We all have a patient that is a relatively “thin” individual (with a normal BMI) and has an excess of VAT, and may be metabolically obese, normal weight (MONW) . Then there are those with a large “pot bellies” who may have a great capacity to store fat as SCAT with relatively little VAT. Eric S. Freedland, MD, Boston University School of Medicine, helps us understand The Role Of A Critical Visceral Adipose Tissue Threshold (CVATT) In MONW, MNO Patients, and why this occurs.
Implications for Controlling Dietary Carbohydrates
Eric S. Freedland, MD
Boston University School of Medicine
Part 5 Critical Visceral Adipose Tissue Threshold (CVATT)—Individual Variations among MONW, MNO patients
The CVATT has tremendous individual variation; thus a relatively “thin” individual (with a normal BMI) and an excess of VAT for him, may be metabolically obese, normal weight (MONW) . Meanwhile, another individual with a large “pot belly” may have a great capacity to store fat as SCAT with relatively little VAT or he may have a high threshold for VAT. This may explain the finding that some individuals weighing even up to 200 kg do not show any signs of type 2 diabetes or dyslipidemia. Meanwhile in others, diabetes or dyslipidemia either develop or deteriorate with an increase in body weight of only one kg —perhaps just enough to exceed the CVATT.
A number of studies have looked at a possible CVATT [175-181]. Using CT scans to measure VAT volume, Williams et al found that a value of above 110 cm2 was associated with an increased risk of CHD in pre-and postmenopausal women . Similarly, Despres and Lamarche observed a VAT cutoff of 100 cm2 was associated with increased CHD risk in young adult men and premenopausal women (mostly of French Canadian descent) , and a cutoff range of 100-110 cm2 has also been observed by others [175, 180]. Other studies have suggested thresholds of > 130 cm2 for metabolic deterioration [182, 183]. De Nino et al found that insulin resistance did not appear until women were older than 60 years and had accumulated levels of VAT that approximated the levels seen in men, suggesting a possible threshold effect of VAT on insulin resistance . As discussed below with MONW, genetic and ethnic factors play a role. For example, in nonobese and obese Japanese males and females, fat areas at the umbilicus (as determined by CT) had threshold values for metabolic syndrome with only > 100 cm2 for men and > 90 cm2 for women .
Brochu et al were unable to demonstrate that obese postmenopausal women who reduced their weight and attained a level of VAT below 110 cm2 would show greater improvement in their metabolic profile compared to those who also lost weight but remained above the 110 cm2 VAT threshold . However, there were only 25 total subjects and the women had relatively normal metabolic profiles at baseline. Perhaps due to the relatively small number of subjects, only five lost less than 20 percent of their baseline VAT value. Thus it is unclear whether even smaller losses of VAT than those observed improved metabolic outcomes. The researchers did find larger losses of VAT and a greater improvement in insulin sensitivity in those who attained a VAT level < 110 cm2 . It should also be noted that in postmenopausal women, peripheral SCAT may be protective, even in the face of large amounts of VAT, and this needs to be accounted for [120, 121, 125]. While studying obese Japanese women, Tanaka et al recently validated the 100 cm2 CVATT but their longitudinal data from both pre- and posttreatment suggest that these women should reduce their VAT area to
Metabolically obese normal weight (MONW)
VAT accumulation contributes to metabolic risk factors in nonobese individuals [186, 187]. Ruderman et al have shown that normal weight individuals may also have insulin resistance and the disorders of the metabolic syndrome . They designated such individuals as “metabolically obese normal weight—MONW [188, 189].” MONW subjects (BMI < 25 kg/m2) have been characterized by an excess of VAT area (> 100 cm2 by abdominal CT), insulin resistance, and hyperinsulinemia [25-27]. As pointed out earlier, the development of insulin resistance may limit further weight gain [34, 38-41, 190]. A rapid and early development of insulin resistance prior to significant weight gain would explain that a significant number of the normal-weight population have insulin resistance . The prevalence of MONW could be as high as 13-18 percent [27, 191, 192].
