Abstract
Original language | Undefined/Unknown |
---|---|
Pages (from-to) | 1799-1809 |
Number of pages | 11 |
Journal | Diabetologia |
Volume | 54 |
Issue number | 7 |
DOIs | |
Publication status | Published - 2011 |
Keywords
- Adipose
- AMP-activated protein kinase
- Biguanide
- Diabetes
- Glucose transport
- Insulin
- Metformin
- acetyl coenzyme A carboxylase
- adiponectin
- gliclazide
- glucose
- hydroxymethylglutaryl coenzyme A reductase kinase
- insulin
- metformin
- placebo
- serine
- sulfonylurea
- threonine
- triacylglycerol lipase
- absence of side effects
- adipocyte
- adipose tissue
- adult
- aged
- animal cell
- article
- clinical article
- controlled study
- crossover procedure
- diabetic diet
- double blind procedure
- drug mechanism
- enzyme activation
- enzyme activity
- enzyme phosphorylation
- glucose blood level
- human
- human cell
- human tissue
- lipid metabolism
- male
- monotherapy
- mouse
- non insulin dependent diabetes mellitus
- nonhuman
- priority journal
- protein blood level
- randomized controlled trial
- treatment duration
- Aged
- AMP-Activated Protein Kinases
- Cross-Over Studies
- Diabetes Mellitus, Type 2
- Gliclazide
- Humans
- Hypoglycemic Agents
- Male
- Middle Aged
Access to Document
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Diabetologia, Vol. 54, No. 7, 2011, p. 1799-1809.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin
T2 - a randomised glycaemia-controlled crossover study
AU - Boyle, J.G.
AU - Logan, P.J.
AU - Jones, G.C.
AU - Small, M.
AU - Sattar, N.
AU - Connell, J. M. C.
AU - Cleland, S.J.
AU - Salt, I.P.
N1 - Cited By (since 1996): 2 Export Date: 19 March 2012 Source: Scopus CODEN: DBTGA doi: 10.1007/s00125-011-2126-4 PubMed ID: 21455728 Language of Original Document: English Correspondence Address: Salt, I. P.; Institute of Cardiovascular and Medical Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom; email: [email protected] Chemicals/CAS: acetyl coenzyme A carboxylase, 9023-93-2; adiponectin, 283182-39-8; gliclazide, 21187-98-4; glucose, 50-99-7, 84778-64-3; hydroxymethylglutaryl coenzyme A reductase kinase, 172522-01-9, 72060-32-3; insulin, 9004-10-8; metformin, 1115-70-4, 657-24-9; serine, 56-45-1, 6898-95-9; threonine, 36676-50-3, 72-19-5; triacylglycerol lipase, 9001-62-1; AMP-Activated Protein Kinases, 2.7.11.1; Gliclazide, 21187-98-4; Hypoglycemic Agents; Metformin, 657-24-9 References: Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Moller, D.E., Role of AMP-activated protein kinase in mechanism of metformin action (2001) Journal of Clinical Investigation, 108 (8), pp. 1167-1174. , DOI 10.1172/JCI200113505; Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R.A., Montminy, M., Cantley, L.C., Medicine: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin (2005) Science, 310 (5754), pp. 1642-1646. , DOI 10.1126/science.1120781; Turner, R., Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) (1998) Lancet, 352 (9131), pp. 854-865. , DOI 10.1016/S0140-6736(98)07037-8; Hardie, D.G., AMPK: A key regulator of energy balance in the single cell and the whole organism (2008) Int J Obes, 32, pp. 7-S12. , 10.1038/ijo.2008.116 1:CAS:528:DC%2BD1cXhtVWnsLjJ; Zhang, B.B., Zhou, G., Li, C., AMPK: An emerging drug target for diabetes and the metabolic syndrome (2009) Cell Metab, 9, pp. 407-416. , 19416711 