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Glucose-dependent insulinotropic polypeptide stimulates insulin secretion via increased cyclic AMP and [Ca2+]1 and a
1Department of Pharmacology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Abstract:
The effect of wortmannin, a fungal metabolite which is known to inhibit phosphatidylinositol 3-kinase (PI3-kinase) at low concentrations, has been examined for its effect on insulin secretion stimulated by glucose-dependent insulinotropic polypeptide (GIP). Using a hamster derived clonal beta-cell line, the HIT-T15 cell, wortmannin inhibited GIP-stimulated insulin secretion under both static incubation and perfusion conditions. In contrast, wortmannin did not inhibit glucose-stimulated or forskolin-stimulated insulin secretion. The inhibitory effect was of large magnitude, although always partial, and occurred within a few minutes of the onset of stimulation by GIP. Thus GIP, like vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), exerts some of its stimulatory effect on insulin release via a wortmannin-sensitive signal transduction pathway.
Insights
Wortmannin, a PI3-kinase inhibitor, partially blocked insulin secretion stimulated by glucose-dependent insulinotropic polypeptide (GIP) in beta-cells. This indicates GIP uses a wortmannin-sensitive pathway for insulin release.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Signaling
Background:
- Phosphatidylinositol 3-kinase (PI3-kinase) is a key enzyme in cellular signaling pathways.
- Glucose-dependent insulinotropic polypeptide (GIP) is a crucial incretin hormone regulating insulin secretion.
- Wortmannin is a specific inhibitor of PI3-kinase activity.
Purpose of the Study:
- To investigate the role of PI3-kinase in GIP-stimulated insulin secretion.
- To determine if wortmannin affects insulin release mediated by GIP.
Main Methods:
- Utilized the HIT-T15 hamster clonal beta-cell line.
- Administered wortmannin to assess its impact on GIP-stimulated insulin secretion.
- Compared wortmannin's effect on GIP, glucose, and forskolin-stimulated insulin release under static and perfusion conditions.
Main Results:
- Wortmannin significantly inhibited GIP-stimulated insulin secretion in HIT-T15 cells.
- The inhibition by wortmannin was partial but substantial and rapid.
- Wortmannin did not affect insulin secretion stimulated by glucose or forskolin.
Conclusions:
- GIP-mediated insulin secretion involves a wortmannin-sensitive signaling pathway, likely involving PI3-kinase.
- This pathway is distinct from those activated by glucose or forskolin for insulin release.
- Findings highlight the specific role of PI3-kinase in GIP's action on pancreatic beta-cells.