Rosiglitazone 4mg tablets

BACKGROUND: Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined. METHODS: We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes. RESULTS: Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). CONCLUSIONS: Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

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Rosiglitazone has been proposed as a treatment strategy for type 2 diabetes mellitus (T2DM), and it could provide robust glucose-lowering capability with risk of cardiovascular events. We thus performed a systematic review and meta-analysis of controlled trials to assess the effect of this treatment on glycaemic control and cardiovascular events in patients with T2DM. We systematically search PubMed, Embase, and the Cochrane Central Register of Controlled Trials comparing rosiglitazone to other anti-diabetic treatments. These studies included randomised controlled trials (RCTs), cohort studies, and case-control studies that had treatment with at least six months of follow-up in patients with T2DM. We aimed to evaluate the long-term effect on cardiovascular risk of rosiglitazone compared with a basal insulin drug. The main outcomes included myocardial infarction, heart failure, stroke, cardiovascular mortality, and all-cause mortality. We included 11RCTs and four observational studies involving 20,079 individuals with T2DM allocated to rosiglitazone and a similar number to comparison groups of which only five compared rosiglitazone with placebo and collected data on cardiovascular outcomes. Among patients with T2DM, rosiglitazone is associated with a significantly increased risk of heart failure, with little increased risk of myocardial infarction, without a significantly increased risk of stroke, cardiovascular mortality, and all-cause mortality compared with placebo or active controls. Alternative methods to reduce the uncertainty in long-term pragmatic evaluations, inclusion of rosiglitazone in factorial trials, publication of cardiovascular outcome data from adverse event reporting in trials of rosiglitazone and a cardiovascular endpoint trial of rosiglitazone among people without diabetes.

Abstract licence: CC BY-NC-ND

The therapeutic targeting of peroxisome proliferator-activated receptor gamma (PPARγ) for type 2 diabetes (T2D) remains a double-edged sword: while thiazolidinediones are efficacious, their severe side effects necessitate the discovery of safer modulators. We propose a novel nutrient-centred hypothesis that thiamine (vitamin B1), an essential micronutrient, may act as a natural ligand for PPARγ. To investigate this, we adopted a translational approach. Molecular docking and dynamics simulations established that thiamine forms a stable, high-affinity interaction with the PPARγ ligand-binding domain. Functionally, in 3T3-L1 adipocytes, thiamine induced adipogenesis and PPARγ-response element binding with a potency analogous to rosiglitazone, suggesting direct agonistic activity. Corroborating these mechanistic insights at the clinical level, a new meta-analysis of randomized controlled trials demonstrates that high-dose benfotiamine, a synthetic thiamine derivative, significantly improves neuropathic and vascular outcomes in T2D patients. While the contribution of thiamine’s established antioxidant effects to these clinical benefits cannot be ruled out, the synergy of computational, cellular, and human evidence provides a compelling foundation for our hypothesis. This study suggests that thiamine could act as a PPARγ ligand and serve as a safer treatment option for metabolic disorders, which needs to be tested in vivo .