10.1016/j.cmet.2009.03.012; Sullivan, J.E., Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase (1994) FEBS Letters, 353 (1), pp. 33-36. , DOI 10.1016/0014-5793(94)01006-4; Garton, A.J., Yeaman, S.J., Identification and role of the basal phosphorylation site on hormone-sensitive lipase (1990) European Journal of Biochemistry, 191 (1), pp. 245-250. , DOI 10.1111/j.1432-1033.1990.tb19116.x; Corton, J.M., Gillespie, J.G., Hawley, S.A., Hardie, D.G., 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? (1995) Eur J Biochem, 229, pp. 558-565. , 7744080 10.1111/j.1432-1033.1995.tb20498.x 1:CAS:528:DyaK2MXltFOks78%3D; Daval, M., Diot-Dupuy, F., Bazin, R., Hainault, I., Viollet, B., Vaulont, S., Hajduch, E., Foufelle, F., Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes (2005) Journal of Biological Chemistry, 280 (26), pp. 25250-25257. , DOI 10.1074/jbc.M414222200; Koh, H.-J., Hirshman, M.F., He, H., Li, Y., Manabe, Y., Balschi, J.A., Goodyear, L.J., Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes (2007) Biochemical Journal, 403 (3), pp. 473-481. , DOI 10.1042/BJ20061479; Gauthier, M.S., Miyoshi, H., Souza, S.C., AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: Potential mechanism and physiological relevance (2008) J Biol Chem, 283, pp. 16514-16524. , 18390901 10.1074/jbc.M708177200 1:CAS:528:DC%2BD1cXmslOjtbo%3D; Villena, J.A., Viollet, B., Andreelli, F., Kahn, A., Vaulont, S., Sul, H.S., Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-a 2 subunit (2004) Diabetes, 53 (9), pp. 2242-2249. , DOI 10.2337/diabetes.53.9.2242; Habinowski, S.A., Witters, L.A., The effects of AICAR on adipocyte differentiation of 3T3-L1 cells (2001) Biochemical and Biophysical Research Communications, 286 (5), pp. 852-856. , DOI 10.1006/bbrc.2001.5484; Salt, I.P., Connell, J.M., Gould, G.W., 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes (2000) Diabetes, 49, pp. 1649-1656. , 11016448 10.2337/diabetes.49.10.1649 1:CAS:528:DC%2BD3cXntVyhtr0%3D; Gaidhu, M.P., Fediuc, S., Ceddia, R.B., 5-Aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes (2006) Journal of Biological Chemistry, 281 (36), pp. 25956-25964. , http://www.jbc.org/cgi/reprint/281/36/25956, DOI 10.1074/jbc.M602992200; Gaidhu, M.P., Perry, R.L., Noor, F., Ceddia, R.B., Disruption of AMPKa1 signaling prevents AICAR-induced inhibition of AS160/TBC1D4 phosphorylation and glucose uptake in primary rat adipocytes (2010) Mol Endocrinol, 24, pp. 1434-1440. , 20501641 10.1210/me.2009-0502 1:CAS:528:DC%2BC3cXpt1Cnt7w%3D; Chavez, J.A., Roach, W.G., Keller, S.R., Lane, W.S., Lienhard, G.E., Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation (2008) J Biol Chem, 283, pp. 9187-9195. , 18258599 10.1074/jbc.M708934200 1:CAS:528:DC%2BD1cXjslyru70%3D; Park, H., Kaushik, V.K., Constant, S., Prentki, M., Przybytkowski, E., Ruderman, N., Saha, A.K., Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3- phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise (2002) Journal of Biological Chemistry, 277 (36), pp. 32571-32577. , DOI 10.1074/jbc.M201692200; Sponarova, J., Mustard, K.J., Horakova, O., Flachs, P., Rossmeisl, M., Brauner, P., Bardova, K., Kopecky, J., Involvement of AMP-activated protein kinase in fat depot-specific metabolic changes during starvation (2005) FEBS Letters, 579 (27), pp. 6105-6110. , DOI 10.1016/j.febslet.2005.09.078, PII S001457930501197X; LeBrasseur, N.K., Kelly, M., Tsao, T.