Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes.
The action of repaglinide, a novel insulin secretagogue, was compared with the sulfonylurea glibenclamide with regard to the hypoglycemic action in vivo, binding to betaTC-3 cells, insulin secretion from perifused mouse islets, and capacity to stimulate exocytosis by direct interaction with the secretory machinery in single voltage-clamped mouse beta-cells. Two binding sites were identified: a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glibenclamide (14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l). In contrast to glibenclamide, repaglinide (in concentrations as high as 5 micromol/l) lacked the ability to enhance exocytosis in voltage-clamped beta-cells. Repaglinide was more potent than glibenclamide in stimulating insulin release from perifused mouse islets (EC50 29 vs. 80 nmol/l). The greater potency of repaglinide in vitro was paralleled by similar actions in vivo. The ED50 values for the hypoglycemic action were determined to be 10.4 and 15.6 microg/kg after intravenous and oral administration, respectively. The corresponding values for glibenclamide were 70.3 microg/kg (intravenous) and 203.2 microg/kg (oral). Further, repaglinide (1 mg/kg p.o.) was effective (P < 0.001) as an insulin-releasing agent in a rat model (low-dose streptozotocin) of type 2 diabetes. These observations suggest that the insulinotropic actions of repaglinide and glibenclamide in vitro and in vivo are secondary to their binding to the high-affinity repaglinide site and that the insulinotropic action of repaglinide involves both distinct and common cellular mechanisms.
Fuhlendorff
J
J
Diabetes Discovery, Novo Nordisk A/S, Bagsvaerd, Denmark. jfu@novo.dk
Rorsman
P
P
Kofod
H
H
Brand
C L
CL
Rolin
B
B
MacKay
P
P
Shymko
R
R
Carr
R D
RD
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis* / Q000187:drug effects; D002219:Carbamates / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D015331:Cohort Studies; D046508:Culture Techniques; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010880:Piperidines / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium
D001786:Blood Glucose; D002219:Carbamates; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D014316:Tritium; C072379:repaglinide; D005947:Glucose; D005905:Glyburide