PMID- 16283248 OWN - NLM STAT- MEDLINE DCOM- 20060216 LR - 20211203 IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 48 IP - 12 DP - 2005 Dec TI - Insulin signalling downstream of protein kinase B is potentiated by 5'AMP-activated protein kinase in rat hearts in vivo. PG - 2591-601 AB - AIMS/HYPOTHESIS: 5'AMP-activated protein kinase (AMPK) and insulin stimulate glucose transport in heart and muscle. AMPK acts in an additive manner with insulin to increase glucose uptake, thereby suggesting that AMPK activation may be a useful strategy for ameliorating glucose uptake, especially in cases of insulin resistance. In order to characterise interactions between the insulin- and AMPK-signalling pathways, we investigated the effects of AMPK activation on insulin signalling in the rat heart in vivo. METHODS: Male rats (350-400 g) were injected with 1 g/kg 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) or 250 mg/kg metformin in order to activate AMPK. Rats were administered insulin 30 min later and after another 30 min their hearts were removed. The activities and phosphorylation levels of components of the insulin-signalling pathway were subsequently analysed in individual rat hearts. RESULTS: AICAR and metformin administration activated AMPK and enhanced insulin signalling downstream of protein kinase B in rat hearts in vivo. Insulin-induced phosphorylation of glycogen synthase kinase 3 (GSK3) beta, p70 S6 kinase (p70S6K)(Thr389) and IRS1(Ser636/639) were significantly increased following AMPK activation. To the best of our knowledge, this is the first report of heightened insulin responses of GSK3beta and p70S6K following AMPK activation. In addition, we found that AMPK inhibits insulin stimulation of IRS1-associated phosphatidylinositol 3-kinase activity, and that AMPK activates atypical protein kinase C and extracellular signal-regulated kinase in the heart. CONCLUSIONS/INTERPRETATIONS: Our data are indicative of differential effects of AMPK on the activation of components in the cardiac insulin-signalling pathway. These intriguing observations are critical for characterisation of the crosstalk between AMPK and insulin signalling. FAU - Longnus, S L AU - Longnus SL AD - INSERM U145, IFR 50, Faculty of Medicine, Avenue de Valombrose, 06107,, Nice Cedex 2, France. vanobbeg@unice.fr FAU - Segalen, C AU - Segalen C FAU - Giudicelli, J AU - Giudicelli J FAU - Sajan, M P AU - Sajan MP FAU - Farese, R V AU - Farese RV FAU - Van Obberghen, E AU - Van Obberghen E LA - eng GR - R01 DK065969/DK/NIDDK NIH HHS/United States GR - R01-DK065969-01A1/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20051111 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (Blood Glucose) RN - 0 (Insulin) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Irs1 protein, rat) RN - 0 (Multienzyme Complexes) RN - 0 (Phosphoproteins) RN - 0 (Ribonucleotides) RN - 360-97-4 (Aminoimidazole Carboxamide) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - F0X88YW0YK (AICA ribonucleotide) SB - IM CIN - Diabetologia. 2005 Dec;48(12):2451-3. PMID: 16283241 MH - AMP-Activated Protein Kinases MH - Aminoimidazole Carboxamide/analogs & derivatives/pharmacology MH - Animals MH - Blood Glucose/analysis MH - Enzyme Activation/drug effects MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Heart/*physiology MH - Insulin/blood/pharmacology/*physiology MH - Insulin Receptor Substrate Proteins MH - Male MH - Metformin/pharmacology MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Multienzyme Complexes/*physiology MH - Myocardium/*enzymology MH - Phosphatidylinositol 3-Kinases/physiology MH - Phosphoproteins/physiology MH - Phosphorylation/drug effects MH - Protein Kinase C/physiology MH - Protein Serine-Threonine Kinases/*physiology MH - Proto-Oncogene Proteins c-akt/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Ribonucleotides/pharmacology MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction/*physiology EDAT- 2005/11/12 09:00 MHDA- 2006/02/17 09:00 CRDT- 2005/11/12 09:00 PHST- 2005/06/14 00:00 [received] PHST- 2005/08/11 00:00 [accepted] PHST- 2005/11/12 09:00 [pubmed] PHST- 2006/02/17 09:00 [medline] PHST- 2005/11/12 09:00 [entrez] AID - 10.1007/s00125-005-0016-3 [doi] PST - ppublish SO - Diabetologia. 2005 Dec;48(12):2591-601. doi: 10.1007/s00125-005-0016-3. Epub 2005 Nov 11.