Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lipodystrophies are rare disorders characterized by selective but variable loss of adipose tissue. Metabolic complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver, increase in severity with the extent of fat loss. The lipodystrophies can be classified into two major types: familial and acquired. The main subtypes of familial lipodystrophies are congenital generalized lipodystrophy, an autosomal recessive disorder characterized by near complete lack of metabolically active adipose tissue from birth, and familial partial lipodystrophy, Dunnigan type, an autosomal dominant disorder characterized by loss of subcutaneous fat from the extremities at puberty and excess fat accumulation in the face and neck. Recently, a gene for congenital generalized lipodystrophy was localized to chromosome 9q34, and a gene for familial partial lipodystrophy, Dunnigan type, to chromosome 1q21-22; the genes, however, remain to be identified. Patients with acquired generalized lipodystrophy have generalized loss of subcutaneous fat, but those with acquired partial lipodystrophy have fat loss limited to the face, trunk, and upper extremities. Both varieties occur approximately three times more often in women, begin during childhood, and have underlying autoimmunity. Patients infected with the human immunodeficiency virus (HIV) who are receiving therapy that includes HIV-1 protease inhibitors have been reported to develop a lipodystrophy characterized by loss of subcutaneous fat from the extremities and face but excess fat deposition in the neck and trunk. Localized lipodystrophies can be caused by drugs, pressure, panniculitis, or unknown mechanisms. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia.
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PMID:Lipodystrophies. 1112 8

The rising prevalence of obesity is accompanied by an increasing number of patients with the metabolic complications of obesity. The major complications come under the heading of the metabolic syndrome. This syndrome is characterized by plasma lipid disorders (atherogenic dyslipidemia), raised blood pressure, elevated plasma glucose, and a prothrombotic state. The clinical consequences of the metabolic syndrome are coronary heart disease and stroke, type 2 diabetes and its complications, fatty liver, cholesterol gallstones, and possibly some forms of cancer. At the heart of the metabolic syndrome is insulin resistance, which represents a generalized derangement in metabolic processes. Obesity is the predominant factor leading to insulin resistance, although other factors play a role. The mechanistic link between insulin resistance and the metabolic syndrome is complex. The relationship is modulated by yet other factors, such as physical activity, body fat distribution, hormones, and a person's genetic polymorphic architecture. A better understanding of the molecular basis of this relationship is needed to suggest new targets for prevention and treatment of the complications of obesity. In addition, understanding at the clinical level will lead to improved management of these complications.
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PMID:Metabolic complications of obesity. 1118 17

Three categories of highly active antiretroviral therapy (HAART)-associated major toxic effects have been identified: nucleoside-related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life-threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long-term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.
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PMID:Long-term exposure to lifelong therapies. 1183 99

The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.
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PMID:Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. 1194 43

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that occurs in nondrinkers but which cannot be distinguished from alcohol-induced liver disease histologically. There are no diagnostic blood tests for NAFLD but the disease is associated with several insulin-resistant states, including obesity, type 2 diabetes mellitus and dyslipidemia. Most of the liver-related morbidity and mortality that accompany NAFLD occur in patients who develop cirrhosis. The latter is most likely to occur in individuals who have progressed from simple steatosis (fatty liver) to steatohepatitis, a chronic inflammatory liver lesion. The mechanisms that promote the transition from steatosis to nonalcoholic steatohepatitis appear to involve multiple cellular adaptations to the oxidative stress that occurs when fatty acid metabolism is deranged during insulin resistance. A better understanding of these mechanisms is desired to target treatments to prevent and/or reverse nonalcoholic steatohepatitis, thereby aborting the evolution of cirrhosis.
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PMID:Fat and the liver--a molecular overview. 1194 31

Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin-resistance syndrome, at present defined as the metabolic syndrome, whose limits were recently set. We assessed the prevalence of the metabolic syndrome in 304 consecutive NAFLD patients without overt diabetes, on the basis of 3 or more criteria out of 5 defined by the U.S. National Institutes of Health (waist circumference, glucose, high-density lipoprotein [HDL]-cholesterol, triglycerides, and arterial pressure). The prevalence of the metabolic syndrome increased with increasing body mass index, from 18% in normal-weight subjects to 67% in obesity. Insulin resistance (Homeostasis Model Assessment method) was significantly associated with the metabolic syndrome (odds ratio [OR], 2.5; 95% CI, 1.5-4.2; P <.001). Liver biopsy was available in 163 cases (54%). A total of 120 patients (73.6%) were classified as having nonalcoholic steatohepatitis (NASH); 88% of them had a metabolic syndrome (vs. 53% of patients with pure fatty liver; P <.0001). Logistic regression analysis confirmed that the presence of metabolic syndrome carried a high risk of NASH among NAFLD subjects (OR, 3.2; 95% CI, 1.2-8.9; P =.026) after correction for sex, age, and body mass. In particular, the syndrome was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1-11.2; P =.032). In conclusion, the presence of multiple metabolic disorders is associated with a potentially progressive, severe liver disease. The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension, and ultimately the metabolic syndrome puts a very large population at risk of forthcoming liver failure in the next decades.
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PMID:Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. 1266 87

The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.
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PMID:Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. 1295 38

Nonalcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia. We tested the hypothesis that there may be an association between NAFLD and insulin resistance (IR); and its correlation with glucose tolerance status of subjects who aren't known patients with diabetes. One hundred and seventy-six consecutive patients with elevated serum aminotransferase levels and bright liver were evaluated. Sixty-two patients were excluded from the study. Age, gender, height, weight, body mass index, waist circumferences, and family history of diabetes were recorded. Fasting plasma glucose, insulin, lipid profile were measured. A standard oral glucose tolerance test (OGTT) was performed and the index of IR was calculated according to the HOMA method. Patients with a normal glucose tolerance formed group 1 (64 patients) and patients with impaired or diabetic glucose tolerance group 2 (50 patients). Age, female sex, family history of type 2 diabetes, fasting insulin, fasting plasma glucose and HOMA-R index were statistically significantly different between the groups. Although the subjects in the study are not known patients with diabetes, the prevalence of impaired or diabetic glucose tolerance was prominent. In conclusion, performing OGTT in cases with nonalcoholic fatty liver disease may be useful for early screening of diabetes mellitus.
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PMID:Association of nonalcoholic fatty liver disease with insulin resistance: is OGTT indicated in nonalcoholic fatty liver disease? 1820 1

Leptin is the first of a group of adipocyte-secreted hormones to be used clinically to treat hypoleptinemic states. In children with congenital leptin deficiency and extreme obesity, leptin induces satiety and a dramatic loss of weight. In hypoleptinemic patients with extreme insulin resistance and lipodystrophy, leptin ameliorates insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia and hepatic steatosis. In both these leptin-deficient states, leptin therapy restores gonadotrophin secretion, as well as luteinizing hormone and thyroid-stimulating hormone pulsitility.
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PMID:The clinical uses of leptin. 1464 19

The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance - namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations -- is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.
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PMID:Obesity, insulin resistance, and cardiovascular disease. 1474 3


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