Tuesday , November 21 2017
Home / Conditions / MODY/LADA / Role of A Critical Visceral Adipose Tissue Threshold (CVATT) Part 6

Role of A Critical Visceral Adipose Tissue Threshold (CVATT) Part 6

Eric S. Freedland, MD, Boston University School of Medicine, explains the Implications of Controlling Dietary Carbohydrates and other methods to reduce VAT. In the final part of his groundbreaking series The Role Of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome

Role of A Critical Visceral Adipose Tissue Threshold (CVATT)
Implications for Controlling Dietary Carbohydrates

Eric S. Freedland, MD
Boston University School of Medicine

Part 6 Implications of Controlling Dietary Carbohydrates and other methods to reduce VAT
In order to understand how dietary carbohydrates affect VAT we must look at all methods and their effect on lowering CVATT
Surgical Interventions Shed Light on Pathophysiology

Surgical removal of VAT in animals and humans dramatically improves insulin resistance and diabetes. In a Swedish, single-center, randomized and controlled pilot trial of 50 severely obese adults, Thorne et al compared 25 patients who underwent adjustable gastric banding (AGB) alone with AGB plus surgical removal of the total greater omentum. At two-year follow-up there were no statistical differences between groups with regard to weight loss, changes in WHR or sagittal diameter. However, the improvements in oral glucose tolerance insulin sensitivity and fasting plasma glucose and insulin were 2-3 times greater in omentectomized as compared to control subjects, which was statistically independent of the loss in BMI [52]. More recently, this has led to a study of another experimental procedure performed by surgeons at Boston’s Beth Israel Deaconess Medical Center working in conjunction with Joslin Diabetes Center. Using a two-hour laparoscopic procedure that involves extracting strips of only the omentum through tiny incisions, this will be the first study to examine the possible health benefits of removing only the omentum [226].

Recently Klein et al. demonstrated that liposuction conferred no benefits with regard to metabolic profile [53]. Furthermore, Weber et al showed that after 3 months, animals that had lipectomy of > 50 percent of SCAT had more intra-abdominal VAT as percentage of total body fat, higher insulinemic index, a strong trend toward increased liver fat content, and markedly elevated serum TGs compared with animals that had undergone a sham operation and received either a high- or low-fat diet [227].Together with the findings above, these support a pathologic role for VAT and a possible protective role for SCAT. In some cases, removing SCAT might actually increase risk as one removes a buffer or sink for peripheral TGs [227].

Environmental Considerations

Organochlorines, adipose tissue, and energy balance
Since our genes have not changed significantly in the past 10,000 years, the rise in obesity can be attributed to the environment, including what we are exposed to in the way of food as well as the level of physical activity. While the main focus has been on diet and activity, what may be overlooked is the tremendous increase in exposure to synthetic organic and inorganic chemicals, which can damage many of the mechanisms involved in weight control. Most of us have been exposed to organochlorines found in pesticides, dyes, solvents, etc., and we contain residues in our adipose tissue, where they are preferentially stored. Thus, the obese tend to have increased organochlorine concentrations compared to lean individuals [228]. During body weight loss, a decrease in fat mass results in lipid mobilization, and organochlorine concentrations increase both in plasma and remaining adipose tissue. Even after adjustment for weight loss, the related increase in organochlorine concentration has been correlated with decreases in triidothyronine (T3) concentration and resting metabolic rate [229]. This is also associated with a reduction in activity of the skeletal muscle oxidative enzymes that normally are involved in fat oxidation [230]. The net effect could prevent further weight gain and might even encourage weight regain beyond the initial baseline [231], which could contribute to VAT.
Implications of Controlling Dietary Carbohydrates

Reduced fat oxidation and carbohydrates
Frisancho points out that an important contributing factor for obesity in modern as well as developing nations is a reduced fat oxidation and increased metabolism of carbohydrate. This has been brought about by a shift toward the body’s preference toward oxidizing carbohydrate rather than fat—resulting in an increased deposition of body fat. In developing nations, obesity can co-exist with developmental undernutrition, which can result in obesity with short stature [232].

