Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges

Abstract

A quantitative deficiency of normally functioning insulin-producing pancreatic beta cells is a major contributor to all common forms of diabetes. This is the underlying premise for attempts to replace beta cells in people with diabetes by pancreas transplantation, pancreatic islet transplantation, and transplantation of beta cells or pancreatic islets derived from human stem cells. While progress is rapid and impressive in the beta cell replacement field, these approaches are expensive, and for transplant approaches, limited by donor organ availability. For these reasons, beta cell replacement will not likely become available to the hundreds of millions of people around the world with diabetes. Since the large majority of people with diabetes have some residual beta cells in their pancreata, an alternate approach to reversing diabetes would be developing pharmacologic approaches to induce these residual beta cells to regenerate and expand in a way that also permits normal function. Unfortunately, despite the broad availability of multiple classes of diabetes drugs in the current diabetes armamentarium, none has the ability to induce regeneration or expansion of human beta cells. Development of such drugs would be transformative for diabetes care around the world. This picture has begun to change. Over the past half-decade, a novel class of beta cell regenerative small molecules has emerged: the DYRK1A inhibitors. Their emergence has tremendous potential, but many areas of uncertainty and challenge remain. In this review, we summarize the accomplishments in the world of beta cell regenerative drug development and summarize areas in which most experts would agree. We also outline and summarize areas of disagreement or lack of unanimity, of controversy in the field, of obstacles to beta cell regeneration, and of challenges that will need to be overcome in order to establish human beta cell regenerative drug therapeutics as a clinically viable class of diabetes drugs.

Evaluation of the Effects of Harmine on β-cell Function and Proliferation in Standardized Human Islets Using 3D High-Content Confocal Imaging and Automated Analysis

“…Autopsy studies have reported deficits in b-cell mass of up to ~99% in T1D patients, and up to ~65% in T2D patients. Importantly, such studies have suggested that even decades after diagnosis, T1D patients typically maintain a small number of residual bcells (3,5,(7)(8)(9)(10)(11). Restoration of b-cell mass, through the induction of proliferation of residual endogenous b-cells, therefore represents a promising treatment strategy for the recovery of glucose homeostasis in diabetic patients.…”

“…Ki67labeling analysis in postmortem pancreatic tissues has indicated that the highest proliferative rates occur during the perinatal period, with ~2-3.5% of b-cells proliferating, followed by a rapid decline in proliferation during the first two years of life, approaching a rate of <0.5% in adults that continues to decrease with age (12)(13)(14)(15). Epigenomic and transcriptomic analyses have suggested this recalcitrance to replication in adult b-cells to be correlated with repressive histone marks and increased methylation in the promoter regions of cell-cycle related genes, as well as increased expression of senescence markers in adult vs. juvenile b-cells (10,(16)(17)(18).…”

“…Interpretation of these discrepancies is further obscured by the fact that most studies in rodents are performed in juvenile animals, whereas human studies are typically performed using material from older adults. For these reasons and perhaps others, a majority of agents that promote b-cell proliferation in rodents have proven unsuccessful in human islets (10,23). A promising exception is the class of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors, which have recently been identified as an effective strategy to induce b-cell-proliferation in both rodent and human islets (32)(33)(34)(35)(36).…”

“…A promising exception is the class of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors, which have recently been identified as an effective strategy to induce b-cell-proliferation in both rodent and human islets (32)(33)(34)(35)(36). Harmine, an orally bioavailable, naturally occurring compound, is the best studied and a highly potent DYRK1A-inhibitor (36), and has been found to induce human b-cell-proliferation up to 3% (10,37).…”

Induction of antigenic immune tolerance to delay type 1 diabetes – challenges for clinical translation

“…ASIT aims to address exactly that and can, in theory, be applied to both at-risk individuals and those who have been diagnosed with T1D. In fact, ASIT arguably holds potential to cover most, if not all, of the heterogenic disease-stage spectrum characterizing T1D, especially if combined with b-cell-supportive therapies [8][9][10][11][12], and could maintain endogenous insulin production adequate for glucose homeostasis. For T1D, recent studies have provided clear evidence that pro-insulin-reactive CD8 T cells constitute the majority of the final effector cells that stress or eliminate b cells, demonstrating that these cells are present in high numbers in and around the islets of individuals with T1D [13 && ].…”