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The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin, through the release of tumor necrosis factor-alpha (TNF-alpha), provokes liver inflammation with hepatocyte injury in the steatotic liver. This may be particularly relevant in JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this. The relationship between the severity of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic consequence of the metabolic syndrome (or syndrome X). Attention should now shift from steatosis, a generally benign process that is less evident in the advanced stages of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic fibrosis. In particular, the genetic, molecular, and cellular factors that ordain and moderate fibrosis in the context of steatohepatitis will be of greatest relevance to effective therapy and clinical outcome.
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PMID:Etiopathogenesis of nonalcoholic steatohepatitis. 1129 94

A growing number of studies indicate an association between obesity, insulin resistance, dyslipidaemia and cardiovascular disorders, collectively known as Syndrome X. In this study we have aimed to produce a model of Syndrome X by voluntary feeding of Wistar rats with a highly palatable cafeteria diet, and examined its effects on metabolic changes and vascular reactivity of Wistar rats. At the end of the experiment, the cafeteria-diet fed group was divided into two groups of low weight gain (LWG) and high weight gain (HWG). Both LWG and HWG groups had significantly (P<0.01) higher fat-pad mass than their chow-fed counterparts, while gastrocnemius muscle mass were comparable. All cafeteria-diet fed rats had significantly (P<0.01) raised plasma triacylglycerol (TG) levels whereas plasma non-esterified fatty acids, glucose and insulin levels were similar between chow-fed and cafeteria-diet fed rats. Vasorelaxation responses to acteylcholine, insulin and sodium nitroprusside were significantly (P<0.01) attenuated in cafeteria-diet fed animals; however, there were no differences in contractile responses of the mesenteric arteries to noradrenaline or KCl between the groups. Multiple regression analysis showed a significant (P<0.05) negative association between plasma TG levels and reduction in acetylcholine-induced vasorelaxation. Acetylcholine-induced vasorelaxation was also significantly (P<0.05) associated with the amount of fat-pad mass. These data suggest that diet-induced vascular dysfunction can occur in the absence of insulin resistance, and that plasma TGs may have a detrimental effect on vascular reactivity.
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PMID:Diet-induced endothelial dysfunction in the rat is independent of the degree of increase in total body weight. 1135 79

This study was designed to examine whether abnormalities that comprise the metabolic syndrome, including insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, and obesity, are reversible by diet. Female Fischer rats were placed on either a high-fat, refined-carbohydrate (HFS) diet or low-fat, complex-carbohydrate (LFCC) diet for a period of 20 months. After 20 months, a group of HFS rats were switched to the LFCC diet (HFS/LFCC) for a period of 2 months. Skeletal muscle glucose transport, plasma insulin, systolic blood pressure, and plasma lipids were measured in all groups after 22 months. Energy intake and body weight were measured weekly. In the HFS group, insulin-stimulated glucose transport was significantly reduced (67+/-4 versus 98+/-4 pmol. mg(-)(1). 15 s(-)(1)), whereas plasma insulin (300+/-49 versus 82+/-8 pmol/L), blood pressure (147+/-4 versus 123+/-4 mm Hg), plasma triglycerides (2.58+/-0.31 versus 0.39+/-0.04 mmol/L), LDL cholesterol (C) (3.45+/-0.40 versus 0.89+/-0.06 mmol/L), LDL-C to HDL-C ratio (2.9+/-0.1 versus 2.2+/-0.1), VLDL-C (1.53+/-0.23 versus 0.37+/-0.07 mmol/l), Total-C (5.56+/-0.58 versus 1.49+/-0.10 mmol/L), and body weight (360+/-11 versus 260+/-5 g) were all significantly elevated compared with the LFCC. Energy intake did not differ significantly; however, the LFCC had a much poorer feed efficiency. Conversion to a LFCC diet for 2 months led to normalization of glucose transport, blood pressure, plasma insulin, and VLDL-C and significant amelioration of obesity and other lipid abnormalities. These results demonstrate that syndrome X induced by an inappropriate diet is reversed with implementation of a low-fat, unrefined-carbohydrate diet without caloric restriction and suggest that diet may be a possible treatment for multiple simultaneous cardiovascular risk factors.
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PMID:Reversibility of chronic experimental syndrome X by diet modification. 1135 48

