation of 43 obese patients with heart failure. Am. J. Cardiol. 70: 921–924, 1992.
75. Kato, I., A. Nomura, G. N. Stemmermann, and P. H. Chyou. Prospective study of clinical gallbladder disease and its association with obesity, physical activity, and other factors. Digest. Dis. Sci. 37: 784–790, 1992.
76. Kaye, S. A., A. R. Folsom, J. M. Sprafka, R. J. Prineas, and R. B. Wallace. Increased incidence of diabetes mellitus in relation to abdominal adiposity in older women. J. Clin. Epidemiol. 44: 329–334, 1991.
77. Kellgren, J. H., and J. S. Lawrence. Osteoarthritis and disk degeneration in an urban population. Ann. Rheum. Dis. 17: 388–396, 1958.
78. Keys, A., C. Aravanis, H. Blackburn, et al. Coronary heart disease: overweight and obesity as risk factors. Ann. Intern. Med. 77: 15–27, 1972.
79. King, N. A. High-fat foods overcome the energy expenditure induced by high-intensity cycling or running. Eur. J. Clin. Nutr. 49: 114–123, 1995.
80. Kissebah, A. H., N. Vydelingum, R. Murray, et al. Relation of body fat distribution to metabolic complications of obesity. J. Clin. Epidemiol. 54: 254–260, 1982.
81. Knowler, W. C., P. J. Pettit, P. J. Savage, and P. H. Bennett. Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am. J. Epidemiol. 113: 144–156, 1981.
82. Kolterman, O. G., J. Insel, M. Saekow, and J. M. Olefsky. Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J. Clin. Invest. 65: 1272–1284, 1980.
83. Kono, S., K. Shinchi, N. Ikeda, F. Yanai, and K. Imanishi. Prevalence of gallstone disease in relation to smoking, alcohol use, obesity, and glucose tolerance: a study of self-defense officials in Japan. Am. J. Epidemiol. 136: 787–794, 1992.
84. Kopelman, P. G., M. C. Apps, T. Cope, D. A. Ingram, D. W. Empey, and S. J. Evans. Nocturnal hypoxia and sleep apnoea in asymptomatic obese men. Int. J. Obes. 10: 211–217, 1986.
85. La Vecchia, C., F. Parassini, E. Negri, M. Fasoli, A. Gentile, and S. Franceschi. Anthropometric indicators of endometrial cancer risk. Eur. J. Cancer 27: 487–490, 1991.
86. Lapidus, L., C. Bengtsson, B. Larsson, K. Pennert, E. Rybo, and L. Sjöström. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br. Med. J. 289: 1257–1261, 1984.
87. Larsson, B., K. Svärdsudd, L. Welin, L. Wilhelmsen, P. Björntorp, and G. Tibblin. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 y and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br. Med. J. 288: 1401–1404, 1984.
88. Lawrenson, R. A., P. J. Dunn, D. Jury, and J. Sceats. Discover diabetes: screening for diabetes mellitus in the Waikato. N. Z. Med. J. 106: 522–524, 1993.
89. Le Marchand, L., L. R. Wilkens, and M. P. Mi. Early-age body size, adult weight gain and endometrial cancer risk. Int. J. Cancer 48: 807–811, 1991.
90. Levi, F., C. Lavecchia, E. Negri, F. Paraxxini, and S. Francheschi. Body mass at different ages and subsequent endometrial cancer risk. Int. J. Cancer 50: 567–571, 1992.
91. Lew, E. A., and L. Garfinkel. Variations in mortality by weight among 750,000 men and women. J. Chronic Dis. 32: 563–576, 1979.
92. Lipton, R. B., Y. Liao, G. Cao, R. S. Cooper, and D. McGee. Determinants of incident non-insulin-dependent diabetes mellitus among blacks and whites in a national sample: the NHANES I Epidemiologic Follow-Up Study. Am. J. Epidemiol. 138: 826–839, 1993.
93. London S. J., G. A. Colditz, M. J. Stampfer, W. C. Willett, B. R. Rosner, and F. E. Speizer. Prospective study of relative weight, height, and risk of breast cancer. JAMA 262: 2853–2858, 1989.
94. Lubin, F., A. M. Ruder, Y. Wax, and B. Modan. Overweight and changes in weight throughout adult life in breast cancer etiology: a case-control study. Am. J. Epidemiol. 122: 579–588, 1985.
95. Lundgren, H., C. Bengtsson, G. Blohme, L. Lapidus, and Adiposity and adipose tissue distribution in relation to incidence of diabetes in women: results from a prospective population study in Gothenburg, Sweden. Int. J. Obes. 13: 413–423, 1989.