MONW and low birthweight
Both low birthweight (LBW)  and lowest weight at one year of age have been linked to VAT accumulation , insulin resistance, and cardiovascular risk factors in middle-aged and elderly individuals, many of whom could be classified as MONW with metabolic syndrome. By middle age, many LBW subjects have BMIs less than 24-26 kg/m2 and would be classified as MONW. While some data suggest that LBW babies have central adiposity in middle age, definitive measurements of VAT in these individuals are still lacking .
Ethnicity and MONW
One should consider ethnic differences when attempting to identify MONW subjects. Lean appearing individuals, especially in certain ethnic groups such as the Japanese, may have significant amounts of VAT that surpass their CVATT but appear with what, for the general population, would be considered a normal BMI and waist circumference . For example, nonobese Japanese (BMI<25) with increased VAT areas (100-110 cm2) fulfill the criteria for MONW [26, 180]. In another study, relatively lean Japanese patients with newly diagnosed type 2 diabetes had increased VAT. Through diet and without medication for three months, the amount of VAT in these patients became comparable to that in normal-weight control subjects. Therefore, a three-month dietary treatment regimen with small to moderate weight loss was very effective in decreasing excess VAT in this population . This illustrates the importance of early recognition of an individual’s approaching or exceeding his CVATT. Park et al were among the first to demonstrate that healthy, non-obese Asian American women may have higher amounts of VAT, and that normative values or standards for VAT derived from Caucasians may not be applicable to Asians . On the other side of the spectrum, a 10-year prospective study studied increased BMI in Micronesian Nauruans (an ethnic group from the central Pacific Ocean with rapidly increase in prevalence of obesity) and Melanesian- and Indian-Fijians. Overall, there was little evidence to suggest that obesity was a risk factor for total or cardiovascular mortality in these populations .
Metabolically normal obese (MNO)
McGarry found that one of his most obese patients in a series (BMI 32.8 kg/m2) was one of the most insulin-sensitive but had one of the lowest values for intramyocellular lipid (IMCL). Conversely, another subject, with a BMI of only 18.9 kg/m2, proved to be highly insulin-resistant but had a large amount of IMCL. This supports that insulin sensitivity appears to correlate more with where the fat is located rather than the total amount in the body . This has implications for the phenomena of the metabolically obese normal weight (MONW) and the metabolically normal obese (MNO) individuals.
Like some of the Micronesian Nauruans and Indian-Fijians above, there are individuals who are obese and who nevertheless are metabolically normal—“metabolically normal obese; MNO.” Unlike their MONW counterparts, MNO individuals have very little VAT accumulation. They often share an onset of obesity early in childhood, and have normal VAT, lower TGs, and increased HDL. The actively competitive Japanese wrestlers maintain their gross obesity by consuming a 5,000 to 6,000 calorie diet. They are MNO, and their VAT is normal in amount, i.e., they have excessive amounts of SCAT . On retirement, when they discontinue their rigorous training regimen, they markedly develop increased insulin resistance and metabolic syndrome. It is likely that their VAT increases concomitantly [27, 28] and exceeds their CVATT. Data from the European Group for the Study of Insulin Resistance (1146 hyperinslinemic/euglycemic clamp studies from 20 clinical centers in Europe) showed that in “simple” obesity, insulin resistance is not as prevalent as previously thought . MNO could account for as much as 20 percent of the obese population . In another study using HOMA to determine insulin resistance, Bonora et al showed that 11 percent of the entire group of overweight individuals fit the criteria of MNO . Brochu et al extensively studied 43 sedentary, obese, postmenopausal women and found that 17 were MNO, while 26 had reduced insulin sensitivity (estimated by clamp) . The two groups were similar in total body fat mass, SCAT amount, as well as waist circumference, and total daily energy expenditure. However, lean body mass was significantly greater in the metabolically abnormal subjects. Unlike SCAT, VAT measured by CT was inversely related to the insulin sensitivity and to a classification of MNO. In fact, despite similar levels of total body fatness, MNO individuals showed 49 percent less VAT as measured by CT. However, the level of VAT was still significant. Furthermore, using doubly labeled water and indirect calorimetry, Brochu et al were unable to demonstrate a meaningful difference between resting metabolic rate and daily physical energy expenditure between MNO and obese individuals at risk .