The manifestations of syndrome X increase the risk of coronary heart disease (CHD) as much, if not more so, than elevated low-density lipoprotein (LDL) cholesterol concentrations. The fundamental abnormality leading to the manifestations that comprise syndrome X is resistance to insulin regulation of muscle glucose uptake and adipose tissue lipolysis. To prevent decompensation of glucose tolerance, patients with syndrome X secrete large amounts of insulin. Treatment should be aimed at 1) increasing insulin sensitivity, 2) attenuating day-long hyperinsulinemia, and 3) pharmacologic treatment of the specific manifestations of syndrome X if lifestyle interventions are not entirely successful. The two major lifestyle modulators of insulin action are body weight and physical fitness--the heavier and the more sedentary a patient is, the greater the degree of insulin resistance and compensatory hyperinsulinemia. In overweight, insulin-resistant patients, the magnitude of insulin resistance is attenuated with weight loss (10 to 15 pounds). Aerobic exercise (30 minutes a session, three to four times a week) is equally effective, irrespective of the presence of obesity. In the absence of associated weight loss, the usually recommended low-fat, high-carbohydrate diet makes the manifestations of syndrome X worse. This is because the more carbohydrates present in the insulin-resistant patient's diet, the greater the insulinogenic stimulus to the pancreas, and hence day-long plasma insulin levels are higher. Replacing saturated fat with monounsaturated and polyunsaturated fat instead of carbohydrates provides the same favorable effect on LDL cholesterol concentrations without the insulin-stimulating effect of low-fat, high-carbohydrate diets. This intervention does not affect insulin resistance, but maintains day-long insulin levels as low as possible. Although lifestyle changes can be very effective in attenuating the manifestations of syndrome X, it may be necessary to initiate pharmacologic treatment aimed at controlling dyslipidemia and hypertension. The major obstacle to reducing the risk of CHD in patients with syndrome X is becoming aware of its manifestations. After this is accomplished, the relatively simple approaches outlined herein are an effective treatment strategy.
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PMID:Syndrome X. 1144 62

Syndrome X, the clustering of risk factors for cardiovascular disease, is recognized as an obesity-related health concern among adults. In particular, individuals with visceral (intra-abdominal) obesity are prone to developing syndrome X. Although extremes of visceral fat have been detected in prepubertal children, the extent to which visceral fat contributes to the development of disease risk factors in children is not known. This review addresses the occurrence of syndrome X and its antecedents in the pediatric population, as well as two specific issues regarding syndrome X in children: the roles of ethnicity and visceral fat. The central feature to emerge from most studies is that basal and post-challenge insulin are significantly higher in African-American, Mexican-American, and Pima Indian children compared to Caucasian children. Although these ethnic differences are independent of adiposity, adiposity is associated with greater insulin in all ethnic groups examined. Mexican-Americans have a higher lipid risk factor level, which is related to greater obesity, and African-Americans have lesser lipid-associated risk, independent of obesity. African-American children may be more likely to develop type 2 diabetes due to obesity-independent hyperinsulinemia and insulin resistance, but appear less predisposed to the obesity-related clustering of risk factors associated with syndrome X. Mexican-American children may be more likely to develop syndrome X due to greater obesity-related hyperinsulinemia and dyslipidemia. Total body fat, rather than visceral fat, appears be the primary determinant of insulin resistance prior to puberty. However, visceral adipose tissue is uniquely related to both insulin and lipid risk factors in children and adolescents, and thus may contribute to the development of the early stages of syndrome X. Am. J. Hum. Biol. 11:249-257, 1999. Copyright 1999 Wiley-Liss, Inc.
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PMID:Syndrome X in children: Influence of ethnicity and visceral fat. 1153 48

Animal models for insulin resistance and type 2 diabetes are required for the study of the mechanism of these phenomena and for a better understanding of diabetes complications in human populations. Type 2 diabetes is a syndrome that affects 5-10% of the adult population. Hyperinsulinaemia, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol levels, obesity and hypertension, all form a cluster of risk factors that increase the risk of coronary artery disease, and are known as insulin resistance syndrome or syndrome X. The gerbil, Psammomys obesus is characterized by primary insulin resistance and is a well-defined model for dietary induced type 2 diabetes. Weanling Psammomys and Albino rats were held individually for several weeks on high energy (HE) and low energy (LE) diets in order to determine the development of metabolic changes leading to diabetes. Feeding Psammomys on HE diet resulted in hyperglycaemia (303 +/- 40 mg/dl), hyperinsulinaemia (194 +/- 31 microU/ml) and a moderate elevation in body weight, obesity and plasma triglycerides. Albino rats on HE diet demonstrated an elevation in plasma insulin (30 +/- 4 microU/ml), hypertriglyceridaemia (170 +/- 11 mg/dl), an elevation in body weight and obesity, but maintained normoglycaemia (98 +/- 6 mg/dl). Psammomys represent a model that is similar to human populations, with primary insulin resistance expressed in young age, which leads to a high percentage of adult type 2 diabetes. Examples for such populations are the Pima Indians, Australian Aborigines and many other Third World populations. The results indicate that the metabolism of Psammomys is well adapted towards life in a low energy environment, where Psammomys takes advantage of its capacity for a constant accumulation of adipose tissue that will serve for maintenance and breeding in periods of scarcity. This metabolism known as 'thrifty metabolism', is compromised at a high nutrient intake.
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PMID:Psammomys obesus and the albino rat--two different models of nutritional insulin resistance, representing two different types of human populations. 1166 19

