| First Author | Lee-Young RS | Year | 2013 |
| Journal | Diabetologia | Volume | 56 |
| Issue | 3 | Pages | 608-17 |
| PubMed ID | 23224579 | Mgi Jnum | J:194618 |
| Mgi Id | MGI:5474412 | Doi | 10.1007/s00125-012-2787-7 |
| Citation | Lee-Young RS, et al. (2013) AMP-activated protein kinase (AMPK)alpha2 plays a role in determining the cellular fate of glucose in insulin-resistant mouse skeletal muscle. Diabetologia 56(3):608-17 |
| abstractText | AIMS/HYPOTHESIS: We determined whether: (1) an acute lipid infusion impairs skeletal muscle AMP-activated protein kinase (AMPK)alpha2 activity, increases inducible nitric oxide synthase (iNOS) and causes peripheral insulin resistance in conscious, unstressed, lean mice; and (2) restoration of AMPKalpha2 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-beta-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 AMPKalpha2 subunit (alpha2-KD) underwent an insulin clamp to determine the role of AMPKalpha2 in insulin-mediated muscle glucose metabolism. RESULTS: Lipid treatment decreased AMPKalpha2 activity, increased iNOS abundance/activation and reduced whole-body insulin sensitivity in vivo. AICAR increased AMPKalpha2 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 alpha2-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 AMPKalpha2, increases iNOS and causes insulin resistance in vivo. However, these changes do not appear to be interrelated. Rather, a functionally active AMPKalpha2 subunit is required for insulin-stimulated muscle glycogen synthesis. |
