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The obvious syntropy of obesity and type II (non-insulin dependent) diabetes mellitus has always suggested a causal inter-relationship between the two diseases. However, the actual pathophysiological connection still remains to be elucidated. Recent findings have suggested that insulin resistance and hyperinsulinaemia might link glucose intolerance/type II diabetes mellitus, hypertension and hyperlipoproteinaemia in the context of a hypothetical 'syndrome X' characterized by an excessive risk constellation for the development of atherosclerosis. However, as to the practical consequences of the ('diabesity') syndrome of type II diabetes mellitus and structured programmes for effective therapy, very little new information has been gathered during the past 100 years.
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PMID:Risk of obesity in type II diabetes mellitus. 133 84

Mounting data support a causal connection between high-normal fibrinogen levels and atherosclerotic cardiovascular disease. There is clearly a thrombogenic component to atherosclerosis and the onset of clinical manifestations. This offers the possibility to better identify high-risk candidates and also to protect them by reducing blood fibrinogen concentration or blocking its action. The relationship of antecedent fibrinogen to the subsequent development of cardiovascular disease is examined, based on 18 years of surveillance of a cohort of 1274 men and women aged 47 to 79 years who participated in the Framingham Study. The association with the development of peripheral arterial disease and cardiac failure is now examined in addition to previously studied relationships to coronary heart disease and stroke. In men and women, there is a significant age-adjusted relationship of fibrinogen level to coronary heart disease and to cardiovascular disease in general. In women, a significant relationship to cardiac failure and peripheral arterial disease, but not to stroke, was also found. These data on women are unique as they are not available elsewhere. Age-adjusted cardiovascular, all-cause, and coronary heart disease mortality were all related to fibrinogen in both sexes. In men, fibrinogen impact was the greatest for stroke and the least for peripheral arterial disease. For women, the impact on coronary heart disease was greatest. The absolute risk for an elevated fibrinogen level was greatest for coronary heart disease in both sexes. Average fibrinogen values are higher in women and in persons with other risk factors, including hypertension, cigarette smoking, diabetes, obesity, and elevated hematocrit. However, there is an independent contribution of fibrinogen to cardiovascular disease in general and coronary disease in particular, on adjustment for coexistent risk factors. Fibrinogen enhances the risk of cardiovascular disease in hypertensives, diabetics, and cigarette smokers. About half the cardiovascular risk of cigarette smoking appears due to the higher fibrinogen values. Now, five prospective studies document the excess incidence of cardiovascular events in persons with elevated fibrinogen levels within the "normal range." Each standard deviation increase in fibrinogen is associated with a 30% increment of coronary heart disease in men and a 40% increase in women. Fibrinogen should be added to the list of major cardiovascular risk factors. Trials of intervention to lower fibrinogen in high-risk coronary candidates are needed.
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PMID:Update on fibrinogen as a cardiovascular risk factor. 134 96

The levels of lipoprotein A-I (LP A-I) containing apolipoprotein A-I (apo A-I) and devoid of apolipoprotein A-II (apo A-II) have been determined in a group of 86 children and adolescents with insulin-dependent diabetes of age between 1.3 and 22 years. The duration of diabetes in the studied group ranged between 0.25 and 15 years. The patients studied were further divided into subgroups taking into account the duration of diabetes as well as the occurrence of complications of diabetes, obesity and predisposition to early development of atherosclerosis in family history. The analysis of the results took into account the relations between the levels of LP A-I and other parameters of lipid metabolism like cholesterol, triglycerides, HDL-cholesterol, apo A-I and apo A-II concentrations as well as the effectiveness of metabolic control of diabetes. LP A-I concentration was the lowest in group of children with diabetes lasting up to one year. This parameter was correlated positively with the levels of HDL-cholesterol and apo A-I, and negatively with HbA1c. It was not related to the coexisting complications, obesity or predisposition to atherosclerosis in family history. The above results indicate that the state of metabolic control of diabetes significantly influences the level of LP A-I. Considering the importance of LP A-I in preventing atherosclerosis it should be stressed that a decrease in its level during the period of prolonged hypoglycemia constitutes still another risk factor for development of atherosclerosis in diabetic children and adolescents.
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PMID:[Lipid metabolism in children and adolescents with insulin dependent diabetes. II. Evaluation of changes in lipoprotein A-I in children and adolescents with insulin dependent diabetes]. 134 32

