Targeting the AMPK pathway for the treatment of Type 2 diabetes

Abstract

Type 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes.

Figure 1. Structure of AMPK

The mammalian AMPKα (α1 and α2), AMPKβ (β1 and β2) and AMPKγ (γ1, γ2 short form, γ2 long form and γ3) subunits are shown. The α-subunits contains the Thr172 residue that must be phosphorylated (P) by upstram kinases for activity and an autoinhibitory sequence domain that inhibits the activity of the kinase domain. The C-terminal domain is required for binding the β- and γ-subunits. The β-subunits contains central glycogen-binding domains and C-terminal domain that is required for binding the α- and γ subunits. The three γ-subunit isoforms have variable N-terminal domains and four conserved cystathionine beta-synthase motifs (CBS1–4). The CBS motifs act in pairs to form two Bateman domains that bind AMP or ATP.

Figure 2. Regulation of AMPK activation

AMPK is activated by phosphorylation of Thr 172 catalysed by LKB1:STRAD:MO25 complex in response to increase in the AMP/ATP ratio and by CaMKKβ in response to elevated Ca²⁺ levels. Thr172 is dephosphorylated by PP2C protein phosphatase switching active AMPK to the inactive form.

Figure 3. AMPK and the regulation of skeletal muscle metabolism

Proposed model for the role of AMPK in the regulation of lipid and glucose metabolism in skeletal muscle. AMPK activity may be increased by an altered energy nucleotide or by hormonal action. This activation of AMPK may result in an increase in glucose transport as well as an increase in fatty acid oxidation. ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160kDa; CPT1-α, carnitine palmitoyl transferase-1; Glut4, glucose tranporter 4; MCD, malonyl-CoA decarboxylase; PGC1α, PPARγ co-activator 1α; LCACoA, Long Chain acyl CoAs.

Figure 4. AMPK and the regulation of hepatic metabolism

Activation of AMPK leads to the inhibition of cholesterol synthesis by the phopshorylation of HMG-CoA reductase. By inhibiting ACC and activating MCD, AMPK increases fatty acid oxidation via the regulation of malonyl CoA levels, which is both a critical precursor for biosynthesis of fatty acids and a potent inhibitor of CPT-1, the shuttle that controls the transfer of LCACoA into the mitochondria. AMPK inhibits hepatic glucose production via the phosphorylation of TORC2 and inhibition gene expression for key gluconeogenic enzymes, G6Pase and PEPCK, and for the transcriptional co-activator PGC-1α. ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; CPT1-α, carnitine palmitoyl transferase-1; G6Pase, glucose-6-phosphatase; LCACoA, Long Chain acyl CoAs; MCD, malonyl-CoA decarboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α, PPARγ co-activator 1α; TORC2, transducer of regulated CREB activity 2.