A solution to reducing the ectopic fat, as well as VAT, burden would be to enhance its oxidation in nonadipose tissues, e.g., liver, pancreas, and skeletal muscle. This will push the system toward below the CVATT and improve insulin sensitivity. In their review, Westman et al cite many studies that have consistently shown that low-carbohydrate/high-fat diets consumed for more than seven days induce powerful metabolic adaptations to enhance fat oxidation [37]. Such diets will reduce muscle glycogen content and carbohydrate oxidation, even in well-trained athletes who already demonstrate increased oxidation [37, 153]. The authors’ paradigm suggests that, under these conditions, insulin resistance could improve by reducing glucose appearance and cellular influx, resulting in a preferential fat oxidation and protection against lipotoxicity. In an elegant study, Bisschop et al support this by showing that high-fat, low-carbohydrate diets do not affect the action of insulin on total glucose disposal but decrease basal endogenous glucose production and improve insulin-stimulated nonoxidative glucose disposal [233]. Sharman et al demonstrated short term improvements of a ketogenic diet on lipids in normal weight men. These benefits occurred without total weight loss but there was evidence of a change in body composition toward more lean body mass [234]. One would also expect a reduction in VAT as he moves to the left or below his CVATT (See Figure 1). Weight loss does not appear to be necessary to reduce mortality rates in overweight or obese men who increase their aerobic fitness or level of physical activity [223]. Similarly, in overweight, postmenopausal women, exercise may lead to improved metabolic profiles and VAT loss without total weight loss [211].

Dietary carbohydrate and VAT
Optimizing macronutrients and food preparation can have beneficial effects in those with visceral obesity. A number of recent reviews support the metabolic benefits of controlling glycemic index (GI) [235] and glycemic load (GL) [236]. In a 12-month pilot study of teens, compared to a conventional diet, a lower GI diet led to greater total weight and fat loss without regain from months 6-12. While insulin resistance as measured by homeostasis model assessment (HOMA) increased in the conventional group (possibly in part attributable to puberty), the lower GI group showed no change [237]. In the Framingham Offspring Study, the prevalence of the metabolic syndrome was significantly higher among individuals in the highest relative to the lowest quintile category of glycemic index [238]. Recently, Silvestre et al showed that compared to an energy-restricted low-fat diet, a short-term, very low-carbohydrate diet was associated with greater weight and fat loss with an apparent preferential loss of central fat [239].

VAT cells have a two-fold higher glucose uptake rate compared with SCAT cells [87]. It may follow that reducing glucose exposure by reducing glycemic load may reduce the supply of glucose to the VAT depot and possibly impair its accumulation. Glucose raises insulin concentration, which can stimulate 11-ß-HSD1, increase active cortisol in VAT, and enhance VAT accumulation [102]. Feeding rats a high-GI starch diet over five weeks resulted in higher VAT and larger adipocyte volume than did feeding low-GI starch ad libitum. Replacing this with a low-GI starch diet increased insulin–stimulated glucose oxidation, decreased glucose incorporation into total lipids and decreased VAT adipocyte diameter [240, 241].Together, these add to the evidence supporting the benefits of lowering GI to reduce and maintain lower volumes of VAT. Feeding rats a high sucrose diet increases both VAT and muscle insulin resistance [242]. Keno et al. demonstrated in rats that a high sucrose diet compared to a lab chow diet led to a significantly greater fat cell volume in VAT depots [243]. Although fat cell number did not change, the ratio of VAT weight to SCAT weight was also significantly increased in the rats fed a high sucrose diet, providing further evidence for controlling the dietary GI and GL.

A number of studies have demonstrated an association between glycemic load (GL) and levels of CRP [244, 245], which is a powerful predictor for diabetes and CHD, and is positively associated with both insulin resistance and the prevalence of the metabolic syndrome [238]. O’Brien et al showed that compared to a high carbohydrate diet, a low carbohydrate diet reduced SAA and CRP, both markers of inflammation and risk factors for metabolic syndrome [246]. Relative to fat (cream) and protein (casein), a glucose challenge elicits the greatest production of radical oxygen species (ROS) by polymorphonuclear and mononuclear white cells [247, 248]. Chronic carbohydrate ingestion with a high GL diet can lead to hyperinsulinemia, as well as hypertrophy, functional dysregulation, and overresponsiveness of the pancreatic ß cell and hepatic production of newly synthesized fatty acids via de novo lipogenesis [43]. A Johns Hopkins study examined intra-operative liver biopsies obtained from 74 consecutive morbidly obese patients undergoing bariatric surgery. Compared with patients with the lowest carbohydrate intake, a high-carbohydrate diet was associated with an odds ratio of 7.0 for liver inflammation. A high fat diet appeared to be protective, with those in the highest fat intake group having an OR of 0.17 [249]. This is consistent with the findings of others who found that dietary fat explained only two percent of the variance in general adiposity and dietary fat appears to play only a minor role in determining general adiposity and is not related to VAT when measured in cross-sectional studies [250]. Apparently, GL may be more significant in this regard.

