FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W75643452> ?p ?o ?g. }

• W75643452 abstract "The incidences of obesity and type 2 diabetes are reaching epidemic proportions worldwide. A cardinal feature of these conditions is resistance to the effects of the hormone insulin and a resulting hepatic overproduction of glucose. Insulin resistance is also implicated in a range of liver diseases including non-alcoholic fatty liver disease (NAFLD) and hepatitis C infection. Insulin is released after a meal and acts on liver, skeletal muscle and adipose tissue to reduce blood glucose concentration. In the liver, insulin inhibits the production and release of glucose into the circulation and stimulates its storage as glycogen. Glucagon, on the other hand, is present in the fasting state and causes breakdown of hepatic glycogen along with production of new glucose. This glucose is released from hepatocytes into the circulation. For the studies in this thesis, functional assays to measure various aspects of hepatic glucose metabolism in vitro were developed. This included measuring glucose output into culture medium, hepatocyte uptake of radiolabelled glucose and incorporation into glycogen, and total cellular glycogen content. These assays were used to investigate glucose metabolism in primary rat hepatocytes and FaO rat hepatoma cells. Both cell types responded to physiological concentrations of insulin, showing decreased glucose output and increased glycogen synthesis. Glucagon increased glucose output and reduced glycogen synthesis in primary cells but had no effect on FaO cells. Factors that have been identified that may inhibit or potentiate insulin action were investigated. Increased body iron stores have been linked with insulin resistance. De-ironing patients improves insulin sensitivity, suggesting a causal relationship between iron and insulin resistance. Hepatocytes store the majority of the body’s excess iron. This project investigated the effects of increasing hepatocyte iron stores, through addition of ferric ammonium citrate (FAC), or depleting iron stores by chelation with dipyridyl. Small increases or decreases of iron in primary cells had negative effects on cell viability, resulting in significantly reduced glucose output and glycogen synthesis. Dipyridyl treatment had similar effects on FaO cells as on primary cells but FAC treatment increased FaO glucose output, although significant iron loading was not achieved. With concentrations of FAC and dipyridyl low enough to not significantly influence cell viability, insulin sensitivity was not affected. Adiponectin is an insulin sensitiser and appears to exert this effect primarily through the liver. Adiponectin can also reduce hepatic glucose output (HGO) independent of insulin. It is believed adiponectin mediates its effects in liver, skeletal muscle and adipose tissue through activation of AMP-activated protein kinase (AMPK). In muscle, p38 mitogen-activated protein kinase (p38 MAPK) has been implicated as a downstream component of adiponectin signalling. In this study, recombinant human adiponectin was produced and collected in culture medium which was then concentrated. Despite the presence of both high molecular weight (HMW) and low molecular weight (LMW) adiponectin multimers, the concentrated medium had no effect on HGO in the presence or absence of insulin. Concentrated adiponectin medium did not affect AMPK or p38 MAPK phosphorylation in hepatocytes or other cell types previously shown to respond to adiponectin. However, commercially-sourced purified recombinant adiponectin also failed to elicit any observable responses. AICAR and metformin are pharmacological activators of AMPK and were used to treat primary rat hepatocytes and FaO cells. These treatments reduced HGO independent of insulin in both cell types. In primary cells, these reductions were partially inhibited with Compound C, an AMPK inhibitor, suggesting that both AICAR and metformin action is at least partly AMPK dependent. In FaO cells, Compound C only inhibited the AICAR-mediated reduction of glucose output, indicating that metformin may act independently of AMPK in these cells. Compound C significantly inhibited AICAR and metformin-mediated increases in AMPK phosphorylation in primary hepatocytes and FaO cells. There was a trend towards inhibition of AICAR-mediated p38 MAPK phosphorylation with Compound C treatment, suggesting that p38 MAPK may lie downstream of AMPK in hepatocytes. Adenoviral expression of constitutively active (CA) and dominant negative (DN) AMPK in primary rat hepatocytes was used to further study the role of AMPK in hepatic glucose metabolism. Despite significant expression of CA AMPK, phosphorylation of downstream acetyl-CoA carboxylase (ACC) was not affected nor was HGO. CA AMPK did, however, increase phosphorylation of p38 MAPK. DN AMPK completely inhibited AICAR-mediated AMPK phosphorylation and partially inhibited phosphorylation of ACC. In addition, AICAR-mediated phosphorylation of p38 MAPK was inhibited by DN AMPK. Taken together, these results suggest that p38 MAPK is downstream of AMPK in hepatocytes. The implication that p38 MAPK is involved in hepatic AMPK signalling is a novel finding. A greater understanding of this pathway in the liver may identify novel therapeutic targets, leading to improved treatment strategies for metabolic disorders linked to obesity and type 2 diabetes." @default.
