title: ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats.
abstract: 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+]ioscillations 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 KATPchannels 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+]ihandling, and thereby enhanced glucose-induced insulin release.
authors.affiliation: Dept of Molecular Medicine and Surgery, Karolinska Institutet (KI), Stockholm, Sweden.
authors.forename: Carole
authors.initials: C
authors.lastname: Muller
authors.affiliation: Dept of Molecular Medicine and Surgery, Karolinska Institutet (KI), Stockholm, Sweden.
authors.forename: Kamal
authors.initials: K
authors.lastname: Yassin
authors.affiliation: Dept of Molecular Medicine and Surgery, Karolinska Institutet (KI), Stockholm, Sweden.|The Rolf Luft Research Centre for Diabetes and Endocrinology, KI, Stockholm, Sweden.
authors.forename: Luo-Sheng
authors.initials: LS
authors.lastname: Li
authors.affiliation: Dept Vascular Surgery, Leiden University Medical Center, The Netherlands.
authors.forename: Magnus
authors.initials: M
authors.lastname: Palmblad
authors.affiliation: Dept of Molecular Medicine and Surgery, Karolinska Institutet (KI), Stockholm, Sweden.
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
authors.affiliation: Dept of Molecular Medicine and Surgery, Karolinska Institutet (KI), Stockholm, Sweden.|The Rolf Luft Research Centre for Diabetes and Endocrinology, KI, Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Araim Pharmaceuticals, Tarrytown, New York, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.affiliation: Araim Pharmaceuticals, Tarrytown, New York, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.affiliation: Dept of Molecular Medicine and Surgery, Karolinska Institutet (KI), Stockholm, Sweden.|The Rolf Luft Research Centre for Diabetes and Endocrinology, KI, Stockholm, Sweden.
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Östenson