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 pharmacologic 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 in 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-carboxamide 1-beta-ribofuranoside (AICAR) subcutaneously either acutely (single injection) or twice per day for 8 days (chronic treatment). Blood glucose was lowered transiently in both db/db and ob/ob mice by acute AICAR treatment, returning to basal levels approximately 3 h after AICAR administration. In response to chronic treatment, blood glucose (measured 18 h post-AICAR administration) was significantly decreased in both mouse models when compared to vehicle control groups, with morning blood glucose values on Day 8 being decreased approximately 30-35% in both mouse models. Chronic AICAR administration also resulted in an 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, AICAR 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.
Halseth
Amy E
AE
Cardiovascular and Metabolic Diseases, Mail Zone T1G, 800 N. Lindbergh Boulevard, Pharmacia Corporation, St. Louis, MO 63167, USA. amy.e.halseth@pharmacia.com
Ensor
Nancy J
NJ
White
Tommi A
TA
Ross
Stuart A
SA
Gulve
Eric A
EA
D000249:Adenosine Monophosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009132:Muscles / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012265:Ribonucleotides; C495693:Slc2a4 protein, mouse; D014280:Triglycerides; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D002784:Cholesterol; C031143:AICA ribonucleotide