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AMP-activated protein kinase (AMPK) is activated within the cell in response to multiple stresses that increase the intracellular AMP:ATP ratio. Here we show that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK. This finding raises the possibility that a number of the beneficial effects of the thiazolidinediones could be mediated via activation of AMPK. Furthermore, we show that in addition to the classical activation pathway, AMPK can also be stimulated without changing the levels of adenine nucleotides. In muscle cells, both hyperosmotic stress and the anti-diabetic agent, metformin, activate AMPK in the absence of any increase in the AMP:ATP ratio. However, although activation is no longer dependent on this ratio, it still involves increased phosphorylation of threonine 172 within the catalytic (α) subunit. AMPK stimulation in response to hyperosmotic stress does not appear to involve phosphatidylinositol 3-phosphate kinase, protein kinase C, mitogen-activated protein (MAP) kinase kinase, or p38 MAP kinase α or β. Our results demonstrate that AMPK can be activated by at least two distinct signaling mechanisms and suggest that it may play a wider role in the cellular stress response than was previously understood. AMP-activated protein kinase (AMPK) is activated within the cell in response to multiple stresses that increase the intracellular AMP:ATP ratio. Here we show that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK. This finding raises the possibility that a number of the beneficial effects of the thiazolidinediones could be mediated via activation of AMPK. Furthermore, we show that in addition to the classical activation pathway, AMPK can also be stimulated without changing the levels of adenine nucleotides. In muscle cells, both hyperosmotic stress and the anti-diabetic agent, metformin, activate AMPK in the absence of any increase in the AMP:ATP ratio. However, although activation is no longer dependent on this ratio, it still involves increased phosphorylation of threonine 172 within the catalytic (α) subunit. AMPK stimulation in response to hyperosmotic stress does not appear to involve phosphatidylinositol 3-phosphate kinase, protein kinase C, mitogen-activated protein (MAP) kinase kinase, or p38 MAP kinase α or β. Our results demonstrate that AMPK can be activated by at least two distinct signaling mechanisms and suggest that it may play a wider role in the cellular stress response than was previously understood. AMP-activated protein kinase 5-amino-4-imidazolecarboxamide AICA riboside dinitrophenol mitogen-activated protein the synthetic peptide corresponding to the amino acid sequence HMRSAMSGL- HLVKRR The AMP-activated protein kinase (AMPK)1 plays a key role in the regulation of metabolism within the muscle cell and has been implicated as a potential target in type 2 diabetes mellitus and in obesity (1Winder W.W. Hardie D.G. Am. J. Physiol. 1999; 277: 1-10PubMed Google Scholar, 2Moller D.E. Nature. 2001; 414: 821-827Crossref PubMed Scopus (893) Google Scholar, 3Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1679) Google Scholar). AMPK is a heterotrimeric complex consisting of a catalytic (α) subunit and two regulatory subunits (β and γ) (4Woods A. Cheung P.C.F. Smith F.C. Davison M.D. Scott J. Beri R.K. Carling D. J. Biol. Chem. 1996; 271: 10282-10290Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar). Isoforms of all three subunits have been identified, including two isoforms of the catalytic subunit, α1 and α2 (5Stapleton D. Mitchelhill K.I. Gao G. Widmer J. Michell B.J. Teh T. House C.M. Fernandez C.S. Cox T. Witters L.A. Kemp B.E. J. Biol. Chem. 1996; 271: 611-614Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar). Previous studies have shown that AMPK is activated following depletion of cellular ATP together with a concomitant rise in AMP (6Corton J.M. Gillespie J.G. Hardie D.G. Curr. Biol. 1994; 4: 315-324Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 7Hardie D.G. Salt I.P. Hawley S.A. Davies S.P. Biochem. J. 1999; 338: 717-722Crossref PubMed Scopus (317) Google Scholar). An increase in the AMP:ATP ratio causes increased phosphorylation of AMPK on threonine residue 172 within the α subunit by an as yet poorly characterized upstream kinase (8Hawley S.A. Davison M.D. Woods A. Davies S.P. Beri R.K. Carling D. Hardie D.G. J. Biol. Chem. 1996; 271: 27879-27887Abstract Full Text Full Text PDF PubMed Scopus (1009) Google Scholar). In response to activation, AMPK switches off ATP-utilizing pathways and switches on ATP-producing pathways. These combined actions have led to the proposal that AMPK acts as a cellular fuel gauge (9Hardie D.G. Carling D. Eur. J. Biochem. 