| First Author | Duggan BM | Year | 2020 |
| Journal | Endocrinology | Volume | 161 |
| Issue | 8 | PubMed ID | 32473019 |
| Mgi Jnum | J:293893 | Mgi Id | MGI:6452346 |
| Doi | 10.1210/endocr/bqaa086 | Citation | Duggan BM, et al. (2020) RIPK2 Dictates Insulin Responses to Tyrosine Kinase Inhibitors in Obese Male Mice. Endocrinology 161(8) |
| abstractText | 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. |
