Modulation of insulin secretion and glycemia by selective inhibition of cyclic AMP phosphodiesterase III.
The effects of selective inhibition of cyclic AMP phosphodiesterase type III on insulin and glucose levels during an oral glucose challenge were evaluated in obese, diabetic ob/ob mice and in lean, non-diabetic littermates using the selective inhibitor, milrinone. Oral administration of milrinone increased plasma insulin levels both in ob/ob and in lean mice. Glucose tolerance was improved in lean, but not in ob/ob mice, where glucose levels were increased by milrinone treatment. In isolated hepatocytes from normal rats incubation with 200 microM milrinone caused a 30% increase in glucose release with a corresponding depletion of glycogen stores. Stimulation of isolated rat adipocytes with 200 microM milrinone increased glycerol release 7-fold. We conclude that selective inhibitors of cyclic AMP phosphodiesterase III are effective insulin secretagogues, but their therapeutic utility may be limited by their concurrent stimulation of lipolysis and hepatic glucose output.
Parker
J C
JC
Pfizer Inc., Central Research Division, Groton, Connecticut 06340, USA. janice_c_parker@groton.pfizer.com
VanVolkenburg
M A
MA
Nardone
N A
NA
Hargrove
D M
DM
Andrews
K M
KM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005990:Glycerol / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D020105:Milrinone; D009765:Obesity / Q000097:blood; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D006003:Glycogen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone; D005990:Glycerol