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Sunitinib specifically augments glucose-induced insulin secretion

Stefan Z Lutz1, Axel Ullrich2, Hans-Ulrich Häring1

  • 1German Center for Diabetes Research (DZD e.V.), Germany; Institute for Diabetes Research and Metabolic Diseases IDM of the Helmholtz Center Munich at the Eberhard-Karls-University of Tübingen, Germany; University Hospital Tübingen, Internal Medicine IV, Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.

Cellular Signalling
|April 29, 2017
PubMed

Insights

The tyrosine kinase inhibitor sunitinib directly stimulates glucose-induced insulin secretion (GIIS) in beta cells. This action may explain sunitinib's beneficial effects on blood glucose control in diabetic patients.

Area of Science:

  • Endocrinology
  • Pharmacology
  • Cancer Biology

Background:

  • Sunitinib, a tyrosine kinase inhibitor, treats various cancers.
  • It is known to lower blood glucose and improve glycemic control in diabetic patients.

Purpose of the Study:

  • To investigate the direct effects of sunitinib on insulin-secreting beta cells.
  • To analyze sunitinib's impact on insulin secretion, cellular cAMP levels, and signaling pathways.

Main Methods:

  • Rat insulinoma INS-1E cells were exposed to sunitinib under various conditions.
  • Insulin secretion, cellular cAMP levels, and protein phosphorylation were measured.
  • Techniques included RIA, ELISA, and western blotting.

Main Results:

  • Sunitinib dose-dependently enhanced glucose-induced insulin secretion (GIIS), with maximal stimulation at 2μM.
  • It augmented insulin secretion with elevated cAMP and FFAR1 agonists.
  • Adrenaline and PKA inhibition counteracted sunitinib's effect, but sunitinib did not alter cAMP levels or PKA phosphorylation.

Conclusions:

  • Sunitinib directly stimulates GIIS through a mechanism independent of cAMP/PKA and AKT/ERK signaling.
  • This direct beta-cell action likely contributes to sunitinib's glucose-lowering effects in humans.
Keywords:
FFAR1GLP-1RInsulin secretionPKASunitinibcAMP

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