Advances in drug discovery for human beta cell regeneration

Abstract

The numbers of insulin-secreting pancreatic beta cells are reduced in people with type 1 and type 2 diabetes. Driving beta cell regeneration in the pancreases of people with diabetes would be an attractive approach to reversing diabetes. While adult human beta cells have long been believed to be terminally differentiated and, therefore, irreversibly quiescent, it has become clear over recent years that this is not true. More specifically, both candidate and unbiased high-throughput screen approaches have revealed several classes of molecules that are clearly able to induce human beta cell proliferation. Here, we review recent approaches and accomplishments in human beta cell regenerative drug discovery. We also list the challenges that this rapidly moving field must confront to translate beta cell regenerative therapy from the laboratory to the clinic.

Persistent elevations in circulating INS DNA among subjects with longstanding type 1 diabetes

“…Future work is indicated to determine if such a population of cells could be utilized for strategies aiming to regenerate β cell mass in individuals with undetectable serum C-peptide. 33 We also found that unmethylated INS DNA levels were actually reduced among subjects with one or two high-risk HLA-DRB1 alleles compared with subjects without high-risk HLA alleles. This finding could potentially reflect heterogeneity in the T1D course, with high- Consistent with prior work, we also detected increased methylated INS DNA levels in T1D subjects.…”

“…Along these lines, our findings could also reflect a relative predominance of a persistent dysfunctional β cell subpopulation that is relatively resistant to autoimmune destruction. Future work is indicated to determine if such a population of cells could be utilized for strategies aiming to regenerate β cell mass in individuals with undetectable serum C‐peptide …”

β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies

“…Regeneration of β-cell is another process that may account for recovery β-cell mass after remission, and some drugs have been reported to have such proliferative effects. However, evidence of β-cell replication or proliferation is lacking in adult humans [ 108 , 200 , 201 ].…”

Enzymatically stable analogue of the gut‐derived peptide xenin on beta‐cell transdifferentiation in high fat fed and insulin‐deficient Ins1Cre/+;Rosa26‐eYFP mice

“…This could also have a beneficial influence on pancreatic architecture given the established positive effects of GIP on beta‐cell growth and survival 49‐51 . However, it should also be noted that actual proliferation rates of adult pancreatic beta‐cells are low 52 . Indeed, corresponding observations on positive beta‐cell growth effects of approved glucagon‐like peptide‐1 mimetics in animal models of diabetes, are only evidenced in human islets in vitro to date 53 .…”