MNO and childhood obesity
Several investigators have found that there has been a positive association between insulin sensitivity and duration of obesity, i.e., those who are obese since childhood are more likely to remain insulin sensitive. In one study 48 percent of the MNO women presented with a history of an earlier age-related onset of obesity (between 13 and 19 years of age) and less VAT compared with 29 percent of the metabolically abnormal obese .
Insulin sensitivity seems to be dependent upon adipose cell size; as adipocytes within tissue grow larger, they become more insulin resistant . Normal-sized, more insulin-sensitive adipocytes have been Perhaps today we are beginning to see that with the marked increase in overfeeding and extent of obesity at younger ages, hypertrophy of fat cells may occur earlier and hence metabolic syndrome is now occurring with greater frequency in children.
Puberty and VAT
During puberty, a certain degree of insulin resistance is normal, and children who are more insulin resistant have decreased SCAT gain . Early in the development of juvenile obesity, increased VAT, hyperinsulinemia, and insulin resistance are closely linked . Adrenal androgens are elevated in obese children and have been associated with early pubertal development in these children.[205, 206] Sex differences in VAT begin to emerge during puberty, with boys having more VAT than girls. Some studies suggest that the rate of VAT accumulation can be slowed in children by using exercise interventions [207, 208].
Fit and fat
VAT is strongly associated with fitness even within individuals of the same weight. This is illustrated by the earlier mentioned example of the active Sumo wrestler in his prime who has relatively little VAT . Regular exercise can selectively reduce VAT with minimal change in weight [209-211]. This could especially add to the frustration level of the middle-aged or post-menopausal woman who regularly exercises moderately without inducing measurable reduction in body weight or fatness. She may still benefit from reducing her VAT or attenuating the gain of VAT “normally” experienced by sedentary women as they age. It should be emphasized that the lower VAT level associated with increased fitness is modest but nonetheless clinically important. Reduced morbidity is likely explained by factors in addition to a reduced VAT, and VAT likely explains morbidity independent of fitness . Sumo wrestlers tend to have most of their central adiposity stored subcutaneously (as SCAT), and, perhaps a shift toward more VAT accompanies their contracting metabolic syndrome upon their retirement—with premature death to follow [27, 91]. This may also explain the body of work showing that overweight or “fat” individuals who are fit (according to cardiorespiratory testing on a treadmill) are at less risk for a cardiac event or developing type 2 diabetes than a “leaner” individual who is unfit [213, 214]. Thus, the former could be considered “fit and fat.” High levels of cardiorespiratory fitness (CRF) reduce C-reactive protein (CRP) and the rate of cardiovascular morbidity and mortality, independent of obesity . CRF is also associated with lower abdominal fat independent of BMI. For a given BMI or waist circumference (WC), individuals with moderate CRF also had lower levels of total fat mass and abdominal SCAT and VAT than individuals with low CRF for a given BMI or WC value [212, 216]. Low CRF is an independent risk factor for mortality in healthy-appearing and diseased populations, and is associated with elevated CRP and reduced fasting glucose control in women with type 2 diabetes . It is likely that compared to the fit and fat, the unfit and lean-appearing individual may have greater amounts of “hidden” VAT.
Effects of exercise
In obese patients, increasing physical activity can enhance fat oxidation, reduce IMCL, and improve insulin sensitivity . Exercise training may reduce waist size independent of changes in BMI, and exercise without weight loss is effective in reducing VAT and preventing further increases in obesity [212, 219].
Ross et al showed that either modality, caloric restriction alone or daily exercise without calorie restriction, is an effective strategy for reducing obesity in moderately obese men.