96. Maclure, K. M., K. C. Hayes, G. A. Colditz, M. J. Stampfer, F. E. Speizer, and W. C. Willett. Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N. Engl. J. Med. 321: 563–569, 1989.
97. MacMahon, S. W., R. B. Blacket, G. J. Macdonald, and W. Hall. Obesity, alcohol consumption and blood pressure in Australian men and women: the National Heart Foundation of Australia Risk Factor Prevalence Study. J. Hypertens. 2: 85–91, 1984.
98. Maggio, C. A., and F. X. Pi-Sunyer. The prevention and treatment of obesity: application to type II diabetes. Diabetes Care 20: 1744–1766, 1997.
99. Manson, J. E., G. A. Colditz, M. J. Stampfer, et al. A prospective study of obesity and risk of coronary heart disease in women. N. Engl. J. Med. 322: 882–889, 1990.
100. Medalie, J. H., J. B. Herman, U. Golgbourt, and C. M. Papier. Variations in incidence of diabetes among 10,000 adult Israeli males and the factors related to their development. Adv. Metab. Disord. 9: 93–110, 1978.
101. Messerli, F. H., B. D. Nunez, H. O. Ventura, and D. W. Snyder. Overweight and sudden death: increased ventricular ectopy in cardiopathy of obesity. Arch. Intern. Med. 147: 1725–1728, 1987.
102. Naimark, A., and R. M. Cherniak. Compliance of the respiratory system and its components in health and obesity. J. Appl. Physiol.: 377–382, 1960.
103. Neser, W. B. Obesity and hypertension in a longitudinal study of black physicians: the Meharry Cohort Study. J. Chronic Dis. 39: 105–113, 1986.
104. Newman, B. Nongenetic influences of obesity on other cardiovascular disease risk factors: an analysis of identical twins. Am. J. Public Health 80: 675–678, 1990.
105. Nomura, A., L. Helibrun, and G. N. Stemmermann. Body mass index as a predictor of cancer in men. J. Natl. Cancer Inst. 74: 319–324, 1985.
106. Ohlson, L. O., B. Larsson, K. Svärdsudd, et al. The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow up of the participants in the study of men born in 1913. Diabetes 34: 1055–1058, 1985.
107. Ostlund, R. E. J., M. Staten, W. M. Kohrt, J. Schultz, and M. Malley. The ratio of waist-to-hip circumference, plasma insulin level, and glucose intolerance as independent predictors of the HDL2 cholesterol level in older adults. N. Engl. J. Med. 322: 229–234, 1990.
108. Paffenberger, R. S. Jr., J. B. Kampert, and H. G. Chang. Characteristics that predict risk of breast cancer before and after menopause. Am. J. Epidemiol. 112: 258–268, 1980.
109. Palasciano, G., P. Portincasa, V. Vinciguerra, et al. Gallstone prevalence and gallbladder volume in children and adolescents: an epidemiological ultrasonographic survey and relationship to body mass index. Am. J. Gastroenterol. 84: 1378–1382, 1989.
110. Peiris, A. N., M. S. Sothmann, R. G. Hoffmann, et al. Adiposity, fat distribution, and cardiovascular risk. Ann. Intern. Med. 110: 867–872, 1989.
111. Peiris, A. N., M. F. Struve, R. A. Mueller, M. B. Lee, and A. H. Kissebah. Glucose metabolism in obesity: influence of body fat distribution. J. Clin. Epidemiol. 67: 760–767, 1988.
112. Phillips, R. L., and D. A. Snowdon. Dietary relationships with fatal colorectal cancer among Seventh-day Adventists. J. Natl. Cancer Inst. 74: 307–317, 1985.
113. Pi-Sunyer, F. X. Obesity and diabetes in blacks. Diabetes Care 11: 1144–1149, 1990.
114. Pi-Sunyer, F. X. Medical hazards of obesity. Ann. Intern. Med. 119: 655–660, 1993.
115. Rabinowitz, D., and K. L. Zierler. Forearm metabolism in obesity and its response to intra-arterial insulin. J. Clin. Invest. 41: 2173–2181, 1962.
116. Reaven, G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 1595–1607, 1988.
117. Reaven, G. M., Y. D. I. Chen, J. Jeppesen, P. Maheux, and R. M. Krauss. Insulin resistance and hyperinsulinemia in individuals with small, dense, LDL particles. J. Clin. Invest. 92: 141–146, 1993.
