Role of Akt/protein kinase B in metabolism

Whiteman, Eileen L.; Cho, Han; Birnbaum, Morris J.

doi:10.1016/s1043-2760(02)00662-8

Cited by 616 publications

(503 citation statements)

References 58 publications

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“…It is widely accepted that Akt/PKB is required for the metabolic actions of insulin [34]. However, there have been contradictory results on whether the insulin-induced acti- [18,21,23].…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

et al. 2008

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“…It is widely accepted that Akt/PKB is required for the metabolic actions of insulin [34]. However, there have been contradictory results on whether the insulin-induced acti- [18,21,23].…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

et al. 2008

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“…Then cell-cycle progression and apoptosis were investigated using flow cytometry analysis as described in Materials and methods. Graphs are representative of three separate experiments protein production, lipogenesis, glycogen synthesis, suppression of gluconeogenesis, cell survival, determination of cell size and cell-cycle progression [12]. Many reports have also demonstrated that Akt activation plays an important role in promoting pancreatic beta cell survival and preserving beta cell function [16,28].…”

Section: Discussionmentioning

confidence: 99%

“…The relative values of FKHR luciferase activity to β-galactosidase are shown as means±SEM of three independent experiments. **p<0.01 vs control; && p<0.01 vs CA-Akt-cotransfected only (CA-Akt); ## p<0.01 vs PGE 2 -treated alone; ++ p<0.01 vs IGF-1 and PGE 2 cotreated (I+P) metabolism [12,17,19]. Therefore, we next evaluated the potential effects of PGE 2 on pancreatic beta cell viability using MTT assays.…”

Section: Pge 2 Decreases Phosphorylation Of Foxo In Hit-t15 Cells Andmentioning

confidence: 99%

“…Accumulating evidence indicates that upon activation in response to many different growth factors, hormones and external stresses, Akt serves as a pivotal regulator of glucose transport, glycolysis, protein production, lipogenesis, glycogen synthesis, suppression of gluconeogenesis, cell survival, determination of cell size and cell-cycle progression as well as insulin synthesis and secretion [12][13][14][15]. However, the precise role of Akt in the beta cell dysfunction associated with diabetes mellitus remains controversial [15,16].…”

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confidence: 99%

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Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction

et al. 2006

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Aims/hypothesis Prostaglandin E 2 (PGE 2 ) is a well-recognised inhibitor of glucose-stimulated insulin secretion (GSIS). The aim of this study was to investigate the signalling pathway of PGE 2 in beta cell function regulation in HIT-T15 cells and isolated rat islets. Materials and methods mRNA levels of the prostaglandin E receptor 3 (Ptger3) were measured by real-time PCR. Western blot analysis was used to detect changes in the levels of PTGER3, phosphorylated and total Akt, phosphorylated and total forkhead box 'Other' (Foxo). Transient transfection and reporter assays were used to measure Foxo transcriptional activity. The biological significance of PGE 2 in beta cell function was analysed using MTT, flow cytometry and GSIS assays. Results We found that treating HIT-T15 cells with exogenous PGE 2 stimulated Ptger3 gene expression specifically, and diminished cAMP generation. These were accompanied by the downregulation of Akt and Foxo phosphorylation in HIT-T15 cells and isolated rat islets. Moreover, PGE 2 upregulated basal and partially reversed constitutively active Akt-inactivated Foxo transcriptional activity. Furthermore, GSIS was impaired in PGE 2 -treated HIT-T15 cells and isolated islets. However, the dosage used in the above experiments did not affect beta cell viability and apoptosis. In addition, insulin-like growth factor 1 (IGF-1) pretreatment reversed the effects of PGE 2 , and wortmannin treatment abolished the preventive effects of IGF-1. Conclusions/interpretation Our observations strongly suggest that PGE 2 can induce pancreatic beta cell dysfunction through the induction of Ptger3 gene expression and inhibition of Akt/Foxo phosphorylation without impacting beta cell viability. These results shed light on the mechanisms of PGE 2 actions in pancreatic beta cell dysfunction.

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“…Firstly, aPKCs are able to phosphorylate insulin receptor substrate-1 (IRS-1) on serine residues, thereby downregulating the recruitment and activation of phosphatidylinositol-3-kinase (PI3K) by IRS-1, especially under prolonged stimulation with insulin [3][4][5]. Secondly, when stimulated with ceramide, aPKCs directly inhibit protein kinase B(α) [6], one of the key molecules required for insulin-dependent glucose transport and glycogen synthesis [7,8].…”

Section: Introductionmentioning

confidence: 99%

A novel functional polymorphism (?336A/G) in the promoter of the partitioning-defective protein-6? gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids

et al. 2005

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Aims/hypothesis: Partitioning-defective protein-6α (Par6α) has recently been demonstrated to negatively regulate insulin signalling in murine myoblasts. To address whether Par6α plays a role in human physiology, the present study investigated whether mutations exist in the Par6α gene and whether these mutations, if present, are associated with pre-diabetic phenotypes in non-diabetic subjects. Methods: The complete gene (part of the promoter [2.1 kb], all exons/introns and the 3′ untranslated region) encoding Par6α was analysed in 664 non-diabetic subjects. We investigated possible associations between single nucleotide polymorphisms and percentage of body fat, glucose tolerance (as determined by OGTT), serum NEFA concentrations and whole-body insulin sensitivity (estimated during the OGTT, and for a subgroup of 242 subjects determined by the euglycaemic-hyperinsulinaemic clamp). Results: A rare A/G polymorphism was found 336-bp upstream of the translational start codon (allele frequency 0.03). The data for subjects homozygous and heterozygous for −336G (R/G, n=43) were combined and compared with those for subjects homozygous for −336A (A/A, n=621). Subjects with the R/G genotype had lower fasting (4.84± 0.09 mmol/l, means±SEM, p=0.049) and 2-h (5.50±0.02 mmol/l, p=0.050) plasma glucose concentrations than subjects with the A/A genotype (5.02±0.02 and 5.94±0.06 mmol/l, respectively). Subjects with the R/G genotype also had lower fasting (448±31 μmol/l, p=0.018) and 2-h serum NEFA concentrations (61±7 μmol/l, p= 0.015) than subjects with the A/A genotype (529±9 and 75± 2 μmol/l, respectively), adjusted for age, sex and percentage of body fat. There were no differences in adiposity or whole-body insulin sensitivity between the two genotype groups (all p> 0.36). A luciferase reporter gene assay revealed that the −336G promoter variant had a significantly lower (−22.8%, p=0.006) transcriptional activity in transfected C2C12 murine myoblasts than the −336A promoter variant. Conclusions/interpretation: A novel functional variant in the promoter of the Par6α gene is associated with reduced fasting glycaemia, increased glucose tolerance and reduced serum NEFA concentrations.

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Role of Akt/protein kinase B in metabolism

Cited by 616 publications

References 58 publications

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction

A novel functional polymorphism (?336A/G) in the promoter of the partitioning-defective protein-6? gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids

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