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Publication
AMP-activated protein kinase (AMPK)a2 plays a role in determining the cellular
fate of glucose in insulin-resistant mouse skeletal muscle
Authors Lee-Young RS, Bonner JS, Mayes WH, Iwueke I, Barrick BA, Hasenour CM, Kang L,
Wasserman DH
Submitted By Fran Tripp on 3/5/2013
Status In press
Journal Diabetologia
Year 2012
Date Published 12/8/2013
Volume : Pages 56 : 608 - 617
PubMed Reference 23224579
Abstract AIMS/HYPOTHESIS: We determined whether: (1) an acute lipid infusion impairs
skeletal muscle AMP-activated protein kinase (AMPK)a2 activity, increases
inducible nitric oxide synthase (iNOS) and causes peripheral insulin resistance
in conscious, unstressed, lean mice; and (2) restoration of AMPKa2 activity
during the lipid infusion attenuates the increase in iNOS and reverses the
defect in insulin sensitivity in vivo.

METHODS: Chow-fed, 18-week-old C57BL/6J male mice were surgically catheterised.
After 5 days they received: (1) a 5 h infusion of 5 ml? kg(-1)?h(-1)
Intralipid?+?6 U/h heparin (Lipid treatment) or saline (Control); (2) Lipid
treatment or Control, followed by a 2 h hyperinsulinaemic-euglycaemic clamp
(insulin clamp; 4 mU kg(-1)?min(-1)); and (3) infusion of the AMPK activator,
5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) (1 mg
kg(-1)?min(-1)), or saline during Lipid treatment, followed by a 2 h insulin
clamp. In a separate protocol, mice producing a muscle-specific kinase-dead
AMPKa2 subunit (a2-KD) underwent an insulin clamp to determine the role of
AMPKa2 in insulin-mediated muscle glucose metabolism.

RESULTS: Lipid treatment decreased AMPKa2 activity, increased iNOS
abundance/activation and reduced whole-body insulin sensitivity in vivo. AICAR
increased AMPKa2 activity twofold; this did not suppress iNOS or improve
whole-body or tissue-specific rates of glucose uptake during Lipid treatment.
AICAR caused a marked increase in insulin-mediated glycogen synthesis in
skeletal muscle. Consistent with this latter result, lean a2-KD mice exhibited
impaired insulin-stimulated glycogen synthesis even though muscle glucose uptake
was not affected.

CONCLUSIONS/INTERPRETATION: Acute induction of insulin resistance via lipid
infusion in healthy mice impairs AMPKa2, increases iNOS and causes insulin
resistance in vivo. However, these changes do not appear to be interrelated.
Rather, a functionally active AMPKa2 subunit is required for insulin-stimulated
muscle glycogen synthesis.




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