Their findings also suggest that exercise without weight loss is a useful method for reducing VAT and preventing further increases in obesity . Irwin et al studied 168 overweight, postmenopausal, previously sedentary women in a randomly controlled trial of exercise versus no exercise. While the body weight lost at 12 months among the exercisers was modest, the amount of intra-abdominal fat lost was considerable (8.5 g/ cm2) and was dose-dependent. The women who exercised for approximately 200 min/wk lost 4.2 percent of total body fat and 6.9 percent of VAT without reducing their energy intake . Exercise may counteract the abnormal metabolic profiles associated with abdominal obesity by reducing VAT along with other independent mechanisms. It promotes adaptive responses including those causing muscles to increase their use of lipid stores rather than relying primarily on carbohydrate reserves. Even a single bout of exercise can reduce triglyceride levels, increase HDL levels, reduce resting blood pressure, increase glucose tolerance, and reduce insulin resistance .
While evidence supports that CRF may be associated with a lower VAT, this is certainly not proven. However, study results suggest that individuals with moderate to high CRF levels have lower WC than men with low CRF independent of BMI [212, 221]. Data support that the substantial reductions in health risk often associated with modest weight loss
Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-2004). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject
174. Matsuzawa Y: Establishing the concept of visceral fat syndrome and clarifying its molecular mechanisms. JMAJ 2002, 45:103-110.
175. Nicklas BJ, Goldberg AP, Bunyard LB, Poehlman ET: Visceral adiposity is associated with increased lipid oxidation in obese, postmenopausal women. Am J Clin Nutr 1995, 62:918-22.
176. Williams MJ, Hunter GR, Kekes-Szabo T, Trueth MS, Snyder S, Berland L, Blaudeau T: Intra-abdominal adipose tissue cut-points related to elevated cardiovascular risk in women. Int J Obes Relat Metab Disord 1996, 20:613-7.
177. Brochu M, Tchernof A, Turner AN, Ades PA, Poehlman ET: Is there a threshold of visceral fat loss that improves the metabolic profile in obese postmenopausal women? Metabolism 2003, 52:599-604.
178. Despres JP, Lamarche B: Effects of diet and physical activity on adiposity and body fat distribution: implications for the prevention of cardiovascular disease. Nutr Res Rev 1993, 6:137-59.
179. Hunter GR, Snyder SW, Kekes-Szabo T, Nicholson C, Berland L: Intra-abdominal adipose tissue variables associated with risk of possessing elevated blood lipids and blood pressure. Int J Obes 1994, 2:563-569.
180. Tanaka K, Okura T, Shigematsu R, Nakata Y, Lee DJ, Wee SW, Yamabuki K: Target value of intraabdominal fat area for improving coronary heart disease risk factors. Obes Res 2004, 12:695-703.
181. Lemieux S, Prud’homme D, Bouchard C, Tremblay A, Despres JP: A single threshold value of waist girth identifies normal-weight and overweight subjects with excess visceral adipose tissue. Am J Clin Nutr 1996, 64:685-93.
182. Perusse L, Despres JP, Lemieux S, Rice T, Rao DC, Bouchard C: Familial aggregation of abdominal visceral fat level: results from the Quebec family study. Metabolism 1996, 45:378-82.
183. Nicklas BJ, Penninx BW, Ryan AS, Berman DM, Lynch NA, Dennis KE: Visceral adipose tissue cutoffs associated with metabolic risk factors for coronary heart disease in women. Diabetes Care 2003, 26:1413-20.
184. DeNino WF, Tchernof A, Dionne IJ, Toth MJ, Ades PA, Sites CK, Poehlman ET: Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women. Diabetes Care 2001, 24:925-32.
185. Saito Y, Kobayashi J, Seimiya K, Hikita M, Takahashi K, Murano S, Bujo H, Morisaki N: Contribution of visceral fat accumulation to postprandial hyperlipidemia in human obesity. Eighth International Congress on Obesity. Int J Obes 1998, Suppl 3:S226.
186. Boyko EJ, Fujimoto WY, Leonetti DL, Newell-Morris L: Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans. Diabetes Care 2000, 23:465-71.
187. Hayashi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell-Morris L, Kahn SE, Fujimoto WY: Visceral adiposity is an independent predictor of incident hypertension in Japanese Americans. Ann Intern Med 2004, 140:992-1000.
