Effects of an alpha 2-adrenoceptor antagonist on glucose tolerance in the genetically obese mouse (C57BL/6J ob/ob).
This study examines the effects of a relatively selective alpha 2-adrenoceptor antagonist, 8-(L-piperazinyl)imado-[1,2-alpha] pyrazine (compound A), and the preferential alpha 2-agonist clonidine on blood glucose, glucose tolerance, and plasma insulin levels in the C57BL/6J ob/ob mouse and its lean littermate. While clonidine raised blood glucose levels and impaired glucose tolerance, oral administration of compound A resulted in decreased blood glucose levels, as well as improved glucose tolerance in ob/ob mice. Insulin levels in ob/ob mice treated with clonidine were significantly reduced, while compound A raised insulin levels threefold and blocked the effects of clonidine when co-administered to the same animals. Clonidine-induced hyperglycemia in lean littermates was not accompanied by a decrease in insulin levels, while a small but significant increase in insulin levels was observed by compound A administration. Glycogen synthesis in diaphragm of ob/ob mice was enhanced after oral administration of compound A and was accompanied by an increase in plasma insulin levels. Concomitant treatment with a potent somatostatin analog to inhibit insulin release blocked the effects of the alpha 2-adrenoceptor antagonist, compound A. These observations suggest that the alpha 2-antagonist studied, increased plasma insulin levels with an accompanying reduction in blood glucose and an improvement in glucose tolerance in a genetic model of insulin resistance. Differential sensitivity to alpha 2-agonist in these genetically obese mice, ob/ob, was demonstrated by decreased insulin levels due to clonidine administration.
Saperstein
R
R
Department of Biochemistry and Molecular Biology, Merck, Sharp, & Dohme Research Laboratories, Rahway, NJ 07065.
Chapin
E W
EW
Brady
E J
EJ
Slater
E E
EE
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology; D003964:Diaphragm / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000096:biosynthesis; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives
D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D007328:Insulin; D010879:Piperazines; D011719:Pyrazines; D013004:Somatostatin; C064014:8-(1-piperazinyl)imidazo(1,2-a)pyrazine; D006003:Glycogen; D003000:Clonidine