ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats
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 β-cell glucose metabolism and [Ca2+]i handling, and thereby enhanced glucose-induced insulin release.
This study was supported by grants from the Swedish Research Council, the Swedish Diabetes Association, the Strategic Research Program in Diabetes at Karolinska Institutet, the ERC-2013-AdG 338936-BetaImage, the Novo Nordisk Foundation, Knut and Alice Wallenberg Foundation, Berth von Kantzow’s Foundation, The Skandia Insurance Co. Ltd, the Family Erling-Persson Foundation and the Stichting af Jochnick Foundation. The skilled technical assistance of Elisabeth Norén-Krog and Yvonne Strömberg is acknowledged. AC and MB are officers of Araim Pharmaceuticals and own stock or stock options. All other authors declare no conflict of interest.
- 16.Uhlén P. (2004) Spectral analysis of calcium oscillations. Sci. STKE. 258:pl15.Google Scholar
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