-S., Farmer, S.R., Saha, A.K., Ruderman, N.B., Tomas, E., Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues (2006) American Journal of Physiology - Endocrinology and Metabolism, 291 (1), pp. E175-E181. , http://ajpendo.physiology.org/cgi/reprint/291/1/E175, DOI 10.1152/ajpendo.00453.2005; Kola, B., Hubina, E., Tucci, S.A., Kirkham, T.C., Garcia, E.A., Mitchell, S.E., Williams, L.M., Korbonits, M., Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase (2005) Journal of Biological Chemistry, 280 (26), pp. 25196-25201. , DOI 10.1074/jbc.C500175200; Christ-Crain, M., Kola, B., Lolli, F., Fekete, C., Seboek, D., Wittmann, G., Feltrin, D., Korbonits, M., AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: A novel mechanism in Cushing's syndrome (2008) FASEB Journal, 22 (6), pp. 1672-1683. , http://www.fasebj.org/cgi/reprint/22/6/1672, DOI 10.1096/fj.07-094144; Gaidhu, M.P., Anthony, N.M., Patel, P., Hawke, T.J., Ceddia, R.B., Dysregulation of lipolysis and lipid metabolism in visceral and subcutaneous adipocytes by high-fat diet: Role of ATGL, HSL, and AMPK (2010) Am J Physiol Cell Physiol, 298, pp. 961-C971. , 20107043 10.1152/ajpcell.00547.2009 1:CAS:528:DC%2BC3cXksl2qtb8%3D; Kola, B., Christ-Crain, M., Lolli, F., Changes in adenosine 5'-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome (2008) J Clin Endocrinol Metab, 93, pp. 4969-4973. , 18782871 10.1210/jc.2008-1297 1:CAS:528:DC%2BD1cXhsVyqtbnF; Ota, S., Horigome, K., Ishii, T., Metformin suppresses glucose-6-phosphatase expression by a complex i inhibition and AMPK activation-independent mechanism (2009) Biochem Biophys Res Commun, 388, pp. 311-316. , 19664596 10.1016/j.bbrc.2009.07.164 1:CAS:528:DC%2BD1MXhtVOisrvL; Foretz, M., Hébrard, S., Leclerc, J., Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state (2010) J Clin Invest, 120, pp. 2355-2369. , 20577053 10.1172/JCI40671 1:CAS:528:DC%2BC3cXovFarsbc%3D; Musi, N., Hirshman, M.F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., Zhou, G., Goodyear, L.J., Metformin increases AMP-activated protein-kinase activity in skeletal muscle of subjects with type 2 diabetes (2002) Diabetes, 51 (7), pp. 2074-2081; Boyle, J.G., Logan, P.J., Ewart, M.A., Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase (2008) J Biol Chem, 283, pp. 11210-11217. , 18303014 10.1074/jbc.M710048200 1:CAS:528:DC%2BD1cXkvVSgsLg%3D; Nelson, S.M., Freeman, D.J., Sattar, N., Lindsay, R.S., Role of adiponectin in matching of fetal and placental weight in mothers with type 1 diabetes (2008) Diabetes Care, 31, pp. 1123-1125. , 18339975 10.2337/dc07-2195 1:CAS:528:DC%2BD1cXotVantr8%3D; Huang, Y.C., Chang, W.L., Huang, S.F., Lin, C.Y., Lin, H.C., Chang, T.C., Pachymic acid stimulates glucose uptake through enhanced GLUT4 expression and translocation (2010) Eur J Pharmacol, 648, pp. 39-49. , 20816811 10.1016/j.ejphar.2010.08.021 1:CAS:528:DC%2BC3cXht1OgsL%2FN; Wu, X., Motoshima, H., Mahadev, K., Stalker, T.J., Scalia, R., Goldstein, B.J., Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes (2003) Diabetes, 52 (6), pp. 1355-1363. , DOI 10.2337/diabetes.52.6.1355; Phillips, S.A., Ciaraldi, T.P., Kong, A.P.S., Bandukwala, R., Aroda, V., Carter, L., Baxi, S., Henry, R.R., Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy (2003) Diabetes, 52 (3), pp. 667-674. , DOI 10.2337/diabetes.52.3.667; Drzewoski, J., Zurawska-Klis, M., Effect of gliclazide