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.

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

“…The energy sensor AMPK has been suggested to be an attractive target for the pharmacological treatment of T2DM (68) and is involved in the mechanism of action of several antidiabetic drugs (66,67). Although our results demonstrate that bone formation is not directly enhanced …”

Endurance Training Activates Pancreatic Islets Amp-Activated Kinase-Uncoupling Protein 2 Pathway and Reduces Insulin Secretion

“…Thus, the higher levels of CaMKII phosphorylation also explain the increased levels of AMPK activation in islets from trained rats. Moreover, these results suggest that endurance exercise increases, somehow, pancreatic islet CaMKII gene expression as well as calcium sensitivity, as this specific kinase phosphorylation is mediated by cytosolic calcium increase (Viollet et al 2009). …”

“…It is well established that AMPK is a substrate for CaMKII (Viollet et al 2009). Thus, the higher levels of CaMKII phosphorylation also explain the increased levels of AMPK activation in islets from trained rats.…”

“…In light of this, the AMPK pathway has been proposed to be an important intracellular target against diabetes development. It has been argued that type 2 diabetes treatment would be associated with insulin-sensitive tissues and AMPK activation, whereas in pancreatic islets, this pathway might be inhibited, raising insulin secretion and sensitivity (Viollet et al 2009). It was recently reported that AMPK is involved with glucose sensing and insulin secretion, probably by increased expression of uncoupling protein 2 (UCP2) and granule docking control (Beall et al 2010, Sun et al 2010b.…”

AMP-activated protein kinase pathway and bone metabolism

“…Daval et al (2005) reported no difference in body mass in AMPKa1 KO mice, but these mice had less fat. Energy expenditure and food intake were not modified in AMPKa1 KO mice (Viollet et al 2009b). These mice also had normal glucose tolerance and normal response to insulin (Jorgensen et al 2004).…”