Defective Activation of Protein Kinase C-ζ in Muscle by Insulin and Phosphatidylinositol-3,4,5,-(PO&lt;SUB&gt;4&lt;/SUB&gt;)&lt;SUB&gt;3&lt;/SUB&gt; in Obesity and Polycystic Ovary Syndrome

Beeson, Mary; Sajan, Mini P.; Gomez-Daspet, Joaquin; Luna, Victor M.; Dizon, M.; Grebenev, Dmitry; Powe, J. L.; Lucidi, Scott; Miura, Akira; Kanoh, Yoshinori; Bandyopadhyay, Gautam; Standaert, Mary L.; Yeko, Timothy R.; Farese, Robert V.

doi:10.1089/1540419041978872

Cited by 3 publications

(27 citation statements)

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“…In addition to the diabetic subjects, five age-matched non-diabetic men were simultaneously studied in the clamp/biopsy procedure to provide control samples for side-by-side analyses with samples from diabetic subjects (see below). Note that responses to Clamp/biopsy studies Hyperinsulinaemic-euglycaemic clamp/muscle biopsy studies were conducted in the morning after an overnight fast, as described [16,19]. Subjects received physiological saline i.v., and after anaesthetisation of the biopsy site by s.c. injection of 0.5% lidocaine (without epinephrine), a small incision was made in the skin and a percutaneous biopsy of the vastus lateralis muscle was performed with a 14-gauge biopsy needle.…”

Section: Patientsmentioning

confidence: 99%

“…Samples were homogenised (Polytron) in buffer containing 20 mmol/l Tris-HCl (pH 7.5), 50 mmol/l sucrose, 2 mmol/l EDTA, 2 mmol/l EGTA, 2 mmol/l Na 3 VO 4 , 2 mmol/l NaF, 2 mmol/l Na 4 P 2 O 7 , 1 mmol/l phenylmethylsulphonylfluoride (PMSF), 20 μg/ml leupeptin, 10 μg/ml aprotinin and 1 μmol/l LR-microcytstin, as described [15,16,19]. Muscle homogenates were supplemented with 150 mmol/l NaCl, 1% Triton X-100 and 0.5% Nonidet, and 500 μg of lysate were protein-immunoprecipitated at 4°C with antiserum for determination of total aPKC or IRS-1-dependent PI 3-kinase enzyme activity.…”

Section: Muscle Kinase Analysesmentioning

confidence: 99%

“…Atypical PKC activation Atypical PKC activity was measured as described previously [15,16,19]. In brief, aPKCs were immunoprecipitated with a rabbit polyclonal antiserum (Santa Cruz Biotechnologies) that recognises a common epitope in the C-termini of PKC-ζ and PKC-λ/ι, collected on Sepharose-AG beads, and incubated for 8 min at 30°C in 100 μl buffer containing 50 mmol/l Tris-HCl (pH 7.5), 100 μmol/l Na 3 VO 4 , 100 μmol/l Na 4 P 2 O 7 , 1 mmol/l NaF, 100 μmol/l PMSF, 4 μg phosphatidylserine (Sigma Chemical Co., St Louis, MO, USA), 50 μmol/l [γ-32 P]ATP (NEN/Life Science Products, Boston, MA, USA), 5 mmol/l MgCl 2 and, as substrate, 40 μmol/l serine analogue of the PKC-ɛ pseudosubstrate (BioSource, Camarillo, CA, USA).…”

Section: Muscle Kinase Analysesmentioning

confidence: 99%

“…In some assays, 10 μmol/l PIP 3 (Matreya, State College, PA, USA), a maximally effective concentration [see 16,19,21], was added to directly activate aPKCs in immunoprecipitates prepared from basal unstimulated muscles. Note that aPKC immunoprecipitates contain coprecipitated PDK1, which promotes the phosphorylation of the activation loop of aPKCs [21,22].…”

