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Molecular Medicine

, Volume 21, Issue 1, pp 969–978 | Cite as

ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats

  • Carole Muller
  • Kamal Yassin
  • Luo-Sheng Li
  • Magnus Palmblad
  • Suad Efendic
  • Per-Olof Berggren
  • Anthony Cerami
  • Michael Brines
  • Claes-Göran Östenson
Research Article

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+]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.

Notes

Acknowledgments

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.

Supplementary material

10020_2015_2101969_MOESM1_ESM.pdf (646 kb)
Supplementary material, approximately 646 KB.

References

  1. 1.
    Frayling TM. (2007) Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat. Rev. Genet. 8:657–62.CrossRefGoogle Scholar
  2. 2.
    Ostenson CG, Efendic S. (2007) Islet gene expression and function in type 2 diabetes; studies in the Goto-Kakizaki rat and humans. Diabetes Obes. Metab. 9 Suppl 2:180–6.CrossRefGoogle Scholar
  3. 3.
    Homo-Delarche F, et al. (2006) Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat. Diabetes. 55:1625–33.CrossRefGoogle Scholar
  4. 4.
    Donath MY, Storling J, Maedler K, Mandrup-Poulsen T. (2003) Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J. Mol. Med. (Berl) 81:455–70.CrossRefGoogle Scholar
  5. 5.
    Fenjves ES, et al. (2003) Human, nonhuman primate, and rat pancreatic islets express erythropoietin receptors. Transplantation. 75:1356–60.CrossRefGoogle Scholar
  6. 6.
    Brines M, Cerami A. (2006) Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int. 70:246–50.CrossRefGoogle Scholar
  7. 7.
    Choi D, et al. (2010) Erythropoietin protects against diabetes through direct effects on pancreatic beta cells. J. Exp. Med. 207:2831–42.CrossRefGoogle Scholar
  8. 8.
    Brines M, et al. (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 105:10925–30.CrossRefGoogle Scholar
  9. 9.
    Brines M, Cerami A. (2012) The receptor that tames the innate immune response. Mol. Med. 18:486–96.CrossRefGoogle Scholar
  10. 10.
    Brines M, et al. (2015) ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol. Med. 20:658–66.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Herbert V, Lau KS, Gottlieb CW, Bleicher SJ. (1965) Coated charcoal immunoassay of insulin. J. Clin. Endocrinol. Metab. 25:1375–84.CrossRefGoogle Scholar
  12. 12.
    Quynh NT, Islam MS, Floren A, Bartfai T, Langel U, Ostenson CG. (2005) Effects of galnon, a nonpeptide galanin-receptor agonist, on insulin release from rat pancreatic islets. Biochem. Biophys. Res. Commun. 328:213–20.CrossRefGoogle Scholar
  13. 13.
    Yang Y, Gillis KD. (2004) A highly Ca2+-sensitive pool of granules is regulated by glucose and protein kinases in insulin-secreting INS-1 cells. J. Gen. Physiol. 124:641–51.CrossRefGoogle Scholar
  14. 14.
    Healy JA, et al. (2010) Cholinergic augmentation of insulin release requires ankyrin-B. Sci. Signal. 3:ra19.CrossRefGoogle Scholar
  15. 15.
    Wiederkehr A, Wollheim CB. (2006) Minireview: implication of mitochondria in insulin secretion and action. Endocrinology. 147:2643–9.CrossRefGoogle Scholar
  16. 16.
    Uhlén P. (2004) Spectral analysis of calcium oscillations. Sci. STKE. 258:pl15.Google Scholar
  17. 17.
    Stein KM, et al. (1993) Prognostic value and physiological correlates of heart rate variability in chronic severe mitral regurgitation. Circulation. 88:127–35.CrossRefGoogle Scholar
  18. 18.
    Welsh PD. (1967) The use of fast Fourier transform for the estimation of power spectra: a method based on time averaging over short, modified periodograms. IEEE Trans. Audio. Electroacoust. 15:70–3.CrossRefGoogle Scholar

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Authors and Affiliations

  • Carole Muller
    • 1
  • Kamal Yassin
    • 1
  • Luo-Sheng Li
    • 1
    • 2
  • Magnus Palmblad
    • 3
  • Suad Efendic
    • 1
  • Per-Olof Berggren
    • 1
    • 2
  • Anthony Cerami
    • 4
  • Michael Brines
    • 4
  • Claes-Göran Östenson
    • 1
    • 2
  1. 1.Department of Molecular Medicine and SurgeryKarolinska Institutet (KI), Karolinska University HospitalStockholmSweden
  2. 2.The Rolf Luft Research Centre for Diabetes and EndocrinologyKIStockholmSweden
  3. 3.Dept Vascular SurgeryLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Araim PharmaceuticalsTarrytownUSA

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