Highlights d Adult human pancreatic beta cells can be induced to proliferate at high rates d Driven by synergy between DYRK1A inhibitors and TGFb superfamily inhibitors d Reflects activation of cyclins and CDKs accompanied by CDK inhibitor suppression d Proliferation occurs in type 2 diabetic beta cells, with enhanced differentiation SUMMARYSmall-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGFbSF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers. This synergy reflects activation of cyclins and cdks by DYRK1A inhibition, accompanied by simultaneous reductions in key cell-cycle inhibitors (CDKN1C and CDKN1A). The latter results from interference with the basal Trithorax-and SMAD-mediated transactivation of CDKN1C and CDKN1A.Notably, combined DYRK1A and TGFb inhibition allows preservation of beta cell differentiated function. These beneficial effects extend from normal human beta cells and stem cell-derived human beta cells to those from people with type 2 diabetes, and occur both in vitro and in vivo.

Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist–DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist–DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity.

Background Growth of online education has increased the demand for satisfied educators with perceived self-efficacy in online teaching. Teaching self-efficacy is an indicator of the belief that one can make a difference in student learning outcomes. Purpose The aim of this study was to examine the level of teaching self-efficacy and satisfaction of online nursing faculty. Methods This study used a descriptive cross-sectional survey design. Faculty satisfaction was measured by the Online Instructor Satisfaction Measure, and self-efficacy for online teaching was measured by the Michigan Nurse Educator's Sense of Efficacy for Online Teaching instrument. Results The sample included 100 faculty in multiple schools of nursing who taught at least 1 online course in RN to BSN or graduate nursing programs. Overall, participants had relatively high levels of online teaching self-efficacy and satisfaction. Conclusions Teacher self-efficacy can be facilitated through faculty development and increased experience teaching online.