118. Remmers, J. E., W. J. deGroot, E. K. Sauerland, and A. M. Anch. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol. 44: 931–938, 1978.
119. Richman, R. M., L. M. Elliott, C. M. Burns, H. M. Bearpark, K. S. Steinbeck, and I. D. Caterson. The prevalence of obstructive sleep apnea in an obese female population. Int. J. Obes. Relat. Metab. Disord. 18: 173–177, 1994.
120. Rimm, A. A., L. H. Werner, B. V. Yserloo, and R. A. Bernstein. Relationship of obesity and disease in 73,532 weight-conscious women. Public Health Rep. 90: 44–54, 1975.
121. Rimm, E. B., M. J. Stampfer, E. Giovannucci, et al. Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am. J. Epidemiol. 141: 1117–1127, 1995.
122. Ronnemaa, T., J. Marniemi, M. J. Savoleinen, et al. Serum lipids, lipoproteins, and lipid metabolizing enzymes in identical twins discordant for obesity: differences in lipid and glucose metabolism. J Clin Endocrinol Metab 83: 2792–2799, 1998.
123. Saad, M. F., W. C. Knowler, D. J. Pettitt, R. G. Nelson, D. M. Mott, and P. H. Bennett. Insulin and hypertension: relationship to obesity and glucose intolerance in Pima Indians. Diabetes 39: 1430–1435, 1990.
124. Sharp, J. T., M. Barrocas, and S. Chokroverty. The cardiorespiratory effects of obesity. Clin. Chest Med. 1: 103–118, 1980.
125. Shu, X. O., L. A. Brinton, W. Zheng, et al. Relation of obesity and body fat distribution to endometrial cancer in Shanghai, China. Cancer Res. 52: 3865–3870, 1992.
126. Sparrow, D., G. A. Borkan, S. G. Gerzof, C. Wisniewski, and C. K. Silbert. Relationship of fat distribution to glucose tolerance: results of computed tomography in male participants of the Normative Aging Study. Diabetes 35: 411–415, 1986.
127. Staessen, J., R. Fagard, and A. Amery. The relationship between body weight and blood pressure. J. Hum. Hypertens. 2: 207–217, 1988.
128. Stamler, J. Overweight, hypertension, hypercholesterolemia and coronary heart disease. In: Medical Complications of Obesity, M. Mancini, B. Lewis and F. Contaldo (Eds.). London: Academic Press, 1979, pp. 191–216.
129. Stamler, R., J. Stamler, W. F. Riedlinger, G. Algera, and R. H. Roberts. Weight and blood pressure: findings in hypertension screening of 1 million Americans. JAMA 240: 1607–1610, 1978.
130. Stampfer, M. J., K. M. Maclure, G. A. Colditz, J. E. Manson, and W. C. Willett. Risk of symptomatic gallstones in women with severe obesity. Am. J. Clin. Nutr. 55: 652–658, 1992.
131. Stern, M. Epidemiology of obesity and its link to heart disease. Metabolism 44: 1–3, 1995.
132. Swanson, C. A., N. Potischman, G. D. Wilbanks, et al. Relation of endometrial cancer risk to past and contemporary body size and body fat distribution. Cancer Epidemiol. Biomarkers Prev. 2: 321–327, 1993.
133. Symonds, B. Blood pressure of healthy men and women. JAMA 8: 232, 1923.
134. Terry, R. B. High-density apolipoprotein A-I and A-II kinetics in relation to regional adiposity. Metabolism 41: 1386–1392, 1992.
135. Terry, R. B., P. D. Wood, W. L. Haskell, M. L. Stefanick, and R. M. Krauss. Regional adiposity pattern in relation to lipids, lipoprotein cholesterol, and lipoprotein subfraction mass in men. J. Clin. Endocrinol. Metab. 68: 191–199, 1989.
136. Tretli, S. Height and weight in relation to breast cancer morbidity and mortality: a prospective study of 570,000 women in Norway. Int. J. Cancer 44: 23–30, 1989.
137. Tretli, S., and K. Magnus. Height and weight in relation to uterine corpus cancer morbidity and mortality: a follow-up study of 570,000 women in Norway. Int. J. Cancer 46: 165–172, 1990.
138. Tucker, L. E., T. N. Tangedahl, and S. R. Newmark. Prevalence of gallstones in obese Caucasian women. Int. J. Obes. 6: 247–251, 1982.
139. Tulinus, H., N. Sigfusson, S. Sigvaldason, and N. E. Day. Can anthropometric biochemical measurement illustrate the diet-cancer in man. J. Natl. Cancer Inst. 37: 527–545, 1966.