modified release on adiponectin, interleukin-6, and tumor necrosis factor-a plasma levels in individuals with type 2 diabetes mellitus (2006) Current Medical Research and Opinion, 22 (10), pp. 1921-1926. , DOI 10.1185/030079906X132424; Huypens, P., Quartier, E., Pipeleers, D., Van De Casteele, M., Metformin reduces adiponectin protein expression and release in 3T3-L1 adipocytes involving activation of AMP activated protein kinase (2005) European Journal of Pharmacology, 518 (2-3), pp. 90-95. , DOI 10.1016/j.ejphar.2005.06.016, PII S0014299905006680; Bourron, O., Daval, M., Hainault, I., Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase (2010) Diabetologia, 53, pp. 768-778. , 20043143 10.1007/s00125-009-1639-6 1:CAS:528:DC%2BC3cXis1Cmu7o%3D; Hong, Y., Rohatagi, S., Habtemariam, B., Walker, J.R., Schwartz, S.L., Mager, D.E., Population exposure-response modeling of metformin in patients with type 2 diabetes mellitus (2008) Journal of Clinical Pharmacology, 48 (6), pp. 696-707. , DOI 10.1177/0091270008316884; Ranganathan, G., Unal, R., Pokrovskaya, I., Yao-Borengasser, A., Phanavanh, B., Lecka-Czernik, B., Rasouli, N., Kern, P.A., The lipogenic enzymes DGAT1, FAS, and LPL in adipose tissue: Effects of obesity, insulin resistance, and TZD treatment (2006) Journal of Lipid Research, 47 (11), pp. 2444-2450. , http://www.jlr.org/cgi/reprint/47/11/2444, DOI 10.1194/jlr.M600248-JLR200; Ciaraldi, T.P., Kong, A.P.S., Chu, N.V., Kim, D.D., Baxi, S., Loviscach, M., Plodkowski, R., Henry, R.R., Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects (2002) Diabetes, 51 (1), pp. 30-36; Abbasi, F., Carantoni, M., Chen, Y.-D.I., Reaven, G.M., Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin (1998) Diabetes Care, 21 (8), pp. 1301-1305. , DOI 10.2337/diacare.21.8.1301; James, A.P., Watts, G.F., Mamo, J.C.L., The effect of metformin and rosiglitazone on postprandial lipid metabolism in obese insulin-resistant subjects (2005) Diabetes, Obesity and Metabolism, 7 (4), pp. 381-389. , DOI 10.1111/j.1463-1326.2004.00407.x; Mooney, M.H., Fogarty, S., Stevenson, C., Gallagher, A.M., Palit, P., Hawley, S.A., Hardie, D.G., Furman, B.L., Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice (2008) British Journal of Pharmacology, 153 (8), pp. 1669-1677. , DOI 10.1038/bjp.2008.37, PII BJP200837; Fischer, M., Timper, K., Radimerski, T., Metformin induces glucose uptake in human preadipocyte-derived adipocytes from various fat depots (2010) Diab Obes Metab, 12, pp. 356-359. , 10.1111/j.1463-1326.2009.01169.x 1:CAS:528:DC%2BC3cXltVahtrc%3D; Jensterle, M., Janez, A., Mlinar, B., Marc, J., Prezelj, J., Pfeifer, M., Impact of metformin and rosiglitazone treatment on glucose transporter 4 mRNA expression in women with polycystic ovary syndrome (2008) European Journal of Endocrinology, 158 (6), pp. 793-801. , DOI 10.1530/EJE-07-0857; Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Araki, E., Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells (2006) Diabetes, 55 (1), pp. 120-127. , http://diabetes.diabetesjournals.org/cgi/reprint/55/1/120, DOI 10.2337/diabetes.55.1.120; Nath, N., Khan, M., Paintlia, M.K., Singh, I., Hoda, M.N., Giri, S., Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis (2009) J Immunol, 182, pp. 8005-8014. , 19494326 10.4049/jimmunol.0803563 1:CAS:528:DC%2BD1MXmslCntb8%3D; Dagon, Y., Avraham, Y., Berry, E.M., AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2a