Diabetes Metab J.  2013 Feb;37(1):1-21. 10.4093/dmj.2013.37.1.1.

AMPK and Exercise: Glucose Uptake and Insulin Sensitivity

• O'Neill HM

• KMID: 2280737
• DOI: http://doi.org/10.4093/dmj.2013.37.1.1

Abstract

AMPK is an evolutionary conserved sensor of cellular energy status that is activated during exercise. Pharmacological activation of AMPK promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in obesity and contribute to the development of insulin resistance. AMPK deficient mouse models have been used to provide direct genetic evidence either supporting or refuting a role for AMPK in regulating these processes. Exercise promotes glucose uptake by an insulin dependent mechanism involving AMPK. Exercise is important for improving insulin sensitivity; however, it is not known if AMPK is required for these improvements. Understanding how these metabolic processes are regulated is important for the development of new strategies that target obesity-induced insulin resistance. This review will discuss the involvement of AMPK in regulating skeletal muscle metabolism (glucose uptake, glycogen synthesis, and insulin sensitivity).

Keyword

AMPK; Exercise; Glucose uptake; Insulin resistance; Obesity

MeSH Terms

Animals
Glucose
Glycogen
Insulin
Insulin Resistance
Mice
Organelle Biogenesis
Muscle, Skeletal
Obesity
Glucose
Glycogen
Insulin

Figure

• 

  Fig. 1 Regulation of insulin-stimulated glucose uptake and glycogen synthesis. Insulin stimulates glucose uptake by binding to the insulin receptor (IR), this promotes autophosphorylation and subsequent activation of insulin receptor substrate 1 (IRS1) and PI3 kinase via SH2 interaction with regulatory p85 and catalytic p110 subunits. This promotes association with phosphatidylinositol 4,5-bisphosphate (PIP2) at the plasma membrane, which is converted to phosphatidylinositol 3,4,5-triphosphate (PIP3), which induces a conformational change in Akt that allows Akt phosphorylation and subsequent phosphorylation and inhibition of the Rab-GAP activating protein tre-2/USP6, BUB2, cdc16 domain family member 4 (TBC1D4). Rac/actin can also promote glucose uptake by promoting actin remodeling. Once glucose enters the cell it can be metabolized through glycolysis to produce ATP or utilized for glycogen synthesis. Glycogen synthesis involves phosphorylation and inhibition of glycogen synthase kinase 3 (GSK3) by Akt, which activates glycogen synthase (GS); promoting the conversion of glucose-6 phosphate (G6P) to G1P then uridine diphosphoglucose (UDP-G), which is targeted towards glycogen. AMPK can phosphorylate and inhibit GS; however, G6P can override this inhibitory effect. PTG, protein targeting to glycogen.

• 

  Fig. 2 Regulation of glucose uptake during exercise and muscle contractions. During contraction, there is depolarization of T-tubules (plasma membrane only found in skeletal muscle) that causes calcium (Ca2+) release from the sarcoplasmic reticulum, which triggers actin and myosin interaction (red; thick myosin and thin actin filaments). The energy demand of contraction increases the ratio of adenosine monophosphate (AMP)/adenosine triphosphate (ATP), which stimulates AMP-associated protein kinase (AMPK). Both tre-2/USP6, BUB2, cdc16 domain family member 4 and 1 (TBC1D 4 and 1) are involved in regulating glucose uptake in response to contraction; however, it has recently been discovered that TBC1D1 plays a more pivotal role. AMPK can phosphorylate both TBC1D4 and TBC1D1; however, recent studies have shown that during contraction there is a strong correlation between AMPK phosphorylation of TBC1D1 and 14-3-3 binding (proteins that are proposed to be important for regulation of GAP function of TBC1D1 upon phosphorylation), which allows dissociation of Rab proteins and glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake. AK, adenylate kinase, the enzyme required for generation of AMP.

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