1997; 246: 259-273Crossref PubMed Scopus (1141) Google Scholar, 10Hardie D.G. Carling D. Carlson M. Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1276) Google Scholar). A number of physiological and pathophysiological stimuli that lead to an increase in the AMP:ATP ratio within the cell have been demonstrated to activate AMPK, including muscle contraction, heat shock, metabolic poisoning, and ischemia (6Corton J.M. Gillespie J.G. Hardie D.G. Curr. Biol. 1994; 4: 315-324Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 11Fryer L. Hajduch E. Rencurel F. Salt I. Hundal H. Hardie D. Carling D. Diabetes. 2000; 49: 1978-1985Crossref PubMed Scopus (159) Google Scholar, 12Hayashi T. Hirshman M. Fujii N. Habinowski S. Witters L. Goodyear L. Diabetes. 2000; 49: 527-531Crossref PubMed Scopus (380) Google Scholar, 13Marsin A. Bertrand L. Rider M. Deprez J. Beauloye C. Vincent M. Van den Berghe G. Carling D. Hue L. Curr. Biol. 2000; 10: 1247-1255Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar). Although activation of AMPK appears to be a direct consequence of an increase in the AMP:ATP ratio, it is not clear whether there are other signals, which do not involve changes in adenine nucleotide levels, that can lead to activation of AMPK. Recently, Zhou et al. (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar) demonstrated the activation of AMPK by metformin in both hepatocytes and skeletal muscle. Metformin, one of the most widely used oral drugs for the treatment of type 2 diabetes, decreases hyperglycemia and has beneficial effects on circulating lipids, without affecting insulin secretion (15Wu M.S. Johnston P. Sheu W.H.H. Hollenbeck C.B. Jeng C.Y. Goldfine I.D. Chen Y.D.I. Reaven G.M. Diabetes Care. 1990; 13: 1-8Crossref PubMed Scopus (210) Google Scholar, 16Stumvoll M. Nurjhan N. Perriello G. Dailey G. Gerich J.E. New Engl. J. Med. 1995; 333: 550-554Crossref PubMed Scopus (1015) Google Scholar). The glucose lowering effects of metformin are attributable to both an increase in muscle glucose uptake (17Hundal H.S. Ramal T. Reyes R. Leiter L.A. Klip A. Endocrinology. 1992; 131: 1165-1173Crossref PubMed Scopus (143) Google Scholar) and a decrease in hepatic glucose production (16Stumvoll M. Nurjhan N. Perriello G. Dailey G. Gerich J.E. New Engl. J. Med. 1995; 333: 550-554Crossref PubMed Scopus (1015) Google Scholar, 18Hundal R.S. Krssak M. Dufour S. Laurent D. Lebon V. Chandramouli V. Inzucchi S.E. Schumann W.C. Petersen K.F. Landau B.R. Shulman G.I. Diabetes. 2000; 49: 2063-2069Crossref PubMed Scopus (816) Google Scholar). Activation of AMPK by metformin was found to be required for the decrease in glucose production and the increase in fatty acid oxidation in hepatocytes and for the increase in glucose uptake in skeletal muscle (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar). In addition, we have recently shown that the stimulation of fatty acid oxidation in skeletal muscle by leptin occurs following a biphasic activation of AMPK (3Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1679) Google Scholar). For both metformin and leptin, it was not clear whether the mechanism leading to activation of AMPK involved a significant decrease in ATP levels (3Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1679) Google Scholar,14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar). In this study we report that in muscle cells AMPK can be activated by two distinct pathways: one that involves changes in the AMP:ATP ratio and one that is independent of this ratio. Furthermore, we report the novel finding that AMPK is activated acutely by the thiazolidinedione, rosiglitazone via the AMP:ATP-dependent pathway. These results will aid further work on the potential benefit of therapeutic agents aimed at targeting AMPK in diseases such as type 2 diabetes and obesity. H-2Kb cells were derived from skeletal muscle of heterozygous H-2Kb tsA58 transgenic mice (19Jat P.S. Noble M.D. Ataliotis P. Tanaka Y. Yannoutsos N. Larse L. Kioussis D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 5096-5100Crossref PubMed Scopus (628) Google Scholar). Myoblasts were maintained under permissive conditions in Dulbecco's modified medium containing heat-inactivated fetal calf serum (20% (v/v)), chick embryo extract (2% (v/v)),l-glutamine (2% (v/v)), and penicillin/streptomycin (1% (w/v)) at 33 °C in the presence of was following a to conditions by of and incubation at °C J.E. M. Ataliotis P. P.S. Noble M.D. Biol. 1994; PubMed Scopus Google Scholar). For all cells were for containing fetal calf and AMPK α1 and α2 was in H-2Kb cell as previously L. Hajduch E. Rencurel F. Salt I. Hundal H. Hardie D. Carling D. Diabetes. 