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

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.
 ...
PMID:Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus. 250 Oct 61

Hepatic steatosis and steatonecrosis occur in nonalcoholic individuals, usually in a setting of obesity, type II diabetes mellitus, and after jejunoileal bypass. We propose an hypothesis for the pathogenesis of these hepatic lesions based on an observation in peritoneal dialysis patients. Hepatic histology was examined at autopsy in 11 patients with type I diabetes mellitus and renal failure who had received i.p. insulin in conjunction with continuous ambulatory peritoneal dialysis (CAPD). Steatosis in a unique subcapsular distribution occurred in 10 of 11 patients treated with i.p. insulin and in 0 of 9 controls receiving CAPD without insulin. Three of the 11 had steatonecrosis, 2 of whom had Mallory bodies. We suggest that insulin has an important role in the pathogenesis of steatosis and steatonecrosis. In CAPD patients the lesions occurred only under the capsule where concentrations of insulin are high secondary to its i.p. administration. In obese patients the lesions occur throughout the liver where insulin concentrations are high because of elevated levels in the portal vein. Free fatty acids (FFA) are oxidized in the liver by a pathway that is blocked by insulin. In the presence of insulin, FFA are preferentially esterified into triglycerides which accumulate in large quantities leading to steatosis; small amounts of FFA escaping local control may lead to membrane injury and steatonecrosis. Steatosis and/or steatonecrosis will occur when there is insulin secretion sufficient to block FFA oxidation but not sufficient to block FFA mobilization from adipose tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Subcapsular steatonecrosis in response to peritoneal insulin delivery: a clue to the pathogenesis of steatonecrosis in obesity. 265 21

A 54-year-old woman with obesity, type II diabetes mellitus, hyperlipidemia, and massive hepatomegaly was found to have severe steatosis and cirrhosis on liver biopsy. Complete evaluation led to the diagnosis of fatty cirrhosis associated with obesity and diabetic mellitus. She underwent four months of fasting with a protein-carbohydrate and vitamin-mineral liquid supplement to control her weight and metabolic abnormalities and to evaluate the effect of this diet on her liver disease. She lost 40 pounds to ideal body weight, normalized her serum glucose and lipids, and decreased total liver height by one third. Liver biopsy at the completion of her diet showed inactive cirrhosis and complete resolution of steatosis. Supplemented fasting with only modest weight loss can safely resolve fatty liver in obese diabetics with nonalcoholic steatosis and cirrhosis. Aggressive dietary approaches to achieve long-term weight loss deserve study in this subgroup of diabetics with unexplained chronic liver disease.
 ...
PMID:Steatosis and cirrhosis in an obese diabetic. Resolution of fatty liver by fasting. 382 84

Effects of dietary carbohydrates on triglyceride production and hepatic lipogenic enzyme activities were examined in Wistar fatty rats, an animal model of noninsulin dependent diabetes mellitus, fed fructose or glucose and were compared with those of Wistar lean rats. Carbohydrates were supplied in 10% drinking solutions for 21 days. As compared with lean rats, Wistar fatty rats were characterized by hyperglycemia, hyperinsulinemia and hypertriglyceridemia, the last of which was associated with an increased hepatic activity of fatty acid synthetase and an increased rate of triglyceride secretion from the liver to the circulation. Feeding fructose to genetically obese diabetic rats produced a threefold increase in the hepatic activity of fatty acid synthetase, a twofold increase in NADPH-generating enzymes (malic enzyme and glucose-6-phosphate dehydrogenase) and a 56% increase in the rate of triglyceride secretion, with a resultant 86% increase in plasma triglyceride concentrations. Feeding glucose produced a similar increase in the activity of NADPH-generating enzymes and triglyceride production in the fatty liver but it differed in producing no change in plasma triglyceride concentrations or hepatic fatty acid synthetase activity. Neither dietary fructose nor glucose changed glycemia or insulinemia. These results show that in genetically obese, diabetic rats feeding fructose and glucose is associated with an increase in hepatic lipogenic enzyme activities and triglyceride production, and suggest that fructose stimulates triglyceride production but impairs triglyceride removal, whereas glucose stimulates both of them.
 ...
PMID:Effects of dietary fructose or glucose on triglyceride production and lipogenic enzyme activities in the liver of Wistar fatty rats, an animal model of NIDDM. 922 59