The levels of the following blood serum lipid constituents: total cholesterol, triglycerides, phospholipids, HDL-cholesterol, apolipoproteins AI, AII and B, and lipoprotein fractions have been determined in patients with insulin-dependent diabetes in relation to sex, age, duration of diabetes, coexistence of obesity, insulin dosage and history of genetic predispositions. The age of the patients was between 1.3 and 22 years and the duration of the disease ranged between 3 months and 15 years. The analysis of the results revealed that sex, age, daily insulin dose and the known genetic predispositions have no influence on the values of the parameters of lipid metabolism. However, an increase in the levels of cholesterol, HDL-cholesterol, triglycerides and apolipoproteins AI and B was observed along with the progressing duration of the disease. An increase in the levels of cholesterol, apolipoprotein B and beta-lipoprotein, and a decrease in the level of alpha-lipoprotein have been found in diabetic children with coexisting obesity. The above analysis indicates that besides metabolic control of diabetes its duration and accompanying obesity may negatively influence the course of the disease contributing to the precocious development of atherosclerosis.
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PMID:[Lipid metabolism in patients with insulin dependent diabetes. IV. Effect of sex, age, excess body weight, duration of diabetes, insulin dosage and family history on lipid metabolism in patients with insulin dependent diabetes]. 134 34

Obesity is a multifactorial disease with a marked genetic component. The situation is further complicated by the heterogeneity of obesity demonstrated by the topographical distribution of body fat, e.g. upper body (central) and lower body (gluteal) obesity. Furthermore, the distribution of fat shows a stronger heritable tendency compared with total body fat. Central obesity is characterized by hyperinsulinaemia and insulin resistance, a feature in common with non-insulin dependent diabetes mellitus, hypertension and atherosclerosis. In order to study the molecular genetics of central obesity we have examined 56 severely obese (mean body mass index 40), unrelated British Caucasoid young non-diabetic women for associations of restriction fragment length polymorphism of candidate genes with anthropometric measurements and indices of insulin secretion and resistance. The candidate genes examined were insulin receptor, insulin sensitive glucose transporter and insulin. An association of the class 3 allele of the hypervariable region in the 5' flanking region of the insulin gene was found with upper segment obesity (P = 0.005). Furthermore, the class 3 allele was also associated with fasting hyperinsulinaemia (P = 0.01), stimulated insulin secretion (P = 0.01) and insulin resistance as calculated from the homeostatic model of assessment (HOMA; P = 0.008). No such associations were found with the other candidate genes studied. This data suggests that polymorphisms in the 5' flanking region of the insulin gene may affect expression of the gene and thereby modulate insulin production in severely obese female subjects.
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PMID:Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flanking region of the human insulin gene. 135 60

The level of lipoprotein Lp(a), one of the risk factors of atherosclerosis, was determined in 91 children and adolescents of age ranging from 3.3 to 22 years suffering from insulin-dependent diabetes. The changes in Lp(a) were analyzed in relation to the group of patients, the duration of diabetes, possible genetic factors, other factors predisposing to early onset of atherosclerosis, and occurrence of obesity in the analyzed group. The relation between the level of Lp(a) and other parameters of lipid metabolism (total cholesterol, triglycerides, phospholipids, HDL-cholesterol and apolipoprotein B) as well as a degree of metabolic normalization of diabetes (as assessed by the determination of glycosylated hemoglobin and fructosamine) was studied in addition. No relation between Lp(a) and the factors mentioned above, with exception of glycosylated hemoglobin and fructosamine concentrations, could be demonstrated. The elevated level of Lp(a) in children and adolescents during the period of poor metabolic control of diabetes may constitute an additional risk factor for early onset of atherogenic changes.
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PMID:[State of lipid metabolism in children and adolescents with insulin-dependent diabetes. I. Evaluation of lipoprotein (A) behavior in children and adolescents with insulin-dependent diabetes]. 136 93

Dietary intakes, anthropometric indices and plasma lipoprotein and alpha-tocopherol concentrations were measured in premenopausal vegetarian women of Indian descent (n = 22) and in white women of European descent consuming either mixed (n = 22) or vegetarian diets (n = 18). The Indian women were shorter in height than the white women and had a higher proportion of body fat. Energy intakes were lower in the Indian women, both in absolute terms and per kg body weight. The proportion of energy derived from saturated fatty acids was lower and that from polyunsaturated fatty acids was greater in both Indian and white vegetarians compared with the subjects on mixed diets. Intakes of dietary fibre and vitamins C and E were higher in the white vegetarians compared with the other groups. Plasma concentrations of total and LDL cholesterol and apolipoprotein B and the ratio of apolipoprotein B/apolipoprotein AI were lower and HDL and HDL2 cholesterol, alpha-tocopherol concentrations and the ratio of alpha-tocopherol/cholesterol were greater in the white vegetarian group than in the other groups. Total plasma cholesterol was associated with measures of truncal obesity, especially subscapular skinfold thickness and the percentage energy derived from saturated fatty acids. Plasma concentrations of apo(a) were higher and those of HDL and HDL2 cholesterol and sex hormone binding globulin (SHBG) were lower in the Indian vegetarian women compared with both groups of white women. No relationship could be found between apo(a), HDL and HDL2 cholesterol concentration and nutrient intake but HDL and HDL2 were negatively associated with the proportion of body fat and apo(a) weakly with subscapular skinfold thickness.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1992 Aug
PMID:Lipoprotein risk factors in vegetarian women of Indian descent are unrelated to dietary intake. 141 95