2000; 49: 1978-1985Crossref PubMed Scopus (159) Google Scholar). cells were for at °C in containing glucose in the presence or absence of rosiglitazone, 2 metformin, 5-amino-4-imidazolecarboxamide dinitrophenol or as in the this cells were in and by addition of of was by at for the and protein the AMPK were from and of protein by incubation with an to protein for 2 at AMPK were from the of this incubation by with an to protein For AMPK were a to protein AMPK in the was by the peptide S.P. Carling D. Hardie D.G. Eur. J. Biochem. PubMed Scopus Google Scholar). of protein as were by on or and to were in for at were with an or an in this at °C and with The were for at with by were and a was H-2Kb cells were in addition of of acid was by at for 2 acid was from the by three with of a of and were by on a on a The was in and with a from to containing at a of were by at and with the of under the AMP and ATP were by and used to the AMP:ATP have previously shown that AMPK is activated in H-2Kb muscle cells in response to a number of L. Hajduch E. Rencurel F. Salt I. Hundal H. Hardie D. Carling D. Diabetes. 2000; 49: 1978-1985Crossref PubMed Scopus (159) Google and results have other of AMPK in including metformin (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar) and leptin (3Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1679) Google Scholar). Here we show that incubation of H-2Kb muscle cells with the thiazolidinedione, rosiglitazone, leads to a activation of AMPK. the of of rosiglitazone on the of and AMPK in H-2Kb muscle Activation was at with activation at a and rosiglitazone following a a stimulation by rosiglitazone to with However, the activation of to rosiglitazone, with a stimulation at with for the and the for activation of AMPK was for of AMPK by rosiglitazone A 2 that activation of AMPK is by an increase in the phosphorylation of threonine 172 within the α subunit, an that the of this residue J. M. Biol. 2001; Google Scholar). Previous studies have shown that threonine 172 is the phosphorylation within AMPK (8Hawley S.A. Davison M.D. Woods A. Davies S.P. Beri R.K. Carling D. Hardie D.G. J. Biol. Chem. 1996; 271: 27879-27887Abstract Full Text Full Text PDF PubMed Scopus (1009) Google Scholar). also that phosphorylation of was increased in with AMPK and phosphorylation 2 These demonstrate that activation of AMPK by rosiglitazone leads to effects on of activation of AMPK and phosphorylation of AMPK and in response to H-2Kb cells were with rosiglitazone for and AMPK in and was shown are the from two independent which by than C, protein of H-2Kb cell with rosiglitazone for the were by and with for 172 within the AMPK α subunit or In addition to a number of cellular stresses that ATP production D.G. Carling D. Carlson M. Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1276) Google AMPK has recently been shown to be activated in response to metformin (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar). The finding that rosiglitazone also AMPK to the of whether stimulation of AMPK in muscle occurs the in response to by the possibility of effects on AMPK activation in response to we have previously both and are activated following incubation of H-2Kb muscle cells with AICA in response to hyperosmotic stress in the presence of and following incubation with the agent, activation of both and by was at a of the not in any further increase in AMPK not of cells in the presence of AICA riboside and not increase AMPK to cells with In treatment of cells with and in a and increase in the of both and the stimulation with stress a on the stimulation of AMPK by AICA riboside AICA riboside is within the cell to the which in cells can to levels and the actions of AMP on AMPK J.E. F. Carling D. Beri R.K. 1994; PubMed Scopus Google Scholar, J.M. Gillespie J.G. Hawley S.A. Hardie D.G. Eur. J. Biochem. 