Harnessing beta-cell replication: advancing molecular insights to regenerative therapies in diabetes

Abstract

Diminished functional beta-cell mass is a key pathogenic mechanism underlying both type 1 and type 2 diabetes (T1D and T2D), precipitated by the progressive impairment of insulin secretion, loss of cellular identity, and ultimately, beta-cell death. The replenishment of beta-cell deficit through the transplantation of pancreatic islets from cadaveric donors or beta-cells derived from human embryonic stem cells has shown transformative therapeutic potential. However, the regeneration of functional beta-cell mass in vivo remains an important therapeutic goal, as a more physiological and scalable approach. Effective beta-cell replenishment must address the underlying causes of beta-cell loss, such as cellular stress and autoimmunity, while simultaneously promoting beta-cell regeneration, function, and survival. Advances in the mechanistic underpinnings of beta-cell differentiation, growth, and survival, coupled with cutting-edge high-throughput screening methods have accelerated the discovery of novel therapeutic targets and small-molecule interventions. Current strategies for in vivo beta-cell expansion include modulating the cell-cycle to promote replication, reprogramming non-beta-cell lineages into beta-cells, and enhancing beta-cell survival. However, the limited regenerative capacity and inherently high stress sensitivity of beta-cells pose significant barriers to their in vivo expansion, further complicated by the fundamental conflict between replication and functional maintenance, and the high vulnerability of replicating cells in a metabolically stressed environment. There has been tremendous progress in developing approaches that simultaneously promote beta-cell expansion and function. In this review, we discuss the recent advances in beta-cell expansion, along with remaining challenges and emerging opportunities to address them.

Keywords: beta cells; diabetes; proliferation; regeneration; replication; therapeutics.

Figure 1

Beta-cell proliferation: natural history and therapeutic considerations. (A) Physiological control of beta-cell expansion in health and disease. The beta-cell proliferation landscape changes substantially throughout life. Early in postnatal life, beta-cells rapidly expand to accommodate growth and establish beta-cell mass. As growth gradually tapers out, beta-cells exit cell-cycle and assume a functionally mature and quiescent state, which retains the capacity to expand on demand, in response to physiological challenges for increased insulin needs, such as pregnancy, obesity, islet injury etc. This capacity of adaptive replication, however, declines with aging due to the onset of p16 accumulation dependent replicative senescence. The replicative response of beta-cells not only depends on age but also varies depending on the nature of the metabolic demand. Continuously high metabolic demand and/or exposure to inflammation can trigger maladaptation and result in dysfunction and a state of permanent cell-cycle exit marked by a pro-inflammatory phenotype: stress-induced senescence. If the stress persists, beta-cells can eventually succumb and undergo cell-death. Ultimately, this can result in diabetes. (B) Factors influencing the efficacy of mitogenic agents on beta-cell expansion in diabetes. The beta-cell phenotype evolves through the course of the initiation and progression of diabetes, amounting to significant heterogeneity of disease. To promote beta-cell expansion in these conditions, the therapeutic agents must not only overcome barriers to beta-cell replication that are especially stringent in human beta-cells, but must also promote resilience to stress and survival, support optimal insulin secretion post-replication, and ensure a healthy milieu by combating inflammation and/or promoting optimal islet niche. This can be achieved either by using mitogenic agents that inherently support beta-cell health or by combining them with therapeutic agents that resolve stress and boost function. Ideally, an optimal therapeutic agent must also selectively target beta-cells to avoid off-target effect. Finally, there is considerable heterogeneity in beta-cell phenotypes, which is further remodeled in disease. Identifying which beta-cell subset maybe most responsive for expansion remains an ongoing line of enquiry that will benefit approaches that involve replication to boost beta-cell mass in diabetes.