TRPC3 regulates islet beta-cell insulin secretion
Abstract: Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3’s involvement in glucose-stimulated insu...
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| Autores principales: | , , , , , , , , |
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| Formato: | Artículo |
| Lenguaje: | Inglés |
| Publicado: |
Wiley
2023
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| Materias: | |
| Acceso en línea: | https://repositorio.uca.edu.ar/handle/123456789/16494 |
| Aporte de: |
| Sumario: | Abstract: Insulin release is tightly controlled by glucose-stimulated calcium (GSCa)
through hitherto equivocal pathways. This study investigates TRPC3, a
non-selective cation channel, as a critical regulator of insulin secretion and
glucose control. TRPC3’s involvement in glucose-stimulated insulin secretion
(GSIS) is studied in human and animal islets. TRPC3-dependent in vivo
insulin secretion is investigated using pharmacological tools and Trpc3−/−
mice. TRPC3’s involvement in islet glucose uptake and GSCa is explored
using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)
amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a
small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice.
TRPC3 is functionally expressed in human and mouse islet beta cells.
TRPC3-controlled insulin secretion is KATP-independent and primarily
mediated by diacylglycerol channel regulation of the cytosolic calcium
oscillations following glucose stimulation. Conversely, glucose uptake in islets
is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in
mice lead to defective insulin secretion and glucose intolerance. Subsequently,
TRPC3 activation through targeted small-molecule enhances insulin secretion
and alleviates diabetes hallmarks in animals. This study imputes a function
for TRPC3 at the onset of GSIS. These insights strengthen one’s knowledge of
insulin secretion physiology and set forth the TRPC3 channel as an appealing
candidate for drug development in the treatment of diabetes. |
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