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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coexistence of hyperinsulinemia and normal or impaired carbohydrate tolerance indicates insulin resistance which is frequently observed in patients with liver diseases such as liver cirrhosis, fatty liver, acute and chronic hepatitis and idiopathic haemochromatosis. Insulin resistance in liver diseases can be due to circulating insulin antagonists or a target tissue defect in insulin action, either due to changes in the state of the insulin receptor or due to a postreceptor defect, that means any abnormality in the insulin action sequence following the initial binding step. High insulin levels in liver diseases are caused by diminished degradation of insulin by the liver whereas hypersecretion only plays a minor role under basal conditions. High levels of glucagon, free fatty acids and growth hormone are well known in liver diseases but until now there is no evidence of the pathogenetic importance of these factors. Conflicting results on insulin binding, methodological criticism on binding data and the question whether or not diminished insulin binding on peripheral blood cells plays any physiological role make it unlikely that studies on insulin receptors of peripheral blood cells contribute to the revelation of insulin resistance in liver diseases. The clamp technique allows to quantify the sensitivity of the body to exogenous insulin. The results on liver cirrhosis in connection with studies on glucose metabolism show that under basal conditions insulin insensitivity is due to peripheral resistance (primarily muscle) according to a postreceptor defect. Finally the causes of insulin resistance in liver diseases are still not known.
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PMID:[Insulin resistance in liver diseases]. 353 94

Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob/ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared with lean controls. Hepatic DNL was increased approximately 10-fold in ob/ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by approximately 60% and approximately 75%, respectively, in lean mice but only by approximately 20% and approximately 20%, respectively, in ob/ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob/ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably because of impaired insulin signaling.
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PMID:Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin. 1271 36

Lipodystrophy is characterized by the complete or partial absence of adipose tissue, insulin resistance, hepatic steatosis, and leptin deficiency. Here, we show that low-dose central leptin corrects the insulin resistance and fatty liver of lipodystrophic aP2-nSREBP-1c mice, while the same dose given peripherally does not. Central leptin also repressed stearoyl-CoA desaturase-1 (SCD-1) RNA and enzymatic activity, which were increased in livers of lipodystrophic mice. aP2-nSREBP-1c mice homozygous for an SCD-1 deletion had markedly reduced hepatic steatosis, increased saturated fatty acids, decreased acetyl-CoA carboxylase activity, and decreased malonyl-CoA levels in the liver. Despite the reduction in hepatic steatosis, these mice remained diabetic. A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity. Leptin treatment at this dose improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K activity, and Akt activity in liver. Together, these data suggest that CNS-mediated repression of SCD-1 contributes to leptin's antisteatotic actions. Intracerebroventricular leptin improves glucose homeostasis by improving insulin signal transduction in liver, but in this case the effect appears to be independent of SCD-1.
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PMID:Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. 1475 38

Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor-gamma agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPARgamma agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.
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PMID:Small-molecule insulin mimetic reduces hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes. 1529 48

By screening 204 diabetes patients, a male with age 38 was found to have increased C-peptide levels in plasma (over 6 ng/ml) and urine (430 microg/day), both of which were the highest among the screened subjects. He developed type 2 diabetes at age 31, without history of obesity (weight was 52 kg and height 170 cm). He had bilateral testicular atrophy. Fasting plasma glucose level was 160 mg/dl and HbA1c was 8% at age 38. There was hypertriglycemia (290-662 mg/dl). There were no abnormal peaks of IRI or CPR in the serum fractionated by gel filtration (Biogel P 30). Molar ratio of p-CPR/s-IRI was 10.8. Islet cell antibody, anti-insulin binding antibody and anti-insulin receptor antibody were negative. LSH and FSH were both elevated, and free testosterone was decreased. TSH and Leptin levels were elevated. Other laboratory data were within normal range. CT scan revealed fatty liver and horse-shoe kidney. These clinical pictures do not match the criteria to known syndromes associated with diabetes. Although the single case report is insufficient to discuss the C-peptide mechanism of action, this case may give us a hint to understand an aspect of the pathophysiology of C-peptide's bioactivity dysfunction.
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PMID:A case of type 2 diabetes with high levels of plasma and urinary C-peptide. 1556 62

Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) and typically are indistinguishable, histologically. The diagnosis relies on reporting of alcohol consumption. The metabolic syndrome involving insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates the insulin receptor (IR). Increased PTP1B expression is seen in obesity and possibly is responsible for the insulin resistance seen in the metabolic syndrome. The study objective was to determine whether biopsy specimens with steatohepatitis could be classified accurately as alcoholic or nonalcoholic by immunohistochemical stains. We selected 241 cases of steatohepatitis, comprising 53 and 188 cases of alcoholic and NAFLD, respectively. Specimens were stained with PTP1B and IR (b subunit) and classified as NASH or ASH. The staining pattern predicted 60 cases of ASH and 181 cases of NASH. Results correlated with clinical diagnoses in 70% and 88% of ASH and NASH cases, respectively (odds ratio, 16.6; 95% confidence interval, 8.2-35.4).
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PMID:The use of protein tyrosine phosphatase 1B and insulin receptor immunostains to differentiate nonalcoholic from alcoholic steatohepatitis in liver biopsy specimens. 1574 53

Childhood NAFLD has become an important childhood liver disease, and it is probably highly prevalent. The full of spectrum of NAFLD has been identified in children. It is not currently known whether or not simple hepatic steatosis in children is benign or whether it evolves to NASH over time. In contrast, childhood NASH certainly can have serious consequences. Cirrhosis is apparently rare in children with NAFLD, but it definitely occurs. Childhood NAFLD may occur in very young children, and there is no female predominance in the pediatric age bracket. Children present with vague abdominal pain, if they have any symptoms at all, but frequently hepatic steatosis is found incidentally on abdominal imaging. Laboratory studies show that serum aminotransferase abnormalities are rather moderate, with serum alanine aminotransferase (ALT) more elevated than serum aspartate aminotransferase (AST). Hypertriglyceridemia is the typical blood lipid abnormality, although hypercholesterolemia may occur. NASH may be more severe in children from certain ethnic groups, including Hispanics and Asians, or in association with certain metabolic disorders characterized by abnormalities in insulin receptor structure or signaling, such as lipodystrophy syndromes. Weight loss through dietary redesign and a regimen of regular exercise remains the mainstay for treatment for childhood NAFLD. A dietary strategy to minimize postprandial hyperinsulinemia and overall fat intake, such as a low glycemic index diet, may be the best dietary strategy. The real efficacy of drug treatments in children requires further investigation. The overriding message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.
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PMID:Non-alcoholic fatty liver disease (NAFLD) in children. 1597 Apr 96

Fatty acid binding proteins (FABPs) are cytosolic fatty acid chaperones whose biological role and mechanisms of action are not well understood. Here, we developed mice with targeted mutations in two related adipocyte FABPs, aP2 and mal1, to resolve their role in systemic lipid, glucose, and energy metabolism. Mice lacking aP2 and mal1 exhibited a striking phenotype with strong protection from diet-induced obesity, insulin resistance, type 2 diabetes, and fatty liver disease. These mice have altered cellular and systemic lipid transport and composition, leading to enhanced insulin receptor signaling, enhanced muscle AMP-activated kinase (AMP-K) activity, and dramatically reduced liver stearoyl-CoA desaturase-1 (SCD-1) activity underlying their phenotype. Taken together with the previously reported strong protection against atherosclerosis, these results demonstrate that adipocyte/macrophage FABPs have a robust impact on multiple components of metabolic syndrome, integrating metabolic and inflammatory responses in mice and constituting a powerful target for the treatment of these diseases.
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PMID:Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. 1605 52

Hepatic insulin resistance is associated with hepatic steatosis and is thought to play an important role in the pathogenesis of steatohepatitis. Using a murine model of steatohepatitis (mice fed a diet deficient in methionine and choline-MCD diet), we tested the effects of the insulin-sensitising, PPARgamma agonist drug pioglitazone (PGZ) on systemic and intrahepatic insulin sensitivity and on liver pathology. Compared to controls, mice fed the MCD diet develop a significant steatohepatitis, have enhanced glucose tolerance and enhanced systemic response to insulin. PGZ did not affect the systemic insulin sensitivity in control or MCD-fed mice as assessed in vivo by intraperitoneal glucose or insulin dynamic tests. However, PGZ prevented hepatic fat accumulation and steatohepatitis induced by the MCD diet. This effect was associated with an increased mass of adipose tissue and increased expression and release of adiponectin, while hepatic acyl co-enzyme A oxidase and acyl-co-enzyme A carboxylase, regulating hepatic beta-oxidation of fatty acid, remained unchanged. Steatohepatitis in MCD-diet-fed mice was associated with intrahepatic insulin resistance as shown by a reduced phosphorylation of hepatic insulin receptor, and Akt in response to an insulin stimulus. PGZ to MCD-fed mice restored the activation of the insulin receptor and of the Akt pathway in response to insulin. In conclusion, PGZ alleviates steatosis and steatohepatitis induced by the MCD diet, an effect associated with correction of intrahepatic insulin resistance.
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PMID:Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone. 1707 77

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C zeta (PKC zeta) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC zeta with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.
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PMID:Prenatal and postnatal pathways to obesity: different underlying mechanisms, different metabolic outcomes. 1727 92


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