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.

Keywords: Beta cell; Diabetes; Drug discovery; High-throughput screen; Human; Pancreas; Proliferation; Regeneration; Review.

Fig. 1

Strategies for beta cell regenerative drug discovery. Drug discovery may be candidate-based, or may involve unbiased high- or medium-throughput screens. Candidates may be derived from the literature, from large data sets or from data mines. Examples of human beta cell mitogenic compounds discovered through these processes are shown in yellow boxes. These include DYRK1A, harmine analogues, gamma aminobutyric acid (GABA), glucagon-like peptide-1 (GLP-1), prolactin and placental lactogens (PRL/PL), osteoprotegerin, and its mimetic, the monoclonal antibody denosumab (OPG), TLQP-21 (a small fragment of a parent peptide called V-growth factor [VGF]), TGF-β, p18 and p21 (cell cycle inhibitors encoded by CDKN2C and CDKN1A, respectively), lysine demethylase 6A (KDM6A) and CDKN1C (encoding p57Kip2). The goal of human beta cell regenerative studies, beta cell proliferation, is illustrated by showing a small, beta cell-deficient islet becoming a larger islet with a higher number of cells. The different coloured cells represent some of the different endocrine cell types within the human islet: beta cells are shown in blue; glucagon-producing alpha cells are shown in red; and somatostatin-producing delta cells are shown in green. This figure is available as part of a downloadable slideset

Fig. 2

The calcium-calmodulin-calcineurn-NFaT-DYRK1A pathway to human beta cell proliferation. Increases in intracellular calcium (Ca⁺⁺), induced, for example, by glucose, sulfonylureas and the glucagon-like peptide-1 (GLP-1) family of drugs, activate calmodulin (CAM), which in turn activates the calcineurins (CnA and CnB). CnA and CnB form a phosphatase complex, which de-phosphorylates a number of substrates, including the NFaT family of transcription factors that, in their phosphorylated state, are tethered to 14-3-3 scaffold proteins in the cytoplasm. De-phosphorylation by calcineurin allows these transcription factors to translocate into the nuclear compartment, where they bind to and activate promoters of cyclins E and A, and cyclin-dependent kinase 1 (CDK1), and repress promoters of the cell cycle inhibitor genes, CDKN2A, CDKN2B and CDKN1C, encoding p16^INK4, p15^INK4 and p57Kip2, respectively. Collectively these events result in cell cycle entry. The kinase DYRK1A serves as the normal termination mechanism in this process by re-phosphorylating NFaT members. This results in their return to the cytoplasm, and return to quiescence. Thus, DYRK1A is the ‘brake’ on cell cycle entry or proliferation. Harmine, INDY, 5-iodo-tubericidin (5-IT) and GNF4877 are all inhibitors of DYRK1A and, in essence, function by disabling the DYRK1A ‘brake’, permitting continued proliferation [14,20,21]. VDCC, voltage-dependent calcium channel. Figure adapted from [14]. This figure is available as part of a downloadable slideset