Effects of
ARA290 on
glucose homeostasis were studied in type 2 diabetic Goto-Kakizaki (GK) rats. In GK rats receiving
ARA290 daily for up to 4 wks, plasma
glucose concentrations were lower after 3 and 4 wks, and
hemoglobin A1c (
Hb A1c) was reduced by ~20% without changes in whole body and hepatic
insulin sensitivity.
Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to
glucose,
carbachol and KCl, islet cytoplasmic free Ca2+ concentrations, [Ca2+]i, were higher and the frequency of [Ca2+]i oscillations enhanced compared with placebo.
ARA290 also improved stimulus-secretion coupling for
glucose in GK rat islets, as shown by an improved
glucose oxidation rate,
ATP production and acutely enhanced
glucose-stimulated insulin secretion.
ARA290 also exerted an effect distal to the
ATP-sensitive
potassium (
KATP) channel on the
insulin exocytotic pathway, since the
insulin response was improved following islet depolarization by KCl when
KATP channels were kept open by
diazoxide. Finally, inhibition of
protein kinase A completely abolished effects of
ARA290 on insulin secretion. In conclusion,
ARA290 improved
glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved γ-cell
glucose metabolism and [Ca2+]i handling, and thereby enhanced
glucose-induced
insulin release.