Two generations of insulinotropic imidazoline compounds

Area of Science:

• Endocrinology
• Pharmacology
• Molecular Biology

Background:

• Imidazoline compounds can modulate insulin secretion.
• ATP-sensitive K(+) channels and voltage-gated K(+) channels play roles in insulin release.
• Protein kinase C (PKC) and arachidonic acid (AA) pathways are involved in insulin exocytosis.

Purpose of the Study:

• To investigate the insulinotropic effects of novel imidazoline compounds RX871024 and BL11282.
• To elucidate the mechanisms underlying their action on insulin secretion.
• To evaluate the potential of BL11282 in a model of impaired glucose tolerance.

Main Methods:

• In vitro and in vivo studies of insulin release from pancreatic islets.
• Measurement of cytosolic Ca(2+) concentration ([Ca(2+)](i)) and membrane potential.
• Assessment of ATP-sensitive K(+) and voltage-gated K(+) channel activity.
• Evaluation of PKC and AA pathway involvement.
• Studies using islets from spontaneously diabetic GK rats.

Main Results:

• RX871024 inhibited K(+) channels, leading to depolarization, increased [Ca(2+)](i), and insulin release, potentiating glucose effects.
• RX871024's action involved PKC and AA pathways, enhancing insulin exocytosis.
• BL11282 did not affect K(+) channels but stimulated insulin secretion in depolarized/permeabilized islets.
• BL11282 enhanced glucose-stimulated insulin secretion without altering basal levels.
• BL11282 restored glucose responsiveness in GK rat islets.

Conclusions:

• RX871024 acts via K(+) channel inhibition and downstream signaling pathways.
• BL11282 represents a new class of insulinotropic compounds with potent glucose-dependent effects.
• BL11282 demonstrates therapeutic potential for diabetes by improving insulin secretion.