Apr 5, 2020

RIPK2 dictates insulin responses to tyrosine kinase inhibitors in obese mice

BioRxiv : the Preprint Server for Biology
B. M. DugganJonathan D Schertzer

Abstract

Tyrosine kinase inhibitors (TKIs) used in cancer are also being investigated in diabetes. TKIs can improve blood glucose control in diabetic cancer patients, but the specific kinases that alter blood glucose or insulin are not clear. We sought to define the role of Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) in mouse models of insulin resistance. We tested the TKI gefitinib, which inhibits RIPK2 activity, in WT, Nod1-/-, Nod2-/- and Ripk2-/- mice fed an obesogenic high fat diet. Gefitinib lowered blood glucose during a glucose tolerance test (GTT) in a NOD-RIPK2-independent manner in all obese mice. However, gefitinib lowered glucose-stimulated insulin secretion only in obese Ripk2-/- mice. Gefitinib had no effect on insulin secretion in obese WT, Nod1-/-, or Nod2-/- mice. Hence, genetic deletion of Ripk2 promoted the insulin sensitizing potential of gefitinib, since this TKI lowered both blood glucose and insulin only in Ripk2-/- mice. Gefitinib did not alter the inflammatory profile of pancreas, adipose, liver or muscle tissues in obese Ripk2-/- mice compared to obese WT mice. We also tested imatinib, a TKI which does not inhibit RIPK2 activity, in obese WT mice. Imatinib lowered blood glucose during a GTT, consist...Continue Reading

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Mentioned in this Paper

Chromosome Structures
Size
Cohesins
Three-dimensional
Interphase
CTCF
Gene Deletion Abnormality
Polymers
Deletion Mutation
Drug Interactions

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