Mitogen Synergy: An Emerging Route to Boosting Human Beta Cell Proliferation

Abstract

Decreased number and function of beta cells are a key aspect of diabetes mellitus (diabetes), a disease that remains an onerous global health problem. Means of restoring beta cell mass are urgently being sought as a potential cure for diabetes. Several strategies, such as de novo beta cell derivation via pluripotent stem cell differentiation or mature somatic cell transdifferentiation, have yielded promising results. Beta cell expansion is another promising strategy, rendered challenging by the very low proliferative capacity of beta cells. Many effective mitogens have been identified in rodents, but the vast majority do not have similar mitogenic effects in human beta cells. Extensive research has led to the identification of several human beta cell mitogens, but their efficacy and specificity remain insufficient. An approach based on the simultaneous application of several mitogens has recently emerged and can yield human beta cell proliferation rates of up to 8%. Here, we discuss recent advances in restoration of the beta cell population, focusing on mitogen synergy, and the contribution of RNA-sequencing (RNA-seq) to accelerating the elucidation of signaling pathways in proliferating beta cells and the discovery of novel mitogens. Together, these approaches have taken beta cell research up a level, bringing us closer to a cure for diabetes.

Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2

“…With the exception of HG-9-91-01, these agents increase β-cell proliferation in physiological glucose 5,9,51–54 , suggesting they circumvent feedback control of β-cell mass and could risk hypoglycemia if treatment is continued after the deficit in functional β-cell mass is corrected. Combination therapy with agents exhibiting synergism has been proposed as a strategy to maximize β-cell expansion 7 . Here, we found that SIRT2 regulates β-cell proliferation via a novel metabolic mechanism, opening the possibility for new combinatorial therapies utilizing distinct synergistic mechanisms.…”

“…Studies investigating therapeutic targets for expanding b-cell mass have identified several compounds that stimulate proliferation of adult human b-cells [5][6][7][8] . Recent findings from several groups converged upon mechanisms involving inhibition of the kinase DYRK1A, with further increases of b-cell proliferation achieved using combination treatment with DYRK1A inhibitors and other agents including GLP1 6 or inhibitors of the TGFb pathway 5 .…”

Animal Models for Understanding the Mechanisms of Beta Cell Death during Type 2 Diabetes Pathogenesis

“…The expansion of beta cell mass is infrequent in adult humans, with an estimated rate of 0.1–0.5% proliferating cells versus a 4% peak in fetal development [ 83 , 84 , 85 ]. However, under conditions of stress and heightened insulin demand due to factors including excess calorie intake, insulin resistance, and pregnancy, not only beta cell function but also beta cell mass increases to compensate for an amplified insulin need [ 86 , 87 ]. Beta cell mass expansion can occur through a variety of mechanisms, including neogenesis, proliferation, and transdifferentiation ( Figure 2 ).…”

Signaling pathways that regulate adaptive β‐cell proliferation for the treatment of diabetes

“…Increasing insulin secretion in response to insulin resistance by expanding β‐cell mass and enhancing β‐cell function have been shown in rodent models and possibly in humans, although it is uncertain whether a compensatory increase in β‐cell mass undoubtedly exists in humans 3 , 4 , 5 . The strategies to expand the endogenous β‐cell mass include: (i) promoting β‐cell proliferation; (ii) preventing β‐cell death; (ii) inducing β‐cell neogenesis; and (iv) regulating β‐cell transdifferentiation.…”