Compared to SCAT, VAT (both adipose and non-adipose cells within VAT) is associated more with PAI-1—a powerful risk factor for CHD [58, 251]. In patients with type 2 diabetes, a simple and modest lowering of the GI compared to an otherwise similar diet led to dramatic changes: a normalized PAI-1 activity (-54 percent, P<0.001) as well as lowering of both blood glucose and plasma insulin concentrations by 30 percent, and a 29 percent decrease in LDL-C [252]. All subjects began with a BMI < 27, and there was only a slight but similar weight loss in both groups over the 24 days. The results support the potential benefit of lowering dietary GI in patients with metabolic syndrome, especially those with VAT and elevated PAI-1. This is also supported by the observation of hyperglycemia induces PAI-1 gene expression in adipose tissue of rats [253].

Esposito et al demonstrated in both diabetics and non-diabetics that after consuming a high carbohydrate high-fiber meal, IL-18 (a potent pro-inflammatory cytokine) concentrations increased [49]. Adiponectin concentrations decreased after the high-carbohydrate, low-fiber meal in diabetic patients. The fiber content of complex carbohydrates seemed to affect circulating IL-18 and adiponectin concentrations in response to the same carbohydrate load. The pizza that was made with whole flour and was rich in fiber was associated with reduce serum IL-18 concentrations and unchanged serum adiponectin concentrations. Meanwhile, the pizza prepared with refined flour and was low in fiber raised circulating IL-18 concentrations. Serum glucose and TG concentrations were not significantly different between the two types of pizza. The study did not completely resolve the mechanism by which the fiber content of meals influences IL-18 and adiponectin. However, it appears that while the GL of each pizza was the same, the GI of the whole wheat pizza would be much less and may be more beneficial.

Recently, dietary TGs have been demonstrated to contribute to CNS leptin resistance by impairing the transport of leptin across the blood brain barrier where it would usually stimulate the release of neuropeptide-Y and reduce feeding behavior [166]. Reducing dietary carbohydrates lowers serum TGs, which theoretically should protect against this form of leptin resistance [166].

Dietary influences on leptin action
Leptin may enhance fatty acid oxidation and protects against fat deposition and lipotoxicity. As mentioned earlier, normally, rats can tolerate a 60 percent fat diet because 96 percent of the surplus fat is stored in an enlarging adipose tissue mass in which leptin gene expression increases proportionally [165]. However, when leptin is congenitally absent or inactive, or ineffective due to resistance, even on a normal or low-fat diet, unutilized dietary fat is deposited in nonadipose tissues, causing dysfunction

Acute overfeeding can cause circulating leptin levels to rise by 40 percent and more than three-fold after chronic overfeeding, whereas fasting is associated with decreased leptin levels. This may suggest that overfeeding leads to leptin resistance. Dietary carbohydrates may influence leptin action. Some investigators have suggested that the increase in plasma leptin concentration observed after meals is not simply a result of an energy load but is in response to a signal that is not present following a fat load without carbohydrate [156]. SCAT-derived leptin (which circulates in a free form and is bound to a soluble leptin receptor—sOB-R) plays a key role in regulating energy homeostasis and metabolism. sOB-R is positively associated with energy intake from carbohydrates and negatively associated with energy intake from dietary fat [157]. While this suggests that dietary fat and carbohydrates regulate free leptin levels, the implications of this are not yet completely clear.
Stress

There is an association with lifestyle, worry, cortisol levels, and abdominal girth. Those who were found to have the highest levels of chronic stress had the highest levels of cortisol and VAT [254-256]. This is supported by evidence that a number of medications, including prednisone, may cause an excess of cortisol and insulin resistance. Taken orally, cortisol raises blood pressure, and it has been shown to impair brachial artery blood flow in response to an acetylcholine challenge, i.e., an indicator of endothelial dysfunction [88, 254, 256-261]. Even brief episodes of mental stress, such as those encountered in daily life, may cause transient endothelial dysfunction even in young, healthy individuals [262, 263]. In turn, subsequent cytokine release may increase anxiety and have negative effects on emotional and memory functions [264]. Psychological stress has also been demonstrated to acutely reduce clearance of triglycerides [265], which could contribute to CNS leptin resistance [166].

