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Ablation of AMP-activated Protein Kinase 2 Activity Exacerbates Insulin Resistance Induced by High-fat Feeding of Mice

¹Research Division, Joslin Diabetes Center and Department Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
²Division of Endocrinology, Diabetes, and Metabolism, University of Utah School of Medicine, Salt Lake City, UT

Objective: We determined if muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance.

Research Design And Methods: Muscle-specific transgenic mice expressing an inactive form of the AMPK 2 catalytic subunit (2i TG) and their wild type littermates were fed either a high-fat (60% kcal fat) or a control diet (10% kcal fat) for 30 weeks.

Results: Compared with wild type mice, glucose tolerance in 2i TG mice was slightly impaired on the control diet, and significantly impaired on the high-fat diet. To determine whether the whole body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 µU/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by approximately 50% in 2i TG mice compared with wild type mice. High fat feeding partially decreased insulin-stimulated glucose transport in wild type mice, while the high fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the 2iTG mice. High fat feeding in 2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle.

Conclusions: The lack of skeletal muscle AMPK 2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding, and supports the thesis that AMPK 2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g. metformin) treatments.

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