Response to comment on: Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, Butler PC (2006) Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 49:1838–1844

Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization

“…However, introduction of an ethyl ester (15) at this position decreased cytotoxicity (~3-fold) compared to OTSS167 (R-Luc CC 50 = 186 nM (15) vs. 64 nM ( 5)) with little effect on DYRK1A inhibition potency [DYRK1A-Luc EC 50 = 7 nM (15) vs. 5 nM (5)]. Similarly, R 1 substitutions with various carboxamides (17)(18)(19)(20)(21)(22)(23)(24) minimally affected cytotoxicity or DYRK1A inhibition, consistent with our OTS167-DYRK1A interaction model. Carboxamides derived from secondary amines, like the morpholino (25) and dimethyl amide (26), exhibited no cytotoxicity (R-Luc CC 50 = >10,000 nM, both); however these compounds also showed decreased DYRK1A inhibition (DYRK1A-Luc EC 50 = 641 nM (25) and 354 nM (26)).…”

“…3,4 In adult animals, new β-cells generated to increase insulin production capacity may arise from a variety of cell types including partially defined facultative progenitor cells, other islet cells and, most convincingly, previously existing β-cells. [5][6][7][8][9] Among the variety of strategies for replacing an individual's β-cell mass, expansion of endogenous β-cells remains paramount.…”

“…7,10,11 β-cell number increases through early adulthood and modest compensatory β-cell mass expansion is an adaptive mechanism for avoiding hyperglycemia. 6,[12][13][14][15] In T1D, up to 88% of individuals have a residual, functional, β-cell mass despite ongoing β-cell destruction. [16][17][18] In pancreata of T1D patients, β-cells exhibit increased replication, suggesting an ongoing regenerative effort that could be pharmacologically supported.…”

“…[16][17][18] In pancreata of T1D patients, β-cells exhibit increased replication, suggesting an ongoing regenerative effort that could be pharmacologically supported. 16,17,19 Importantly, replacement of β-cell mass with islet/pancreas transplantation can restore glucose homeostasis in T1D and T2D patients. [20][21][22] While islet transplantation, whether cadaveric-or stem-cell-derived, may play an increased role in future T1D treatment, the expense and complexity of these procedures will limit widespread use.…”