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Am J Physiol Endocrinol Metab 282: E117-E124, 2002; doi:10.1152/ajpendo.000031.2001
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Vol. 282, Issue 1, E117-E124, January 2002

Insulinotropic activity of the imidazoline derivative RX871024 in the diabetic GK rat

Alexander M. Efanov1, Ioulia B. Appelskog1, Samy M. Abdel-Halim1, Akhtar Khan1, Robert Bränström1, Olof Larsson1, Claes-Göran Östenson1, Hans-Juergen Mest2, Per-Olof Berggren1, Suad Efendic1, and Sergei V. Zaitsev1,3

1 Endocrine and Diabetes Unit, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden; 2 Department of Pharmacology, Lilly Research Laboratories, Lilly Forschung GmbH, D-22419 Hamburg, Germany; and 3 Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119899, Russia

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 Ca2+ 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.

diabetic rats; pancreatic islets; imidazolines; insulin secretion


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S. Efendic, A. M. Efanov, P.-O. Berggren, and S. V. Zaitsev
Two Generations of Insulinotropic Imidazoline Compounds
Diabetes, December 1, 2002; 51(90003): S448 - 454.
[Abstract] [Full Text] [PDF]


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