1995; PubMed Scopus Google Scholar). The effects of hyperosmotic stress and or AICA riboside suggest that mechanisms of AMPK the finding that there is no on AMPK with AICA riboside and treatment is with both a In with a report (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar) we found that incubation of muscle cells with 2 metformin led to a significant increase in the of both and with the we also found that in muscle cells metformin a on than The results to that pathways for activation of AMPK further this possibility we the levels of adenine in cells with stimuli that activate AMPK. can be from the shown in incubation with causes a increase in the of AMP with A increase in AMP is following incubation of cells with rosiglitazone In to hyperosmotic stress and metformin do not lead to a in nucleotide levels with cells The intracellular AMP:ATP following were by of the AMP and ATP and are in the possibility that the effects of hyperosmotic stress and metformin on AMPK activation were to a increase in the AMP:ATP ratio, we the of required to an increase in AMPK to and the AMP:ATP ratio under the of at which AMPK is stimulated to the as following hyperosmotic stress the AMP:ATP ratio than to at the of required to activate AMPK to the as by metformin, the AMP:ATP ratio was that of the with studies in muscle cells L. Hajduch E. Rencurel F. Salt I. Hundal H. Hardie D. Carling D. Diabetes. 2000; 49: 1978-1985Crossref PubMed Scopus (159) Google incubation with AICA riboside in the of a from the at the as AMP in we were to the AMP:ATP ratio following incubation with AICA However, as can be from the AICA riboside treatment does not a in the levels of ATP and with in H-2Kb cells following AICA from acid of were by The under the AMP and ATP were and used to the AMP:ATP ratio. In the are the S.E. from three to independent was not to the for cells with AICA riboside the the AMP in a from acid of were by The under the AMP and ATP were and used to the AMP:ATP ratio. In the are the S.E. from three to independent was not to the for cells with AICA riboside the the AMP of threonine 172 within the α subunit of AMPK was increased following treatment with and rosiglitazone both of which increase the AMP:ATP ratio. In addition, hyperosmotic stress and metformin, which do not nucleotide levels, also increased threonine 172 that both the and mechanisms of AMPK involve phosphorylation at this stress in addition to a increase in phosphorylation with the direct of the not any for this the effects of hyperosmotic stress and on AMPK appear to be suggest that phosphorylation may be involved in the activation of AMPK. the mechanisms leading to activation of AMPK following an increase in the AMP:ATP ratio are D.G. Salt I.P. Hawley S.A. Davies S.P. Biochem. J. 1999; 338: 717-722Crossref PubMed Scopus (317) Google Scholar, D. Hardie D.G. Eur. J. Biochem. PubMed Scopus Google S.A. Carling D. Hardie D.G. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google the mechanisms that to activate AMPK in response to hyperosmotic stress or metformin, that do not the intracellular levels of adenine are the effects of metformin on intracellular signaling pathways have not been hyperosmotic stress has been shown previously to activate a number of of signaling including phosphatidylinositol J. M. A. C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google protein kinase A. H. J. Eur. J. Clin. Invest. 2000; PubMed Scopus Google mitogen-activated protein (MAP) kinase, and MAP kinase kinase in P. Biol. 1997; Full Text PDF PubMed Scopus Google Scholar). the of a number of of pathways on the activation of AMPK by hyperosmotic was used to signaling phosphatidylinositol to the MAP kinase pathway, to the p38 α and MAP kinase isoforms and the to protein kinase S.P. H. M. P. Biochem. J. 2000; Scopus Google Scholar). can be in of the used any significant on AMPK that activation in response to hyperosmotic stress does not any of pathways. studies will be to the mechanisms by which this nucleotide independent activation of AMPK results the that rosiglitazone, a of the of anti-diabetic AMPK in muscle a mechanism an increase in the AMP:ATP ratio. The of rosiglitazone on cellular adenine nucleotide levels is a increase in the AMP:ATP ratio as that by a of Although the mechanism by which rosiglitazone leads to a in nucleotide levels is thiazolidinediones have been to acutely fuel oxidation in skeletal muscle F. S. M. L. C. Diabetes. 2001; PubMed Scopus Google the for this is not understood. of fuel oxidation is to for the in nucleotide levels in study to be it that such a mechanism will play at least role in the Although we have the of rosiglitazone on AMPK, all the were found to oxidation in muscle F. S. M. L. C. Diabetes. 