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(1) Aim/Hypothesis  Recent studies indicate that tyrosine kinase inhibitors, including imatinib, can reverse hyperglycemia in non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D). Imatinib inhibits c-Abl, c-Kit, and PDGFRs. Next-generation tyrosine kinase inhibitors for T1D treatment should maintain activities required for efficacy while sparing inhibition of targets that might otherwise lead to adverse events. In this study, we investigated the contribution of c-Kit inhibition by imatinib in reversal of hyperglycemia in NOD mice.    (2) Methods  The T670I mutation in c-Kit, which confers imatinib resistance, was engineered into the mouse genome and bred onto the NOD background. Hematopoietic stem cells (HSCs) from NOD.c-Kit T670I  mice and NOD.c-Kit wt  littermates were expanded in the presence or absence of imatinib to verify imatinib resistance of the c-Kit T670I  allele. Diabetic mice were treated with imatinib at the onset of hyperglycemia for three weeks, and blood glucose was monitored.    (3 )Results    In vitro  expansion of HSCs from NOD.c-Kit wt  mice was sensitive to imatinib, while expansion of HSCs from NOD.c-Kit T670I  mice was insensitive to imatinib. However,  in vivo  treatment with imatinib lowered blood glucose levels in both strains of mice.    (4) Conclusions/Interpretation  The HSC experiment confirmed that, in NOD.c-Kit T670I  mice, c-Kit is resistant to imatinib. As both NOD.c-Kit T670I  and NOD.c-Kit wt  mice responded comparably to imatinib, c-Kit inhibition does not substantially contribute to the efficacy of imatinib in T1D. Thus, we conclude that inhibition of c-Kit is not required in next-generation tyrosine kinase inhibitors for T1D treatment, and may be selected against to improve the safety profile.

Inhibition of c-Kit Is Not Required for Reversal of Hyperglycemia by Imatinib in NOD Mice