We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Orexin-a Inhibits Glucagon Secretion and Gene Expression.
- Authors
Göncz, Eva; Grötzinger, Carsten; Mergler, Stefan; El-Zayat, Bilal F.; Theodoropoulou, Marily; Stalla, Günter K.; Wiedenmann, Bertram; Strowski, Mathias Z.; Plöckinger, Ursula
- Abstract
Glucagon plays a major role in regulating glucose homeostasis. Orexin-A (OXA) increases insulin and inhibits glucagon secretion, suggesting a role in regulating glucose homeostasis. We used an in situ perfused rat pancreas model to evaluate the effects of OXA on glucagon secretion. We characterized the activated signal transduction pathways and the changes in proglucagon gene transcription induced by OXA in clonal pancreatic A-cells (InR1-G9). OXR-1 expression in InR1-G9 cells was detected by western blot and immuno-fluorescence. The effects of OXA on intracellular cAMP, AKT, PDK-1, CREB and EGR-1 were measured by ELISA and western blot, changes of the intracellular Ca[sup 2+] by Fura-2 measurement. Proglucagon and Foxo1 mRNA levels were quantified by real-time PCR. Silencing of Foxo1 in InR1-G9 cells was performed by transfection with siRNA. Pancreatic A-cells express OXR-1. OXA reduced glucagon secretion in the perfused rat pancreas and in InR1-G9 cells. In pancreatic A-cells OXA decreased intracellular cAMP, Ca2+, CREB mRNA levels and led to the dephosphorylation of CREB protein. OXA increased the phosphorylation of AKT und PDK-1. Proglucagon gene expression was decreased by OXA and this effect was blocked by PI-3 kinase inhibitor. Furthermore, OXA reduced the expression of EGR-1. OXA inhibited proglucagon gene expression and this effect was reversed by silencing of Foxo1. Our study provides the first in vitro evidence for a direct interaction of OXA with pancreatic A-cells. We identified cAMP/AKT/PDK-1 and Ca[sup 2+] as intracellular target molecules for OXA action. Our results demonstrate that transcription factors Foxo1, CREB and EGR-1 act as downstream targets for OXA signalling, suggesting a role in mediating the inhibitory effects of OXA on proglucagon gene transcription. Inhibition of glucagon secretion by OXA may have potential therapeutical implication at lowering hyperglucagonemia frequently encountered in type 2 diabetes.
- Subjects
OREXINS; GLUCAGON; SECRETION; GENE expression; GENETIC transcription; MESSENGER RNA; TYPE 2 diabetes
- Publication
Diabetes, 2007, Vol 56, pA379
- ISSN
0012-1797
- Publication type
Article