188. Ruderman NB, Schneider SH, Berchtold P: The “metabolically-obese,” normal-weight individual. Am J Clin Nutr 1981, 34:1617-21.
189. Ruderman NB, Berchtold P, Schneider S: Obesity-associated disorders in normal-weight individuals: some speculations. Int J Obes 1982, 6 Suppl 1:151-7.
190. Looker HC, Knowler WC, Hanson RL: Changes in BMI and weight before and after the development of type 2 diabetes. Diabetes Care 2001, 24:1917-22.
191. Dvorak RV, DeNino WF, Ades PA, Poehlman ET: Phenotypic characteristics associated with insulin resistance in metabolically obese but normal-weight young women. Diabetes 1999, 48:2210-4.
192. Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoret R, Poehlman ET: Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 2004, 89:2569-75.
193. Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C: Thinness at birth and insulin resistance in adult life. Diabetologia 1994, 37:150-4.
194. Kuh D, Hardy R, Chaturvedi N, Wadsworth ME: Birth weight, childhood growth and abdominal obesity in adult life. Int J Obes Relat Metab Disord 2002, 26:40-7.
195. Park YW, Allison DB, Heymsfield SB, Gallagher D: Larger amounts of visceral adipose tissue in Asian Americans. Obes Res 2001, 9:381-7.
196. Takami K, Takeda N, Nakashima K, Takami R, Hayashi M, Ozeki S, Yamada A, Kokubo Y, Sato M, Kawachi S, et al: Effects of dietary treatment alone or diet with voglibose or glyburide on abdominal adipose tissue and metabolic abnormalities in patients with newly diagnosed type 2 diabetes. Diabetes Care 2002, 25:658-62.
197. Hodge AM, Dowse GK, Collins VR, Zimmet PZ: Mortality in Micronesian Nauruans and Melanesian and Indian Fijians is not associated with obesity. Am J Epidemiol 1996, 143:442-55.
198. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G: Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest 1997, 100:1166-73.
199. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadona R, Muggeo M: Prevalence of insulin resistance in metabolic disorders: The Bruneck Study. Diabetes 1998, 47:1643-1649.
200. Brochu M, Tchernof A, Dionne IJ, Sites CK, Eltabbakh GH, Sims EA, Poehlman ET: What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women? J Clin Endocrinol Metab 2001, 86:1020-5.
201. Weyer C, Wolford JK, Hanson RL, Foley JE, Tataranni PA, Bogardus C, Pratley RE: Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21–q23 and is associated with a common polymorphism in LMNA in Pima Indians. Mol Genet Metab 2001, 72:231-8.
202. Salans LB, Cushman SW, Weismann RE: Studies of human adipose tissue. Adipose cell size and number in nonobese and obese patients. J Clin Invest 1973, 52:929-41.
203. Travers SH, Jeffers BW, Eckel RH: Insulin resistance during puberty and future fat accumulation. J Clin Endocrinol Metab 2002, 87:3814-8.
204. Caprio S, Hyman LD, Limb C, McCarthy S, Lange R, Sherwin RS, Shulman G, Tamborlane WV: Central adiposity and its metabolic correlates in obese adolescent girls. Am J Physiol 1995, 269:E118-26.
205. l’Allemand D, Schmidt S, Rousson V, Brabant G, Gasser T, Gruters A: Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol 2002, 146:537-43.
206. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg HS, Barthel A, Hauner H, McCann SM, Scherbaum WA, Bornstein SR: Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A 2003, 100:14211-6.
207. Owens S, Gutin B, Allison J, Riggs S, Ferguson M, Litaker M, Thompson W: Effect of physical training on total and visceral fat in obese children. Med Sci Sports Exerc 1999, 31:143-8.
208. Gutin B, Barbeau P, Owens S, Lemmon CR, Bauman M, Allison J, Kang HS, Litaker MS: Effects of exercise intensity on cardiovascular fitness, total body composition, and visceral adiposity of obese adolescents. Am J Clin Nutr 2002, 75:818-26.
209. Irwin ML, Ainsworth BE: Physical activity interventions following cancer diagnosis: methodologic challenges to delivery and assessment. Cancer Invest 2004, 22:30-50.