• W75643452 created "2016-06-24" @default.
• W75643452 creator A5041835600 @default.
• W75643452 date "2009-07-01" @default.
• W75643452 modified "2023-09-24" @default.
• W75643452 title "Investigation of Hepatic Glucose Metabolism" @default.
• W75643452 hasPublicationYear "2009" @default.
• W75643452 type Work @default.
• W75643452 sameAs 75643452 @default.
• W75643452 citedByCount "0" @default.
• W75643452 crossrefType "journal-article" @default.
• W75643452 hasAuthorship W75643452A5041835600 @default.
• W75643452 hasConcept C126322002 @default.
• W75643452 hasConcept C134018914 @default.
• W75643452 hasConcept C17093226 @default.
• W75643452 hasConcept C171089720 @default.
• W75643452 hasConcept C192118531 @default.
• W75643452 hasConcept C202751555 @default.
• W75643452 hasConcept C2776200302 @default.
• W75643452 hasConcept C2777391703 @default.
• W75643452 hasConcept C2777499176 @default.
• W75643452 hasConcept C2777866211 @default.
• W75643452 hasConcept C2778563252 @default.
• W75643452 hasConcept C2779306644 @default.
• W75643452 hasConcept C55493867 @default.
• W75643452 hasConcept C62231903 @default.
• W75643452 hasConcept C71924100 @default.
• W75643452 hasConcept C86803240 @default.
• W75643452 hasConceptScore W75643452C126322002 @default.
• W75643452 hasConceptScore W75643452C134018914 @default.
• W75643452 hasConceptScore W75643452C17093226 @default.
• W75643452 hasConceptScore W75643452C171089720 @default.
• W75643452 hasConceptScore W75643452C192118531 @default.
• W75643452 hasConceptScore W75643452C202751555 @default.
• W75643452 hasConceptScore W75643452C2776200302 @default.
• W75643452 hasConceptScore W75643452C2777391703 @default.
• W75643452 hasConceptScore W75643452C2777499176 @default.
• W75643452 hasConceptScore W75643452C2777866211 @default.
• W75643452 hasConceptScore W75643452C2778563252 @default.
• W75643452 hasConceptScore W75643452C2779306644 @default.
• W75643452 hasConceptScore W75643452C55493867 @default.
• W75643452 hasConceptScore W75643452C62231903 @default.
• W75643452 hasConceptScore W75643452C71924100 @default.
• W75643452 hasConceptScore W75643452C86803240 @default.
• W75643452 hasLocation W756434521 @default.
• W75643452 hasOpenAccess W75643452 @default.
• W75643452 hasPrimaryLocation W756434521 @default.
• W75643452 hasRelatedWork W1974986747 @default.
• W75643452 hasRelatedWork W1979554910 @default.
• W75643452 hasRelatedWork W2010543985 @default.
• W75643452 hasRelatedWork W2042891460 @default.
• W75643452 hasRelatedWork W2060496381 @default.
• W75643452 hasRelatedWork W2092340120 @default.
• W75643452 hasRelatedWork W2105483733 @default.
• W75643452 hasRelatedWork W2122251892 @default.
• W75643452 hasRelatedWork W2136278826 @default.
• W75643452 hasRelatedWork W2334945279 @default.
• W75643452 hasRelatedWork W2479660582 @default.
• W75643452 hasRelatedWork W2801706007 @default.
• W75643452 hasRelatedWork W2899488296 @default.
• W75643452 hasRelatedWork W2903564377 @default.
• W75643452 hasRelatedWork W2914940147 @default.
• W75643452 hasRelatedWork W2955810979 @default.
• W75643452 hasRelatedWork W2985706333 @default.
• W75643452 hasRelatedWork W3042361460 @default.
• W75643452 hasRelatedWork W3121539875 @default.
• W75643452 hasRelatedWork W64318579 @default.
• W75643452 isParatext "false" @default.
• W75643452 isRetracted "false" @default.
• W75643452 magId "75643452" @default.
• W75643452 workType "article" @default.