Section: Muscle Kinase Analysesmentioning

confidence: 99%

“…In this regard, it should be noted that: (1) aPKC activation is defective in muscles of type 2 diabetic [16,17], obese glucoseintolerant [16,18] and obese glucose-tolerant [17,19] humans; and (2) the activities of IRS-1-dependent PI 3-kinase and PKB/Akt are unchanged in muscles of diabetic subjects following metformin treatment [20]. On the other hand, it is not known if basal or insulin-stimulated aPKC activity in muscle is altered by metformin treatment.…”

Section: Introductionmentioning

confidence: 99%

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Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

et al. 2006

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Aims/hypothesis: Metformin is widely used for treating type 2 diabetes mellitus, but its actions are poorly understood. In addition to diminishing hepatic glucose output, metformin, in muscle, activates 5'-AMP-activated protein kinase (AMPK), which alone increases glucose uptake and glycolysis, diminishes lipid synthesis, and increases oxidation of fatty acids. Moreover, such lipid effects may improve insulin sensitivity and insulinstimulated glucose uptake. Nevertheless, the effects of metformin on insulin-sensitive signalling factors in human muscle have only been partly characterised to date. Interestingly, other substances that activate AMPK, e.g., aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), simultaneously activate atypical protein kinase C (aPKC), which appears to be required for the glucose transport effects of AICAR and insulin. Methods: Since aPKC activation is defective in type 2 diabetes, we evaluated effects of metformin therapy on aPKC activity in muscles of diabetic subjects during hyperinsulinaemic-euglycaemic clamp studies. Results: After metformin therapy for 1 month, basal aPKC activity increased in muscle, with little or no change in insulin-stimulated aPKC activity. Metformin therapy for 8 to 12 months improved insulinstimulated, as well as basal aPKC activity in muscle. In contrast, IRS-1-dependent phosphatidylinositol (PI) 3-kinase activity and Ser473 phosphorylation of protein kinase B were not altered by metformin therapy, whereas the responsiveness of muscle aPKC to PI-3,4,5-(PO 4 ) 3 , the lipid product of PI 3-kinase, was improved. Conclusions/ interpretation: These findings suggest that the activation of AMPK by metformin is accompanied by increases in aPKC activity and responsiveness in skeletal muscle, which may contribute to the therapeutic effects of metformin.

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Section: Patientsmentioning

confidence: 99%

Section: Muscle Kinase Analysesmentioning

confidence: 99%

Section: Muscle Kinase Analysesmentioning

confidence: 99%

Section: Muscle Kinase Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

et al. 2006

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Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans

et al. 2006

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Defective PKBbeta activation/phosphorylation, seen on submaximal insulin stimulation in diabetic muscle, may largely reflect impaired activation of insulin signalling factors present in concentrations greater than those needed for full PKB activation/phosphorylation. Defective aPKC activation, seen at all insulin levels, appears to reflect, at least partly, an impaired action of distal factors needed for aPKC activation, or poor aPKC responsiveness.

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Metabolic Syndrome and Cancer: From Bedside to Bench and Back

Extermann

2013

Cancer and Aging

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As older patients present with an average of three comorbidities beside their cancer, geriatric oncology can provide unique clues to translational research in aging and cancer. We illustrate this approach with the example of the metabolic syndrome and cancer. Epidemiologic and clinical cohorts highlighted an association between the metabolic syndrome and a higher risk and worse prognosis of various cancers. In a bedside-to-bench transition, this led to an interest in analyzing the potential mechanisms underlying this association. At least ten potential mechanisms could be implicated, with the challenge of understanding which are the dominant ones in human patients. Bench-to-bedside studies are beginning to shed some light on that aspect, and some therapeutic trials are beginning to exploit the lessons learned.

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Defective Activation of Protein Kinase C-ζ in Muscle by Insulin and Phosphatidylinositol-3,4,5,-(PO<SUB>4</SUB>)<SUB>3</SUB> in Obesity and Polycystic Ovary Syndrome

Cited by 3 publications

References 0 publications

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans

Metabolic Syndrome and Cancer: From Bedside to Bench and Back

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