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.2003 Jan;111(1):91-8.
doi: 10.1172/JCI16567.

The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity

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The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity

Benoit Viollet et al. J Clin Invest.2003 Jan.

Abstract

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.

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Figures

Figure 1
Figure 1
Generation of mice lacking AMPKα2. (a) Schematic representation (not to scale) of genomic structure ofAMPKα2 wild-type allele,AMPKα2 gene-targeting construct,AMPKα2 targeted allele, andAMPKα2 null allele. Squares indicateloxP sites and H’s indicateHindIII restriction sites. C corresponds to the exon encoding theAMPKα2 catalytic domain (amino acids 189–260) (b) Southern blot analysis afterHindIII digestion of tail DNA from offspring derived from heterozygous intercrosses. Expected fragment sizes of theAMPKα2 wild-type (+/+; 5.3 kb) and null (–/–; 3.8 kb) alleles afterHindIII digestion and hybridization with the indicated probe (solid bar ina) are shown. (c) Western blot analysis of AMPKα1 and AMPKα2 proteins in liver and gastrocnemius muscle from control (+/+) andAMPKα2–/– mice. (d) Phosphorylation level of ACC in liver and gastrocnemius muscle from control andAMPKα2–/– mice.
Figure 2
Figure 2
AMPKα2–/– mice are AICAR-resistant, glucose intolerant, and exhibit impaired glucose-stimulated insulin secretion. (a) AICAR tolerance test. (b) OGTT. (c) Plasma glucose and insulin levels at time 20 minutes during OGTT. All results are expressed as mean ± SEM (n = 6–10). *P < 0.05, **P < 0.001, ***P < 0.0001 vs. control group by unpaired, two-tailed Studentt test. NS, not significant.
Figure 3
Figure 3
Glucose- andL-arginine–stimulated (L-Arg) insulin secretion in isolatedAMPKα2–/– islets. All results are expressed as mean ± SEM (n = 4).P not significant between groups by unpaired, two-tailed Studentt test.
Figure 4
Figure 4
Insulin-stimulated glucose transport in isolated muscles fromAMPKα2–/– mice. Basal and insulin-stimulated glucose transport in (a) soleus and (b) extensor digitorum longus muscles from control andAMPKα2–/– mice. All results are expressed as mean ± SEM (n = 4–7). *P < 0.05, **P < 0.01 vs. basal conditions by unpaired, two-tailed Studentt test;P not significant (NS) vs. control group.
Figure 5
Figure 5
Increased daily urinary catecholamine excretion inAMPKα2–/– mice. Daily urinary (a) epinephrine, (b) norepinephrine, and (c) dopamine excretion inAMPKα2–/– mice. All results are expressed as mean ± SEM (n = 6). *P < 0.05, **P < 0.01 vs. control group by unpaired, two-tailedt test. Also shown are effect of phentolamine and propranolol, α- and β-adrenergic blockers, respectively, on the response of glucose challenge of control (d) andAMPKα2–/– (e) mice. All results are expressed as mean ± SEM (n = 5). *P < 0.05, **P < 0.01, saline- vs. phentolamine-treated group by unpaired, two-tailed Studentt test;P not significant for saline- vs. propranolol-treated group.
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