in adipocytes (2006) Biochemical and Biophysical Research Communications, 340 (1), pp. 43-47. , DOI 10.1016/j.bbrc.2005.11.159, PII S0006291X05027117; Ewart, M.A., Kohlhaas, C.F., Salt, I.P., Inhibition of TNFa-stimulated monocyte adhesion to human aortic endothelial cells by AMP-activated protein kinase (2008) Arterioscler Thromb Vasc Biol, 28, pp. 2255-2257. , 18802013 10.1161/ATVBAHA.108.175919 1:CAS:528:DC%2BD1cXhtlKrtr%2FN; Yang, Z., Kahn, B.B., Shi, H., Xue, B.Z., Macrophage a1 AMP-activated protein kinase (a1AMPK) antagonizes fatty acid-induced inflammation through SIRT1 (2010) J Biol Chem, 285, pp. 19051-19059. , 20421294 10.1074/jbc.M110.123620 1:CAS:528:DC%2BC3cXnt1Cnt7s%3D
PY - 2011
Y1 - 2011
N2 - Aims/hypothesis: The hypoglycaemic actions of metformin have been proposed to be mediated by hepatic AMP-activated protein kinase (AMPK). As the effects of metformin and the role of AMPK in adipose tissue remain poorly characterised, we examined the effect of metformin on AMPK activity in adipose tissue of individuals with type 2 diabetes in a randomised glycaemia-controlled crossover study. Methods: Twenty men with type 2 diabetes (aged 50-70 years) treated with diet, metformin or sulfonylurea alone were recruited from North Glasgow University National Health Service Trusts' diabetes clinics and randomised to either metformin or gliclazide for 10 weeks. Randomisation codes, generated by computer, were put into sealed envelopes and stored by the hospital pharmacist. Medication bottles were numbered, and allocation was done in sequence. The participants and investigators were blinded to group assignment. At the end of each phase of therapy adipose biopsy, AMPK activity (primary endpoint) and levels of lipid metabolism and signalling proteins were assessed. In parallel, the effect of metformin on AMPK and insulin-signalling pathways was investigated in 3T3-L1 adipocytes. Results: Ten participants were initially randomised to metformin and subsequently crossed over to gliclazide, while ten participants were initially randomised to gliclazide and subsequently crossed over to metformin. No participants discontinued the intervention and the adipose tissue AMPK activity was analysed in all 20 participants. There were no adverse events or side effects in the study group. Adipose AMPK activity was increased following metformin compared with gliclazide therapy (0.057 ± 0.007 vs 0.030 ± 0.005 [mean ± SEM] nmol min-1 [mg lysate] -1; p < 0.005), independent of AMPK level, glycaemia or plasma adiponectin concentrations. The increase was associated with reduced levels of acetyl-CoA carboxylase (ACC) protein and increased ACC Ser80 phosphorylation. In 3T3-L1 adipocytes, metformin reduced levels of ACC protein and stimulated phosphorylation of AMPK Thr172 and hormone-sensitive lipase Ser565. Conclusions: These results provide the first evidence that metformin activates AMPK and reduces ACC protein levels in human adipose tissue in vivo. Future studies are required to assess the role of adipose AMPK activation in the pharmacological effects of metformin. Trial registration: ISRCTN51336867 Funding: This work was supported by grants from the British Heart Foundation, TENOVUS-Scotland, the Biotechnology and Biological Sciences Research Council and Diabetes UK. © 2011 Springer-Verlag.
