PMID- 32473019
OWN - NLM
STAT- MEDLINE
DCOM- 20210104
LR  - 20210104
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 161
IP  - 8
DP  - 2020 Aug 1
TI  - RIPK2 Dictates Insulin Responses to Tyrosine Kinase Inhibitors in Obese Male 
      Mice.
LID - bqaa086 [pii]
LID - 10.1210/endocr/bqaa086 [doi]
AB  - 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 wild-type (WT), Nod1-/-, Nod2-/-, and Ripk2-/- mice fed an 
      obesogenic high-fat diet. Gefitinib lowered blood glucose during a glucose 
      tolerance test (GTT) in a nucleotide-binding oligomerization domain 
      (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 with obese WT mice. We 
      also tested imatinib, a TKI that does not inhibit RIPK2 activity, in obese WT 
      mice. Imatinib lowered blood glucose during a GTT, consistent with TKIs lowering 
      blood glucose independently of RIPK2. However, imatinib increased 
      glucose-stimulated insulin secretion during the glucose challenge. These data 
      show that multiple TKIs lower blood glucose, where actions of TKIs on RIPK2 
      dictate divergent insulin responses, independent of tissue inflammation. Our data 
      show that RIPK2 limits the insulin sensitizing effect of gefitinib, whereas 
      imatinib increased insulin secretion.
CI  - (c) Endocrine Society 2020. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Duggan, Brittany M
AU  - Duggan BM
AD  - Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive 
      Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, 
      McMaster University, Hamilton, Ontario, Canada.
FAU - Cavallari, Joseph F
AU  - Cavallari JF
AD  - Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive 
      Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, 
      McMaster University, Hamilton, Ontario, Canada.
FAU - Foley, Kevin P
AU  - Foley KP
AD  - Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive 
      Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, 
      McMaster University, Hamilton, Ontario, Canada.
FAU - Barra, Nicole G
AU  - Barra NG
AD  - Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive 
      Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, 
      McMaster University, Hamilton, Ontario, Canada.
FAU - Schertzer, Jonathan D
AU  - Schertzer JD
AD  - Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive 
      Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, 
      McMaster University, Hamilton, Ontario, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Blood Glucose)
RN  - 0 (Insulin)
RN  - 0 (Nod1 Signaling Adaptor Protein)
RN  - 0 (Nod1 protein, mouse)
RN  - 0 (Nod2 Signaling Adaptor Protein)
RN  - 0 (Nod2 protein, mouse)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinase 2)
RN  - EC 2.7.11.1 (Ripk2 protein, mouse)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Adiposity/drug effects/genetics
MH  - Animals
MH  - Blood Glucose/drug effects/genetics/metabolism
MH  - Diet, High-Fat
MH  - Gefitinib/pharmacology
MH  - Insulin/metabolism
MH  - Insulin Resistance/genetics
MH  - Insulin Secretion/*drug effects/*genetics
MH  - Insulin-Secreting Cells/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Obese
MH  - Nod1 Signaling Adaptor Protein/physiology
MH  - Nod2 Signaling Adaptor Protein/physiology
MH  - Obesity/etiology/genetics/*metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Receptor-Interacting Protein Serine-Threonine Kinase 2/*physiology
MH  - Signal Transduction/drug effects/genetics
OTO - NOTNLM
OT  - diabetes
OT  - insulin resistance
OT  - metabolic inflammation
OT  - obesity
OT  - tyrosine kinase inhibitors
EDAT- 2020/05/31 06:00
MHDA- 2021/01/05 06:00
CRDT- 2020/05/31 06:00
PHST- 2020/04/03 00:00 [received]
PHST- 2020/05/22 00:00 [accepted]
PHST- 2020/05/31 06:00 [pubmed]
PHST- 2021/01/05 06:00 [medline]
PHST- 2020/05/31 06:00 [entrez]
AID - 5849113 [pii]
AID - 10.1210/endocr/bqaa086 [doi]
PST - ppublish
SO  - Endocrinology. 2020 Aug 1;161(8):bqaa086. doi: 10.1210/endocr/bqaa086.