140. Tyroler, H. A., S. Heyden, and C. G. Hames. Weight and hypertension; Evans County studies of blacks and whites. In: Epidemiology and Control of Hypertension, P. Oglesby (Ed.). New York: Stratton Intercontinental Medical Book Corp, 1975, pp. 177–205.
141. Urbinati, G. C., F. Angelico, M. Del Ben, et al. Strong association of overweight to high blood pressure in a rural community of central Italy: the “Di.S.Co.” Project. Diab. Res. Clin. Pract. 10(Suppl. 1): S205–S209, 1990.
142. Van Itallie, T. B. Health implications of overweight and obesity in the United States. Ann. Intern. Med. 103: 983–988, 1985.
143. Van Itallie, T. B., and S. Abraham. Some hazards of obesity and its treatment. In: Recent Advances in Obesity Research, J. Hirsch and T. B. Van Itallie (Eds.). London: John Libbey, 1985, pp. 1–19.
144. van Saase, J. L. C., J. P. Vandenbruke, L. K. van Romunde, and H. A. Valkenberg. Osteoarthritis and obesity in the general population: a relationship calling for an explanation. J. Rheumatol. 15: 1152–1158, 1988.
145. Vatten, L. J., and S. Kvinnsland. Prospective study of height, body mass index and risk of breast cancer. Acta Oncol. 31: 195–200, 1992.
146. Vgontzas, A. N., T. L. Tan, E. O. Bixler, L. F. Martin, D. Shubert, and A. Kales. Sleep apnea and sleep disruption in obese patients. Arch. Intern. Med. 154: 1705–1711, 1994.
147. Waltemath, C. L., and N. A. Bergman. Respiratory compliance in obese patients. Anesthesiology 41: 84–85, 1974.
148. Welin, L., K. Svärdsudd, L. Wilhelmsen, B. Larsson, and G. Tibblin. Analysis of risk factors for stroke in a cohort of men born in 1913. N. Engl. J. Med. 317: 521–526, 1987.
149. West, K. M., and J. M. Kalbfleisch. Glucose tolerance, nutrition, and diabetes in Uruguay, Venezuela, Malaya, and East Pakistan. Diabetes 15: 9–18, 1966.
150. West, K. M., and J. M. Kalbfleisch. Influence of nutritional factors on prevalence of diabetes. Diabetes 20: 99–108, 1971.
151. Westlund, K., and R. Nicolaysen. Ten-year mortality and morbidity related to serum cholesterol: a follow-up of 3751 men aged 40–49. Scand. J. Clin. Lab. Invest. 30: 1–24, 1972.
152. White, F. M. M., L. H. Pereira, and J. B. Garner. Association of body mass index and waist: hip ratio with hypertension. Can. Med. Assoc. J. 135: 313–320, 1986.
153. Whitemore, A. S., R. S. Paffenbarger, K. Anderson, and J. E. Lee. Early precursors of site-specific cancers in college men and women. J. Natl. Cancer Inst. 74: 7443–7451, 1985.
154. Willett, W. C., M. L. Browne, C. Bain, et al. Relative weight and risk of breast cancer among premenopausal women. Am. J. Epidemiol. 122: 731–740, 1985.
155. Williams, D. P., S. B. Going, T. G. Lohman, et al. Body fatness and risk for elevated blood pressure, total cholesterol, and serum lipoprotein ratios in children and adolescents. Am. J. Public Health 82: 358–363, 1992.
156. Williams, S. R., P. Sorlie, M. Feinlieb, P. N. McNamara, W. B. Kamiel, and T. R. Dawber. Cancer incidence by levels of cholesterol. JAMA 245: 247–252, 1981.
157. Young, T., M. Palta, J. Dempsey, J. Skatrud, S. Weber, and S. Badr. The occurrence of sleep-disordered breathing among middle-aged adults. N. Engl. J. Med. 328: 1230–1235, 1993.
158. Zahorska-Markiewicz, B., E. Kuagowska, M. Klin. Heart rate variability in obesity. Int. J. Obes. Relat. Metab. Disord. 17: 21–23, 1993.
159. Zimmet, P., S. Faaiuso, J. Ainuu, S. Whitehouse, B. Milne, and W. Deboer. The prevalence of diabetes in the rural and urban Polynesian population of Western Samoa. Diabetes 30: 45–51, 1981.
RISK FACTORS; DISEASE; FAT; FAT DISTRIBUTION
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