5-Aminoimidazole-4-carboxamide riboside (AICAR) enhances GLUT2-dependent jejunal glucose transport: a possible role for AMPK

Abstract

AMPK (AMP-activated protein kinase) is a key sensor of energy status within the cell. Activated by an increase in the AMP/ATP ratio, AMPK acts to limit cellular energy depletion by down-regulating selective ATP-dependent processes. The purpose of the present study was to determine the role of AMPK in regulating intestinal glucose transport. [3H]3-O-methyl glucose fluxes were measured in murine jejunum in the presence and absence of the AMPK activators AICAR (5-aminoimidazole-4-carboxamide riboside) and metformin and the p38 inhibitor, SB203580. To differentiate between a sodium-coupled (SGLT1) and diffusive (GLUT2) route of entry, fluxes were measured in the presence of the SGLT1 and GLUT2 inhibitors phloridzin and phloretin. Glucose transporter mRNA levels were measured by reverse transcriptase-PCR, and localization by Western blotting. Surface-expressed GLUT2 was assessed by luminal biotinylation. Activation of p38 mitogen-activated protein kinase was analysed by Western blotting. We found that treatment of jejunal tissue with AICAR resulted in enhanced net glucose uptake and was associated with phosphorylation of p38 mitogen-activated protein kinase. Inhibition of p38 abrogated the stimulation of AICAR-stimulated glucose uptake. Phloretin abolished the AICAR-mediated increase in glucose flux, whereas phloridzin had no effect, suggesting the involvement of GLUT2. In addition, AICAR decreased total protein levels of SGLT1, concurrently increasing levels of GLUT2 in the brush-border membrane. The anti-diabetic drug metformin, a known activator of AMPK, also induced the localization of GLUT2 to the luminal surface. We conclude that the activation of AMPK results in an up-regulation of non-energy requiring glucose uptake by GLUT2 and a concurrent down-regulation of sodium-dependent glucose transport.

Apical GLUT2

“…Of great interest, apical GLUT2 is the target of a cellular energy-sensing mechanism. Energy depletion provokes activation of AMP-activated protein kinase (AMPK), which causes activation of p38 and then insertion of apical GLUT2 (37). The antidiabetic drug metformin also activates AMPK (38) and promotes apical GLUT2 insertion; while this might potentially lead to an increased rate of delivery, glycemic control is in fact better because intestinal utilization is enhanced (39).…”

Insulin Internalizes GLUT2 in the Enterocytes of Healthy but Not Insulin-Resistant Mice

“…A high sugar intake is a physiological regulator of this process, increasing monosaccharide uptake threefold in vivo (6). The recruitment of GLUT2 in BBM was also observed in conditions of increased calorie demand and glucagon-like peptide 2 treatment (7)(8)(9)(10)(11).…”

Mechanical Stretch-Induced Protection against Myocardial Ischemia-Reperfusion Injury Involves AMP-Activated Protein Kinase

“…It has also been reported that both IPC and heat shock induced protection occurs via the AMPK activation in liver and heart [16,23,24]. Heart treated with AICAR, an activator of AMPK, affords protection against injury during sustained I/R [25,26]. In summary, these reports suggest that AMPK plays an important role in the process of cardioprotection.…”

“…Recently, it has been reported that AMPK prevents ischemic injury in the hearts [21,22], and that IPC and heat shock induced protection occurs via AMPK activation in liver and heart [16,23,24]. Furthermore, AICAR affords the protection against I/R injury [25,26]. Therefore, AMPK has emerged as a new pathway that plays an important protective role in the process of cardioprotection.…”