2001; PubMed Scopus Google that activation of AMPK may be a of the of The thiazolidinediones are a of anti-diabetic that have been shown to glucose and insulin levels and of the of metabolism with type 2 diabetes S. Annu. Rev. Med. 2001; PubMed Scopus Google Scholar). The beneficial actions of the thiazolidinediones have been to effects on the in S. Annu. Rev. Med. 2001; PubMed Scopus Google Scholar, Diabetes. 1998; PubMed Scopus Google Scholar). An increase in insulin in skeletal has also been with S.E. D.G. V. Shulman G.I. N. Engl. J. Med. 1998; 338: PubMed Scopus Google Scholar) and in skeletal muscle cell A. J.M. M. 1990; Full Text PDF PubMed Scopus Google Scholar). studies on transgenic of have that thiazolidinediones do not significant levels of to insulin and that there are direct effects of on other most skeletal muscle S. K.I. J. J. S. J. Clin. Invest. 1997; PubMed Scopus Google Scholar). Our results activation of AMPK by rosiglitazone a number of the mechanisms the beneficial effects of the in the treatment of type 2 AMPK has been shown to be involved in the regulation of in the (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar, A. D. M. S. P. P. F. Carling D. Biol. 2000; PubMed Scopus Google Scholar). In skeletal activation of AMPK E. J. Physiol. 1999; PubMed Scopus Google Scholar) or of a of AMPK F. S.A. Woods A. Carling D. Biochem. J. 2002; PubMed Scopus Google Scholar) has been shown to increase the of a number of that lead to an increase in insulin These effects with of the actions of the including an increase in glucose levels in muscle cells S. 1994; Full Text PDF PubMed Scopus Google Scholar). Furthermore, rosiglitazone has been to decrease in a number of cell in a M. T. Diabetes. 1999; PubMed Scopus Google Scholar). a key in the of is and by AMPK and was one of the for the kinase D. Hardie D.G. PubMed Scopus Google Scholar). Here we show that rosiglitazone both and AMPK and this leads to a increase in the phosphorylation of there have been no to suggest that the activation of AMPK occurs in the absence of it that the phosphorylation of all will be increased following stimulation of AMPK by In this study we have the effects of rosiglitazone on AMPK, and it to be the longer effects on the kinase However, stimulation of AMPK by AICA riboside has been shown to have effects in muscle E. J. Physiol. 1999; PubMed Scopus Google and it is that results be with Our the possibility that a number of the beneficial effects of the thiazolidinediones may be mediated activation of AMPK. The classical for activation of AMPK involves an increase in the intracellular AMP:ATP ratio (9Hardie D.G. Carling D. Eur. J. Biochem. 1997; 246: 259-273Crossref PubMed Scopus (1141) Google Scholar, 10Hardie D.G. Carling D. Carlson M. Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1276) Google Scholar). However, a number of studies have that other pathways also lead to activation of the Activation of in 1998; PubMed Scopus Google Scholar) or in cells T. M. M. A. H. Kemp B.E. Witters L.A. Y. Biochem. 2000; PubMed Scopus Google Scholar) have been demonstrated to increase AMPK Recently, leptin was found to AMPK in a biphasic both and mechanisms (3Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1679) Google Scholar). Activation of AMPK in hepatocytes by metformin was shown to without changing ATP levels, although AMP levels were not in this study (14Zhou G. Myers R., Li, Y. Chen Y. Shen X. Fenyk-Melody J., Wu, M. Ventre J. Doebber T. Fujii N. Musi N. Hirshman M.F. Goodyear L.J. Moller D.E. J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4432) Google Scholar). In study we demonstrate that both hyperosmotic stress and metformin activate AMPK without the AMP:ATP ratio. These results the that AMPK can be activated by that do not changes in the of the Although hyperosmotic stress and metformin both activate AMPK without the AMP:ATP ratio, we are to whether the or it is that stimuli that activate AMPK in with an increase in the AMP:ATP ratio may also activate although the results of the at least for the effects of hyperosmotic stress and In addition to regulation by AMP and AMPK is activated by phosphorylation by as yet upstream kinase AMPK kinase (8Hawley S.A. Davison M.D. Woods A. Davies S.P. Beri R.K. Carling D. Hardie D.G. J. Biol. Chem. 1996; 271: 27879-27887Abstract Full Text Full Text PDF PubMed Scopus (1009) Google Scholar). The phosphorylation within AMPK has been as threonine 172 within the activation of the α subunit (8Hawley S.A. Davison M.D. Woods A. Davies S.P. Beri R.K. Carling D. Hardie D.G. J. Biol. Chem. 1996; 271: 27879-27887Abstract Full Text Full Text PDF PubMed Scopus (1009) Google Scholar). Previous studies have shown that phosphorylation at this is for AMPK B.E. J. Kemp B.E. Witters L.A. