Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations

The enzyme 5'AMP-activated protein kinase (AMPK) is activated by increases in intracellular AMP concentration through a complex interaction of phosphorylation and allosteric regulation. Actions of AMPK elucidated thus far suggest that AMPK may be a viable target for pharmacololgic intervention in type II diabetes. Activation of AMPK is believed to mediate both the acute increase in skeletal muscle glucose uptake during exercise, as well as the adaptive responses to chronic exercise such as regulation of expression of components of the muscle glucose uptake system. In addition. AMPK is known to inhibit key enzymes involved ill lipid and cholesterol synthesis, suggesting that activation of this kinase may also ameliorate dyslipidemia. To investigate the effects of AMPK activation in animal models of type II diabetes, db/db and ob/ob mice were administered 5-aminoimidazole-4-calbox-amide 1-beta-ribofuranoside (A1CAR) Subcutaneously either acutely (single injection) or m ice per clay for 8 days (chronic treatment). Blood glucose was lowered transiently in both db/db and ob/ob mice by acute A1CAR treatment, returning to basal levels similar to3 h after A1CAR administration. In response to chronic treatment, blood glucose (measured 18 h post-A1CAR administration) was significantly decreased in both mouse models when compared to vehicle control groups, with morning blood glucose values oil Day 8 being decreased similar to30-35% in both Mouse models. Chronic A1CAR administration also resulted in ail elevation of total Glut4 concentration in skeletal muscle from ob/ob mice, but not db/db mice. In contrast to the beneficial effects on glucose metabolism, A1CAR treatment of db/db and ob/ob mice led to approximately a 2.5-3-fold increase in serum triglyceride levels compared to vehicle-treated controls. These data Suggest that pharmacological activation of AMPK may enhance glucose uptake in individuals with type II diabetes, however, this benefit may be offset by the concomitant elevation in triglycerides. (C) 2002 Elsevier Science (USA). All rights reserved.