AB - Aims/hypothesis: The hypoglycaemic actions of metformin have been proposed to be mediated by hepatic AMP-activated protein kinase (AMPK). As the effects of metformin and the role of AMPK in adipose tissue remain poorly characterised, we examined the effect of metformin on AMPK activity in adipose tissue of individuals with type 2 diabetes in a randomised glycaemia-controlled crossover study. Methods: Twenty men with type 2 diabetes (aged 50-70 years) treated with diet, metformin or sulfonylurea alone were recruited from North Glasgow University National Health Service Trusts' diabetes clinics and randomised to either metformin or gliclazide for 10 weeks. Randomisation codes, generated by computer, were put into sealed envelopes and stored by the hospital pharmacist. Medication bottles were numbered, and allocation was done in sequence. The participants and investigators were blinded to group assignment. At the end of each phase of therapy adipose biopsy, AMPK activity (primary endpoint) and levels of lipid metabolism and signalling proteins were assessed. In parallel, the effect of metformin on AMPK and insulin-signalling pathways was investigated in 3T3-L1 adipocytes. Results: Ten participants were initially randomised to metformin and subsequently crossed over to gliclazide, while ten participants were initially randomised to gliclazide and subsequently crossed over to metformin. No participants discontinued the intervention and the adipose tissue AMPK activity was analysed in all 20 participants. There were no adverse events or side effects in the study group. Adipose AMPK activity was increased following metformin compared with gliclazide therapy (0.057 ± 0.007 vs 0.030 ± 0.005 [mean ± SEM] nmol min-1 [mg lysate] -1; p < 0.005), independent of AMPK level, glycaemia or plasma adiponectin concentrations. The increase was associated with reduced levels of acetyl-CoA carboxylase (ACC) protein and increased ACC Ser80 phosphorylation. In 3T3-L1 adipocytes, metformin reduced levels of ACC protein and stimulated phosphorylation of AMPK Thr172 and hormone-sensitive lipase Ser565. Conclusions: These results provide the first evidence that metformin activates AMPK and reduces ACC protein levels in human adipose tissue in vivo. Future studies are required to assess the role of adipose AMPK activation in the pharmacological effects of metformin. Trial registration: ISRCTN51336867 Funding: This work was supported by grants from the British Heart Foundation, TENOVUS-Scotland, the Biotechnology and Biological Sciences Research Council and Diabetes UK. © 2011 Springer-Verlag.
KW - Adipose
KW - AMP-activated protein kinase
KW - Biguanide
KW - Diabetes
KW - Glucose transport
KW - Insulin
KW - Metformin
KW - acetyl coenzyme A carboxylase
KW - adiponectin
KW - gliclazide
KW - glucose
KW - hydroxymethylglutaryl coenzyme A reductase kinase
KW - insulin
KW - metformin
KW - placebo
KW - serine
KW - sulfonylurea
KW - threonine
KW - triacylglycerol lipase
KW - absence of side effects
KW - adipocyte
KW - adipose tissue
KW - adult
KW - aged
KW - animal cell
KW - article
KW - clinical article
KW - controlled study
KW - crossover procedure
KW - diabetic diet
KW - double blind procedure
KW - drug mechanism
KW - enzyme activation
KW - enzyme activity
KW - enzyme phosphorylation
KW - glucose blood level
KW - human
KW - human cell
KW - human tissue
KW - lipid metabolism
KW - male
KW - monotherapy
KW - mouse
KW - non insulin dependent diabetes mellitus
KW - nonhuman
KW - priority journal
KW - protein blood level
KW - randomized controlled trial
KW - treatment duration
KW - Aged
KW - AMP-Activated Protein Kinases
KW - Cross-Over Studies
KW - Diabetes Mellitus, Type 2
KW - Gliclazide
KW - Humans
KW - Hypoglycemic Agents
KW - Male
KW - Middle Aged
U2 - 10.1007/s00125-011-2126-4
DO - 10.1007/s00125-011-2126-4
M3 - Article
C2 - 21455728
SN - 0012-186X
VL - 54
SP - 1799
EP - 1809
JO - Diabetologia
JF - Diabetologia
IS - 7
ER -