Insulinotropic activity of the imidazoline derivative RX871024 in the diabetic GK rat.
The insulinotropic activity of the imidazoline derivative RX871024 was compared in pancreatic islets from nondiabetic Wistar rats and spontaneously diabetic Goto-Kakizaki (GK) rats. RX871024 significantly stimulated insulin secretion in islets from both animal groups. The insulinotropic activity of RX871024 was higher than that of the sulfonylurea glibenclamide. This difference was more pronounced in islets from GK rats compared with Wistar rat islets. More importantly, RX871024 substantially improved glucose sensitivity in diabetic beta-cells, whereas glibenclamide stimulated insulin secretion about twofold over a broad range of glucose concentrations in nondiabetic and diabetic rats. RX871024 induced a faster increase in cytosolic free Ca(2+) concentration and faster inhibition of ATP-dependent K(+) channel activity in GK rat islets compared with Wistar rat islets. RX871024 also induced a more pronounced increase in diacylglycerol concentration in GK rat islets. These data support the idea that imidazoline compounds can form the basis for the development of novel drugs for treatment of type 2 diabetes, which can restore glucose sensitivity in diabetic beta-cells.
Efanov
Alexander M
AM
Endocrine and Diabetes Unit, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Appelskog
Ioulia B
IB
Abdel-Halim
Samy M
SM
Khan
Akhtar
A
Bränström
Robert
R
Larsson
Olof
O
Ostenson
Claes-Göran
CG
Mest
Hans-Juergen
HJ
Berggren
Per-Olof
PO
Efendic
Suad
S
Zaitsev
Sergei V
SV
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D010539:Permeability; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics; D017208:Rats, Wistar
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D004075:Diglycerides; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005947:Glucose; D005905:Glyburide; D002118:Calcium