210. Ross R, Janssen I, Dawson J, Kungl AM, Kuk JL, Wong SL, Nguyen-Duy TB, Lee S, Kilpatrick K, Hudson R: Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 2004, 12:789-98.
211. Irwin ML, Yasui Y, Ulrich CM, Bowen D, Rudolph RE, Schwartz RS, Yukawa M, Aiello E, Potter JD, McTiernan A: Effect of exercise on total and intra-abdominal body fat in postmenopausal women: a randomized controlled trial. Jama 2003, 289:323-30.
212. Wong SL, Katzmarzyk P, Nichaman MZ, Church TS, Blair SN, Ross R: Cardiorespiratory fitness is associated with lower abdominal fat independent of body mass index. Med Sci Sports Exerc 2004, 36:286-91.
213. Church TS, Cheng YJ, Earnest CP, Barlow CE, Gibbons LW, Priest EL, Blair SN: Exercise capacity and body composition as predictors of mortality among men with diabetes. Diabetes Care 2004, 27:83-8.
214. Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN: Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes [see comments]. Ann Intern Med 2000, 132:605-11.
215. Church TS, Barlow CE, Earnest CP, Kampert JB, Priest EL, Blair SN: Associations between cardiorespiratory fitness and C-reactive protein in men. Arterioscler Thromb Vasc Biol 2002, 22:1869-76.
216. Katzmarzyk PT, Church TS, Blair SN: Cardiorespiratory fitness attenuates the effects of the metabolic syndrome on all-cause and cardiovascular disease mortality in men. Arch Intern Med 2004, 164:1092-7.
217. McGavock JM, Mandic S, Vonder Muhll I, Lewanczuk RZ, Quinney HA, Taylor DA, Welsh RC, Haykowsky M: Low cardiorespiratory fitness is associated with elevated C-reactive protein levels in women with type 2 diabetes. Diabetes Care 2004, 27:320-5.
218. Goodpaster BH, Wolfe RR, Kelley DE: Effects of obesity on substrate utilization during exercise. Obes Res 2002, 10:575-84.
219. Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I: Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med 2000, 133:92-103.
220. Thompson PD, Crouse SF, Goodpaster B, Kelley D, Moyna N, Pescatello L: The acute versus the chronic response to exercise. Med Sci Sports Exerc 2001, 33:S438-45; discussion S452-3.
221. Janssen I, Katzmarzyk PT, Ross R, Leon AS, Skinner JS, Rao DC, Wilmore JH, Rankinen T, Bouchard C: Fitness alters the associations of BMI and waist circumference with total and abdominal fat. Obes Res 2004, 12:525-37.
222. Dattilo AM, Kris-Etherton PM: Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992, 56:320-8.
223. Paffenbarger RS, Jr., Hyde RT, Wing AL, Lee IM, Jung DL, Kampert JB: The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993, 328:538-45.
224. Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tildesley HD, Frohlich JJ: Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care 2003, 26:2977-82.
225. Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F: Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes 2004, 53:294-305.
226. Grady D: Fat: the secret life of a potent cell. In: Book Fat: the secret life of a potent cell (Editor ed.^eds.). City; July 6, 2004.
227. Weber RV, Buckley MC, Fried SK, Kral JG: Subcutaneous lipectomy causes a metabolic syndrome in hamsters. Am J Physiol Regul Integr Comp Physiol 2000, 279:R936-43.
228. Pelletier C, Despres JP, Tremblay A: Plasma organochlorine concentrations in endurance athletes and obese individuals. Med Sci Sports Exerc 2002, 34:1971-5.
229. Pelletier C, Doucet E, Imbeault P, Tremblay A: Associations between weight loss-induced changes in plasma organochlorine concentrations, serum T(3) concentration, and resting metabolic rate. Toxicol Sci 2002, 67:46-51.
230. Imbeault P, Tremblay A, Simoneau JA, Joanisse DR: Weight loss-induced rise in plasma pollutant is associated with reduced skeletal muscle oxidative capacity. Am J Physiol Endocrinol Metab 2002, 282:E574-9.
