How, When, and Where Do Human β-Cells Regenerate?

Abstract

Purpose of review: Pancreatic β-cells play a critical role in whole-body glucose homeostasis by regulating the release of insulin in response to minute by minute alterations in metabolic demand. As such, β-cells are staunchly resilient but there are circumstances where they can become functionally compromised or physically lost due to pathophysiological changes which culminate in overt hyperglycemia and diabetes.

Recent findings: In humans, β-cell mass appears to be largely defined in the postnatal period and this early replicative and generative phase is followed by a refractory state which persists throughout life. Despite this, efforts to identify physiological and pharmacological factors which might re-initiate β-cell replication (or cause the replenishment of β-cells by neogenesis or transdifferentiation) are beginning to bear fruit. Controlled manipulation of β-cell mass in humans still represents a holy grail for therapeutic intervention in diabetes, but progress is being made which may lead to ultimate success.

Keywords: Diabetes; Islets of Langerhans; Ki67; Proliferation; Transdifferentiation; β-Cell mass.

Fig. 1

Generation of human β-like cells by inducing transdifferentiation from adult somatic cells. Representative scheme summarizing the stimuli and/or genetic manipulations that regulate cell-to-cell conversion into human insulin-positive cells with a β-like phenotype. In particular, β-like cells can be generated by hepatocytes (orange arrow), enterocytes (green arrow), α-cells (yellow arrow), ductal cells (dark blue arrow), acinar cells (light blue arrow), or by self-replication of pre-existing β-cells (circular black arrow). Up arrows indicate gene overexpressions; down arrows indicate gene downregulations. PDX-1, pancreatic and duodenal homeobox 1; NGN3, neurogenin 3; MAFA/B, MAF BZIP transcription factor A/B; FOXO1, forkhead box O1; GLP1, glucagonlike peptide 1; PAX4, paired box 4; ARX, aristaless-related homeobox; DNMT1, DNA methyltransferase 1; GABA, gamma-aminobutyric acid; PDL, pancreatic duct ligation; IL-1β, interleukin 1β; IFN-ɣ, interferon-ɣ; EGF, epidermal growth factor; CNTF, ciliary neurotrophic factor; BMP-7, bone morphogenetic protein 7 (Created with BioRender)

Fig. 2

Molecular mechanism(s) regulating human β-cell proliferation. The nuclear factor kappa-B (NFκB) is retained in the cytosol and its function is repressed by inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKK-ε). WS6 blocks IKK-ε inhibition on NFκB, which can translocate into the nucleus and promote cell growth. TGF-β pathway impacts β-cell proliferation via the activation of SMAD3. SB431542, a TGF-βR inhibitor, promotes cell growth by preventing SMAD3 activation. Insulin receptor (IR)/insulin-like growth factor (IGF1R) and glucagon-like peptide 1 receptor (GLP-1R) signaling pathways trigger β-cell regeneration via modulating PI3K-AKT axis, resulting in the inhibition of glycogen synthase kinase-3β (GSK3β) activity. In addition, inactivation of GSK3β is also obtained by treatments with GNF7156 and GNF4877, GSK3β inhibitors, or osteoprotegerin (OPG) or denosumab. In particular, OPG and denosumab act as mimics of receptor activator of nuclear factor kappa-B ligand (RANKL), preventing its interaction with receptor activator of nuclear factor kappa-B (RANK) and avoiding the activation of the extrinsic apoptotic pathways. Moreover, the hepatokine SerpinB1 and the elastase inhibitor sivelestat stimulate human β-cell proliferation increasing the phosphorylation levels of mitogen-activated protein kinase 3 (MAPK3), protein kinase cAMP-dependent type II regulatory subunit beta (PRKAR2B) and GSK3β, likely following inhibition of proteases as elastase, cathepsin G, or proteinase 3. These effects might involve the protease-activated receptor (PARs) signaling, but such a hypothesis requires further investigations (dotted lines and arrows). The dual-specificity tyrosine-regulated kinase-1a (DYRK1A) represses β-cell proliferation by phosphorylating and retaining into the cytosol the nuclear factor of activated T cells (NFAT). The inhibition of DYRK1A, using small molecules as harmine or 5-iodotubercidin (5-IT), results in the decrease of the phosphorylation state of NFAT, which translocate into the nucleus and activate the mitogenic pathways in human β-cells