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Conference Paper: APPL1 as a novel regulator of hepatic insulin sensitivity and 13 glucose homeostasis: molecular mechanism and physiological relevance

TitleAPPL1 as a novel regulator of hepatic insulin sensitivity and 13 glucose homeostasis: molecular mechanism and physiological relevance
Authors
Issue Date2009
PublisherHong Kong Academy of Medicine Press.
Citation
The 14th Medical Research Conference (MRC 2009), Hong Kong, 10 January 2009. In Hong Kong Medical Journal, 2009, v.15 suppl. 1, p. 13, abstract no. 13 How to Cite?
AbstractIntroduction: Insulin inhibits hepatic glucose production through activation of Akt, which in turn suppresses gluconeogenic gene expression. Hepatic insulin resistance contributes to both fasting and fed hyperglycaemia in patients with type 2 diabetes. APPL1, an adaptor protein, is involved in insulin actions in muscle cells and adipocytes. However, the physiological functions of APPL1 remain elusive. The major objective of this study was to investigate the role of APPL1 in insulin-induced inhibitory effects on gluconeogenesis in mouse models, and to investigate the cellular mechanisms involved. Methods: For the in-vitro study, primary rat hepatocytes were infected with adenovirus encoding full-length of APPL1 or APPL1-specific RNAi for 24 hours, followed by starvation for 24 hours, and then treated with 10 nM insulin for various time points. Total cell lysate was collected for both immunobloting and real-time PCR analysis. For the in-vivo study, male db/db diabetic or C57 wild-type mice were injected with the adenovirus encoding full-length APPL1 or APPL1-specific RNAi via tail vein, respectively. Basic metabolic parameters were measured, and insulin tolerance test and glucose tolerance test were performed. Results and conclusions: In rat hepatocytes, the effects of insulin on Akt phosphorylation and suppression of gluconeogenesis were markedly inhibited by adenovirus-mediated knockdown of APPL1, but were significantly enhanced by APPL1 overexpression. In db/db diabetic mice, hepatic overexpression of APPL1 alleviated hyperglycaemia and glucose intolerance, and increased insulin sensitivity. These metabolic changes were associated with increased Akt activation, and decreased expression of the key gluconeogenic genes in the liver. Conversely, specific knockdown of APPL1 expression in liver decreased insulin-mediated activation of Akt and induced a modest insulin resistance in C57 mice. Taken together, these data suggest that APPL1 is a key signalling molecule mediating the hepatic actions of insulin in suppression of gluconeogenesis via enhancing Akt activation. Acknowledgement: This work was supported by General Research Fund (HKU 779707M).
Persistent Identifierhttp://hdl.handle.net/10722/62307

 

DC FieldValueLanguage
dc.contributor.authorCheng, KYen_HK
dc.contributor.authorLglesias, MAen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorSweeney, Gen_HK
dc.contributor.authorZhu, Wen_HK
dc.contributor.authorHoo, RLCen_HK
dc.contributor.authorKraegen, EWen_HK
dc.contributor.authorXu, Aen_HK
dc.date.accessioned2010-07-13T03:58:28Z-
dc.date.available2010-07-13T03:58:28Z-
dc.date.issued2009en_HK
dc.identifier.citationThe 14th Medical Research Conference (MRC 2009), Hong Kong, 10 January 2009. In Hong Kong Medical Journal, 2009, v.15 suppl. 1, p. 13, abstract no. 13-
dc.identifier.urihttp://hdl.handle.net/10722/62307-
dc.description.abstractIntroduction: Insulin inhibits hepatic glucose production through activation of Akt, which in turn suppresses gluconeogenic gene expression. Hepatic insulin resistance contributes to both fasting and fed hyperglycaemia in patients with type 2 diabetes. APPL1, an adaptor protein, is involved in insulin actions in muscle cells and adipocytes. However, the physiological functions of APPL1 remain elusive. The major objective of this study was to investigate the role of APPL1 in insulin-induced inhibitory effects on gluconeogenesis in mouse models, and to investigate the cellular mechanisms involved. Methods: For the in-vitro study, primary rat hepatocytes were infected with adenovirus encoding full-length of APPL1 or APPL1-specific RNAi for 24 hours, followed by starvation for 24 hours, and then treated with 10 nM insulin for various time points. Total cell lysate was collected for both immunobloting and real-time PCR analysis. For the in-vivo study, male db/db diabetic or C57 wild-type mice were injected with the adenovirus encoding full-length APPL1 or APPL1-specific RNAi via tail vein, respectively. Basic metabolic parameters were measured, and insulin tolerance test and glucose tolerance test were performed. Results and conclusions: In rat hepatocytes, the effects of insulin on Akt phosphorylation and suppression of gluconeogenesis were markedly inhibited by adenovirus-mediated knockdown of APPL1, but were significantly enhanced by APPL1 overexpression. In db/db diabetic mice, hepatic overexpression of APPL1 alleviated hyperglycaemia and glucose intolerance, and increased insulin sensitivity. These metabolic changes were associated with increased Akt activation, and decreased expression of the key gluconeogenic genes in the liver. Conversely, specific knockdown of APPL1 expression in liver decreased insulin-mediated activation of Akt and induced a modest insulin resistance in C57 mice. Taken together, these data suggest that APPL1 is a key signalling molecule mediating the hepatic actions of insulin in suppression of gluconeogenesis via enhancing Akt activation. Acknowledgement: This work was supported by General Research Fund (HKU 779707M).-
dc.languageengen_HK
dc.publisherHong Kong Academy of Medicine Press.-
dc.relation.ispartofHong Kong Medical Journal-
dc.titleAPPL1 as a novel regulator of hepatic insulin sensitivity and 13 glucose homeostasis: molecular mechanism and physiological relevanceen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailCheng, KY: bc_ckyab@hotmail.comen_HK
dc.identifier.emailLam, KSL: ksllam@hku.hken_HK
dc.identifier.emailWang, Y: yuwanghk@hku.hken_HK
dc.identifier.emailZhu, W: zhuwd_ustc@hotmail.comen_HK
dc.identifier.emailHoo, RLC: hooruby@hotmail.comen_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.authorityLam, KSL=rp00343en_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.identifier.hkuros157715en_HK
dc.identifier.volume15-
dc.identifier.issuesuppl. 1-
dc.identifier.spage13, abstract no. 13-
dc.identifier.epage13, abstract no. 13-

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