There are many other ways in which psychological stress might increase the likelihood of developing metabolic syndrome and type 2 diabetes, for example, chronic psychological stress may also be related to central activation of the HPA (hypothalamo-pituitary-adrenal) axis and the sympathetic nervous system (SNS) [266]. Psychological stress also induces IL-6, TNFa, and other cytokine secretions from macrophages [266-270]. Repeated stress with the repeated induction of corticosteroids can damage the hippocampus, which is involved in the downregulation of corticosteroid production by corticosteroid feedback. Impairment of this feedback mechanism can lead to persisting elevated circulating cortisol levels [266], which might play a role in inducing VAT accumulation.

Stress decreases splanchnic blood flow, impairs the integrity of the gastrointestinal tract, increases intestinal permeability, and results in increased absorption of lipopolysaccharide endotoxin (LPS) from the gut (the greatest source of LPS). Elevated portal bloodstream LPS levels stimulate Kupffer cell receptors and cytokine release and possibly other immune-challenging activators, e.g., AGEs in food [270].

Stress and dietary carbohydrates
Dietary carbohydrate has been known to stimulate SNS activity though a number of studies have emphasized the role of insulin. Recent studies in rats have demonstrated that adding glucose to the basic diet increased SNS activity in peripheral tissues and increased GLUT 4 activity in interscapular brown adipose tissue and retroperitoneal fat (but not in epididymal fat) [271]. Overfeeding results in high insulin levels. In the presence of glucose, insulin acts on the brain to increase the SNS tone, which, in turn enhances thermogenesis and dissipation of excess calories [162]. There is a close relationship between postprandial insulinemia, SNS activation, and adipose tissue blood flow (ATBF). ATBF increases in response to stress states such as exercise or mental stress, and also in response to nutrient intake [272]. High insulin levels and increased SNS tone are useful for the maintenance of caloric balance, but in the long term they are conducive to CHD, hypertension, sudden death, and fat storage or obesity as the SNS receptors become down regulated [162].

Chronic stress leads to elevated cortisol levels, which may lead to accumulation of VAT and metabolic syndrome [273]. Stress-induced increased levels of glucocorticoids can also have a major effect on food intake [274]. A subset of stressed or depressed humans may overeat, especially comfort food (e.g., sugar and fat), in an attempt to reduce anxiety and activity in the chronic stress-response network. This is supported by the finding that these people have decreased cerebrospinal corticosteroid releasing factor, catecholamine concentrations, and HPA activity. While comfort foods may calm them down in the short term, they may lead to abdominal obesity if this becomes a long term “solution.” The chronic elevation of systemic glucocorticoids may contribute to VAT deposition. By itself, being obese may be a stressful stimulus to overeating. A weight loss program can be stressful, which can sabotage its success by eliciting the release of stress hormones, which, in turn can make a person crave high energy foods [274]. Feeding rats a long-term high-sucrose diet along with supplemental dexamethasone has been shown to increase fat depots and induce liver steatosis [275]. In addition to dietary intervention, stress management may improve one’s cognitive, behavioral, and physiologic responses to stress, including glycemia [276].

Summary
The role of visceral adipose tissue (VAT) obesity in metabolic syndrome is critical and complex. The paradigm of an individual critical VAT threshold (CVATT) has been presented along with a review of potential mechanisms and contributing factors. This includes the potential role of dietary carbohydrates in VAT obesity. As this area continues to evolve, perhaps the reviewed material and proposed concepts may have relevance to clinical assessment, prevention, and treatment of metabolic syndrome.