Adrenarche is the puberty of the adrenal gland. The descriptive term "pubarche" indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal products of adrenarche are DHEA and DHEAS. The well-documented evolution of adrenarche in primates and men is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspects of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche and/or final height. Mechanisms for initiation of adrenal androgen secretion at adrenarche are still not well understood. Maturational increases in 17-hydroxylase and 17,20-lyase are seen together with a lower activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). There is good evidence that the zona reticularis is the source of adrenal androgens. Adrenarche and gonadarche are regulated differently. Although premature adrenarche has been thought to be a benign, normal variant of puberty, our findings indicate that, for certain girls, premature adrenarche represents an early clinical feature of syndrome X (obesity, hypertension, dyslipidemia, insulin resistance). Perhaps the early identification of these patients will permit early therapy, such as lifestyle changes, including dietary and activity level intervention. As insulin resistance is an underlying feature of premature adrenarche, it seems rational to assess the efficacy and safety of using insulin-sensitizing agents to treat these individuals. In the absence of controlled longitudinal studies, the cross-sectional data available from our studies suggest that premature pubarche driven by premature adrenarche and hyperinsulinemia may precede the development of ovarian hyperandrogenism, and this sequence may have an early origin with low birth weight serving as a marker. Premature adrenarche may thus be a forerunner of syndrome X in some girls.
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PMID:Premature adrenarche. 1171 59

Resistin, the peptide specifically secreted from adipocytes, is a hormone antagonistic to insulin action and, thus, may serve as a link between human obesity due to adiposity and insulin resistance associated with type 2 diabetes. To test this hypothesis, we studied the gene expression of resistin in adipocytes isolated from rats fed with a fructose diet which induced insulin resistance. Compared to the control rats (C) on a normal chow diet, the fructose-fed rats (F) developed hyperinsulinemia, glucose intolerance, hypertriglyceridemia and hypertension, a profile reminiscent of the syndrome X of patients with non-insulin-dependent diabetes mellitus (NIDDM). The F rats had significantly elevated plasma free fatty acids (FFA), enlarged epididymal fat pads, and increased adipocyte size compared with the C rats. We examined the glucose transport and the relative quantity of resistin mRNA produced in the adipocytes of these two groups of rats. Compared to the C rats, the F rats had a clearly reduced insulin-stimulated glucose transport. The gene expression of resistin and other adipocyte peptides was measured on the mRNA by semiquantitative RT-PCR; the validity of this technique was established in advance with a rat-fasting and then refeeding experiment. The F rats showed a decreased expression of the resistin gene, whereas gene expression of leptin and angiotensinogen in contrast increased. Free fatty acids were found to suppress the expression of resistin gene in normal rat adipocytes. These results demonstrate that an insulin-resistant instance in the fructose diet rat model exists with the decreased gene expression of resistin.
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PMID:Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. 1174 41

The occurrence of insulin resistance syndrome (syndrome X) is common in the general population. However, information is scant on the childhood predictors of syndrome X. This study examined the relative contribution of childhood adiposity and insulin to the adulthood risk of developing syndrome X in a biracial (black-white) community-based longitudinal cohort (n = 745; baseline age, 8-17 years; mean +/- SD follow-up period, 11.6 +/- 3.4 years). The four criterion risk variables considered were the highest quartile (specific for age, race, sex, and study year) of 1) BMI, 2) fasting insulin, 3) systolic or mean arterial blood pressure, and 4) total cholesterol to HDL cholesterol ratio or triglycerides to HDL cholesterol ratio. Clustering was defined as the combination of all four risk variables. In addition to the criterion risk variables, clustered adults had adverse levels of total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, diastolic blood pressure, and glucose compared with those who did not cluster (P < 0.001). Childhood variables, except glucose, showed adverse trends with increasing number of criterion risk variables present in adulthood (P for trend, 0.01-0.0001). The proportion of individuals who developed clustering as adults increased across childhood BMI (P for trend <0.0001) and insulin (P for trend <0.01) quartiles. The relationship to childhood BMI remained significant even after adjusting for childhood insulin. In contrast, corresponding association with childhood insulin disappeared after adjusting for childhood BMI. In a logistic regression model, childhood BMI and insulin were significant predictors of adulthood clustering, with BMI being the strongest and showing a curvilinear relationship. Using an insulin resistance index instead of insulin did not change the above findings. These results indicate that childhood obesity is a powerful predictor of development of syndrome X and underscore the importance of weight control early in life.
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PMID:Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: the Bogalusa Heart Study. 1175 42

Type II diabetes and hypertension are two pathologies which are frequently associated in adults, especially in developed countries. All the more so when patients are also obese: obesity is today, and will be in the next future, a true epidemic in these countries. These three pathologies imply a risk for cardiovascular complications much higher than that due to an isolated arterial hypertension. This increased risk is probably due to many factors: hyperglycemia, a dismetabolic syndrome (hyperlipemia, hyperuricemia, thrombophilia, altered Na(+)-H+ membrane exchanges = syndrome X) and hyperinsulinemia which favor atherosclerosis and clinical events. Consequently non-pharmacological and aggressive pharmacological therapy is necessary. Even if the trials done in the last years are questionable and not totally convincing, all researchers agree that lowering blood pressure to normality is the best way to improve prognosis of these patients. Usually for this purpose we need a therapy with more than one drug. Among the antihypertensive drugs, ACE-inhibitors (and perhaps also angiotensin receptor blockers) are preferred, especially in those hypertensives with diabetes who have also microalbuminuria or a frank proteinuria.
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PMID:[Diabetes and arterial hypertension]. 1177 8

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