Nonalcoholic fatty liver disease (NAFL) has been recognized only in the past 20 years. Autopsy studies indicate it is remarkably common, especially among obese persons and patients with type 2 diabetes. Although fatty liver alone is usually benign, an identifiable subset of patients may be at risk of progression to cirrhosis and liver failure. The role of liver biopsy is controversial. No specific, effective therapy as yet exists, although management of weight, lipid levels, and glucose levels is recommended.
 ...
PMID:The spectrum of nonalcoholic fatty liver disease: from steatosis to nonalcoholic steatohepatitis. 1068 Feb 76

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in beta-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.
 ...
PMID:Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. 1072 41

The Nagoya-Shibata-Yasuda (NSY) mouse is an inbred strain with spontaneous development of type 2 (non-insulin-dependent) diabetes mellitus. The purpose of this study was to determine the mode of inheritance of various phenotypes related to diabetes in this strain. Two reciprocal outcrosses, female C3H/He x male NSY F1 (C3NF1) and female NSY x male C3H/He F1 (NC3F1) mice, were performed. The phenotypic characteristics in both F1 mice were investigated. The cumulative incidence of diabetes was 100% (25 of 25) in male C3NF1 mice and 97% (29 of 30) in male NC3F1 mice at 48 weeks of age, indicating that diabetes in NSY mice was transmitted to male F1 hybrids in an autosomal dominant manner. Fatty liver also showed an autosomal dominant mode of inheritance. In contrast, epididymal fat accumulation and impaired insulin secretion showed an autosomal recessive mode of inheritance. The body mass index (BMI) showed a codominant mode of inheritance. Paternal-maternal effects associated with the severity of diabetes were observed. Insulin resistance was much more severe in male F1 mice than in the parental NSY strain. These data indicate different modes of inheritance among phenotypes related to type 2 diabetes. The presence of more severe insulin resistance in F1 mice versus the parental strains suggests the interaction of both parental genomes in the development of insulin resistance. The F1 mouse is expected to be useful for studies of the pathogenesis and genetic synergism of the insulin resistance syndrome.
 ...
PMID:Paternal-maternal effects on phenotypic characteristics in spontaneously diabetic Nagoya-Shibata-Yasuda mice. 1083 Nov 78

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.
 ...
PMID:Metabolic complications of obesity. 1118 17

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.
 ...
PMID:Etiopathogenesis of nonalcoholic steatohepatitis. 1129 94

The liver plays an important role in the pathogenesis of NIDDM. More importantly to the clinician is the myriad of situations in which the care of the patient with diabetes is affected by or causes an effect to the liver. Patients with underlying diabetes can present with abnormal liver chemistries, which can represent findings as benign as hepatic steatosis or as severe as cirrhosis of the liver. The medications used to treat diabetes can be potent hepatotoxins. Several primary liver diseases are associated with increased risk of the development of diabetes. Epidemiologically, there seems to be a correlation between diabetes mellitus, the most common endocrinologic disease, and hepatitis C, the leading cause of chronic liver disease in the United States. In the management of end-stage liver disease, both cirrhosis and orthotopic liver transplantation promote glucose intolerance and diabetes in a number of patients through various mechanisms including insulin resistance and impaired insulin secretion. These relationships highlight both the importance of the liver as an endocrine organ and the multisystem aspects of the patient with diabetes mellitus.
 ...
PMID:Liver disease and diabetes mellitus. 1132 35


1 2 3 4 5 6 7 8 9 10 Next >>