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Woods A. Davison M.D. Carling D. Biochem. J. 2000; PubMed Scopus Google Scholar). with we found that all the stimuli we an increase in phosphorylation at this However, we were not to increased phosphorylation of this in cells to both hyperosmotic stress and cells with that other phosphorylation may be involved in the activation In a study Woods A. Davison M.D. Carling D. Biochem. J. 2000; PubMed Scopus Google Scholar) we that in addition to threonine phosphorylation of other on both the α and subunits are involved in the regulation of AMPK the of the upstream in the AMPK poorly and we whether the protein kinase, or distinct threonine 172 in response to of the upstream is for the mechanisms regulation of AMPK by which in will of the pathways of Our of of signaling that activation of AMPK by hyperosmotic does not activation of phosphatidylinositol p38 α or MAP kinase kinase, or protein kinase C. The results of study have significant for the of the mechanisms leading to activation of AMPK. The finding that AMPK is activated by stimuli that do not increase the AMP:ATP ratio the possibility that other signaling pathways may the AMPK Activation of AMPK by metformin and rosiglitazone, two widely used anti-diabetic via mechanisms may have for the treatment of type 2 diabetes and the that of AMPK could agents for the that in the metabolic for the of

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Parkinson's Disease (PD) is the second most common neurodegenerative disease worldwide, affecting 1 % of the population over 65 years of age. Dopaminergic cell death in the substantia nigra and accumulation of Lewy bodies are the defining neuropathological hallmarks of the disease. Neuronal death and dysfunction have been reported in other central nervous system regions, including the retina. Symptoms of PD typically manifest only when more than 70 % of dopaminergic cells are lost, and the definitive diagnosis of PD can only be made histologically at post-mortem, with few biomarkers available.In this study, a rotenone-induced rodent model of PD was employed to investigate retinal manifestations in PD and their usefulness in assessing the efficacy of a novel therapeutic intervention with a liposomal formulation of the PPAR-γ (Peroxisome proliferator-activated receptor gamma) agonist rosiglitazone.Retinal assessment was performed using longitudinal in vivo imaging with DARC (detection of apoptosing retinal cells) and OCT (optical coherence tomography) technologies and revealed increased RGCs (Retinal Ganglion Cells) apoptosis and a transient swelling of the retinal layers at day 20 of the rotenone insult. Follow-up of this model demonstrated characteristic histological neurodegenerative changes in the substantia nigra and striatum by day 60, suggesting that retinal changes precede the "traditional" pathological manifestations of PD. The therapeutic effect of systemic administration of different formulations of rosiglitazone was then evaluated, both in the retina and the brain. Of all treatment regimen tested, sustained release administration of liposome-encapsulated rosiglitazone proved to be the most potent therapeutic strategy, as evidenced by its significant neuroprotective effect on retinal neurons at day 20, and on nigrostriatal neurons at day 60, provided convincing evidence for its potential as a treatment for PD.Our results demonstrate significant retinal changes occurring in this model of PD. We show that rosiglitazone can efficiently protect retinal neurons from the rotenone insult, and that systemic administration of liposome-encapsulated rosiglitazone has an enhanced neuroprotective effect on the retina and CNS (Central Nervous System). To our knowledge, this is the first in vivo evidence of RGCs loss and early retinal thickness alterations in a PD model. Together, these findings suggest that retinal changes may be a good surrogate biomarker for PD, which may be used to assess new treatments both experimentally and clinically.

Abstract licence: CC BY