231. Baillie-Hamilton PF: Chemical toxins: a hypothesis to explain the global obesity epidemic. J Altern Complement Med 2002, 8:185-92.
232. Frisancho AR: Reduced rate of fat oxidation: A metabolic pathway to obesity in the developing nations. Am J Human Biol 2003, 15:522-32.
233. Bisschop PH, Pereira Arias AM, Ackermans MT, Endert E, Pijl H, Kuipers F, Meijer AJ, Sauerwein HP, Romijn JA: The effects of carbohydrate variation in isocaloric diets on glycogenolysis and gluconeogenesis in healthy men. J Clin Endocrinol Metab 2000, 85:1963-7.
234. Sharman MJ, Kraemer WJ, Love DM, Avery NG, Gomez AL, Scheett TP, Volek JS: A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. J Nutr 2002, 132:1879-85.
235. Ludwig DS: The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. Jama 2002, 287:2414-23.
236. Ludwig DS: Glycemic load comes of age. J Nutr 2003, 133:2695-6.
237. Ebbeling CB, Ludwig DS: Treating obesity in youth: should dietary glycemic load be a consideration? Adv Pediatr 2001, 48:179-212.
238. McKeown NM, Meigs JB, Liu S, Saltzman E, Wilson PW, Jacques PF: Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort. Diabetes Care 2004, 27:538-46.
239. Silvestre R, Sharman MJ, Gomez AL, Judelson DA, Watson G, Ruffin K, Kraemer WJ, Volek JS: A very low-carbohydrate diet results in greater reductions in body weight, whole body fat, and trunk fat than a low-fat diet in overweight subjects. In: Kingsbrook conference on nutritional and metabolic aspects of low carbohydrate diets; 2004; Brooklyn.
240. Kabir M, Rizkalla SW, Quignard-Boulange A, Guerre-Millo M, Boillot J, Ardouin B, Luo J, Slama G: A high glycemic index starch diet affects lipid storage-related enzymes in normal and to a lesser extent in diabetic rats. J Nutr 1998, 128:1878-83.
241. Lerer-Metzger M, Rizkalla SW, Luo J, Champ M, Kabir M, Bruzzo F, Bornet F, Slama G: Effects of long-term low-glycaemic index starchy food on plasma glucose and lipid concentrations and adipose tissue cellularity in normal and diabetic rats. Br J Nutr 1996, 75:723-32.
242. Kim JY, Nolte LA, Hansen PA, Han DH, Kawanaka K, Holloszy JO: Insulin resistance of muscle glucose transport in male and female rats fed a high-sucrose diet. Am J Physiol 1999, 276:R665-72.
243. Keno Y, Matsuzawa Y, Tokunaga K, Fujioka S, Kawamoto T, Kobatake T, Tarui S: High sucrose diet increases visceral fat accumulation in VMH-lesioned obese rats. Int J Obes 1991, 15:205-11.
244. Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM: Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr 2002, 75:492-8.
245. Erickson K: Is there a relation between dietary linoleic acid and cancer of the breast, colon, or prostate? Am J Nutr 1998, 68:5-7.
246. O’Brien KD, Brehm BJ, Seeley RJ: Greater reduction in inflammatory markers with a low carbohydrate diet than with a low fat diet. American Heart Association Scientific Sessions November 19, 2002, Abst # 117597.
247. Mohanty P, Ghanim H, Hamouda W, Aljada A, Garg R, Dandona P: Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells. Am J Clin Nutr 2002, 75:767-772.
248. Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P: Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 2000, 85:2970-3.
249. Clark JM: Dietary composition and fatty liver disease. In: Annual Meeting of the American Assocation for the Study of Liver Disease; 2003; Boston, MA.
250. Larson DE, Hunter GR, Williams MJ, Kekes-Szabo T, Nyikos I, Goran MI: Dietary fat in relation to body fat and intraabdominal adipose tissue: a cross-sectional analysis. Am J Clin Nutr 1996, 64:677-84.
251. Alessi MC, Morange P, Juhan-Vague I: Fat cell function and fibrinolysis. Horm Metab Res 2000, 32:504-8.