Obesity is a major risk factor for cardiovascular disease. However, a direct link between these two states is difficult to establish, since obesity frequently occurs with other disease states such as diabetes, hypertension and atherosclerosis. Clinical studies have clearly shown that uncorrected obesity is associated with cardiac hypertrophy and compromised ventricular function. A number of rodent models of obesity have been studied in terms of cardiovascular adaptations. Cardiac function of the obese Zucker rat appears to be normal at a younger age. Only after several months is depression in cardiac function discernable. These animals are mildly hypertensive, but do not exhibit the characteristic increase in cardiac output associated with human obesity. A unique characteristic of JCR:LA-cp rat is that they develop atherosclerotic and myocardial lesions. Hearts from these animals will maintain normal function when perfused with physiological levels of calcium. At higher calcium concentrations, however, mechanical function becomes impaired. Dietary-induced obese rats exhibit many of the hemodynamic alterations associated with human obesity, but there is no evidence to-date that these animals will develop severe cardiac depression. Short-term weight reduction apparently has beneficial cardiovascular effects, but weight cycling may be harmful. Given the widespread occurrence of obesity, further studies are warranted to characterize the cardiac manifestations of this condition.
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PMID:Cardiovascular abnormalities associated with human and rodent obesity. 143 63

An increased risk of developing premature atherosclerosis is associated with stress, diabetes, obesity, and hypertension. These conditions are associated with insulin resistance, hyperglycemia, hypertriglyceridemia and hypercholesterolemia. An alternative way of interpreting insulin resistance is to consider that metabolism in this condition would be regulated to a greater extent by stress hormones and in particular by cortisol. Glucocorticoids and fatty acids (which are produced in response to stress) antagonise the actions of insulin in promoting glucose uptake and protein synthesis, in decreasing gluconeogenesis and protein catabolism, and promoting the clearance of intermediate density lipoprotein and low density lipoprotein from the circulation by the liver. They also promote the secretion of very low density lipoprotein thus producing hypertriglyceridemia and hypercholesterolemia. By contrast to this antagonism, cortisol can also facilitate the action of insulin in stimulating the storage of energy via glycogen and fatty acid synthesis and through lipoprotein lipase in adipose tissue. These effects are significant in relation to obesity and to weight gain. An increased control of metabolism by cortisol therefore produces changes in metabolism that are potentially atherogenic and it is associated with insulin resistance and the other risk factors for atherosclerosis. Benfluorex treatment improves insulin sensitivity and has antihyperglycemic and hypolipidemic effects in human beings and in experimental animals. These effects can be observed independently of weight loss, but lowering food intake also produces a metabolic benefit. Long-term treatment with benfluorex can also decrease stress responses in terms of glucocorticoid release and the stimulation of lipolysis probably by its serotoninergic control of the hypothalamic-pituitary-adrenal axis. Such an action provides for an integrated treatment of the obese-diabetic-hyperlipidemic syndrome. Benfluorex produces overall changes in metabolism that tend to normalise the major risk factors associated with premature atherosclerosis. This provides a potential advantage over other therapies for atherosclerosis which may ameliorate a symptom (e.g., hyperlipidemia) without treating the underlying metabolic disturbance that predisposes to atherogenesis.
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PMID:[Mode of action of benfluorex. Recent data]. 143 2

We have shown previously that parenterally-administered lipid emulsions can be utilized to induce early atherosclerosis in the aortas of Sprague-Dawley rats. In order to evaluate the effect of obesity on lipid-induced atherogenesis, we have utilized this same approach in the present study to demonstrate that i.v. infusions of the parenteral lipid emulsion, Lipofundin-S, will induce in the genetically obese Zucker rat and its lean littermate aortic endothelial and myofibroelastic changes indicative of early atherogenesis. Four groups of rats were used: 1) obese controls, 2) obese lipid-infused, 3) lean littermate controls, and 4) lean littermate lipid-infused. Observations were made with light and transmission electron microscopy (TEM), using qualitative morphological criteria to evaluate the results. Based on the fact that both untreated control and Lipofundin-S-induced atherosclerosis was more frequent and generally more advanced in the obese animals than in their respective lean counterparts, it appears that the obese Zucker rat is more susceptible to both spontaneous and hyperlipidemia-induced atherosclerosis than its respective lean littermate. Thus, obesity in these animals, as might be the case in humans, could potentiate an atherogenic process already enhanced by hyperlipidemia.
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PMID:Parenteral lipid emulsion-induced atherosclerosis in the obese Zucker rat and its lean littermate. 144 40


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