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

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.
252. Jarvi AE, Karlstrom BE, Granfeldt YE, Bjorck IE, Asp NG, Vessby BO: Improved glycemic control and lipid profile and normalized fibrinolytic activity on a low-glycemic index diet in type 2 diabetic patients. Diabetes Care 1999, 22:10-8.
253. Gabriely I, Yang XM, Cases JA, Ma XH, Rossetti L, Barzilai N: Hyperglycemia induces PAI-1 gene expression in adipose tissue by activation of the hexosamine biosynthetic pathway. Atherosclerosis 2002, 160:115-22.
254. Rosmond R, Bjorntorp P: Quality of life, overweight, and body fat distribution in middle-aged men.[In Process Citation]. Behav Med 2000, 26:90-4.
255. Rosmond R, Bjorntorp P: Occupational status, cortisol secretory pattern, and visceral obesity in middle-aged men. Obes Res 2000, 8:445-50.
256. Rosmond R, Dallman MF, Bjorntorp P: Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities [see comments]. J Clin Endocrinol Metab 1998, 83:1853-9.
257. Mooy JM, de Vries H, Grootenhuis PA, Bouter LM, Heine RJ: Major stressful life events in relation to prevalence of undetected type 2 diabetes: the Hoorn Study. Diabetes Care 2000, 23:197-201.
258. Bjorntorp P, Holm G, Rosmond R, Folkow B: Hypertension and the metabolic syndrome: closely related central origin? Blood Press 2000, 9:71-82.
259. Rosmond R, Bjorntorp P: The role of antidepressants in the treatment of abdominal obesity. Med Hypotheses 2000, 54:990-4.
260. Bjorntorp P, Rosmond R: Obesity and cortisol [In Process Citation]. Nutrition 2000, 16:924-36.
261. Esposito-Del Puente A, Lillioja S, Bogardus C, McCubbin JA, Feinglos MN, Kuhn CM, Surwit RS: Glycemic response to stress is altered in euglycemic Pima Indians. Int J Obes Relat Metab Disord 1994, 18:766-70.
262. Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, O’Connor G, Betteridge J, Klein N, Steptoe A, et al: Mental stress induces transient endothelial dysfunction in humans [In Process Citation]. Circulation 2000, 102:2473-8.
263. Sarabi M, Lind L: Mental stress opposes endothelium-dependent vasodilation in young healthy individuals. Vasc Med 2001, 6:3-7.
264. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmacher T: Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001, 58:445-52.
265. Stoney CM, West SG, Hughes JW, Lentino LM, Finney ML, Falko J, Bausserman L: Acute psychological stress reduces plasma triglyceride clearance. Psychophysiology 2002, 39:80-5.
266. Black PH: Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 2002, 16:622-53.
267. Black PH, Garbutt LD: Stress, inflammation and cardiovascular disease. J Psychosom Res 2002, 52:1-23.
268. Black PH: The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 2003, 17:350-64.
269. Pickup JC, Mattock MB: Activation of the innate immune system as a predictor of cardiovascular mortality in Type 2 diabetes mellitus. Diabet Med 2003, 20:723-6.
270. Pickup JC: Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004, 27:813-23.
271. Young JB, Weiss J, Boufath N: Effects of dietary monosaccharides on sympathetic nervous system activity in adipose tissues of male rats. Diabetes 2004, 53:1271-8.
272. Karpe F, Fielding BA, Ilic V, Macdonald IA, Summers LK, Frayn KN: Impaired postprandial adipose tissue blood flow response is related to aspects of insulin sensitivity. Diabetes 2002, 51:2467-73.
273. Bjorntorp P: Do stress reactions cause abdominal obesity and comorbidities? Obes Rev 2001, 2:73-86.
274. Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F, Houshyar H, Bell ME, Bhatnagar S, Laugero KD, Manalo S: Chronic stress and obesity: a new view of “comfort food”. Proc Natl Acad Sci U S A 2003, 100:11696-701.
275. Franco-Colin M, Tellez-Lopez AM, Quevedo-Corona L, Racotta R: Effects of long-term high-sucrose and dexamethasone on fat depots, liver fat, and lipid fuel fluxes through the retroperitoneal adipose tissue and splanchnic area in rats. Metabolism 2000, 49:1289-94.
276. Surwit RS, van Tilburg MA, Zucker N, McCaskill CC, Parekh P, Feinglos MN, Edwards CL, Williams P, Lane JD: Stress management improves long-term glycemic control in type 2 diabetes. Diabetes Care 2002, 25:30-4.