Maturation of beta cells: lessons from in vivo and in vitro models

Abstract

The ability to maintain normoglycaemia, through glucose-sensitive insulin release, is a key aspect of postnatal beta cell function. However, terminally differentiated beta cell identity does not necessarily imply functional maturity. Beta cell maturation is therefore a continuation of beta cell development, albeit a process that occurs postnatally in mammals. Although many important features have been identified in the study of beta cell maturation, as of yet no unified mechanistic model of beta cell functional maturity exists. Here, we review recent findings about the underlying mechanisms of beta cell functional maturation. These findings include systemic hormonal and nutritional triggers that operate through energy-sensing machinery shifts within beta cells, resulting in primed metabolic states that allow for appropriate glucose trafficking and, ultimately, insulin release. We also draw attention to the expansive synergistic nature of these pathways and emphasise that beta cell maturation is dependent on overlapping regulatory and metabolic networks.

Keywords: AMPK; Beta cells; Circadian; Differentiation; Islets; Maturation; Metabolism; Review; Stem cells; mTOR.

Fig. 1

Overlapping transcriptomic, metabolic and energy-sensing machinery that enables the functional maturation of beta cells. The ability of beta cells to derive GSIS is dependent on the synergistic interplay of many metabolic and regulatory features. The post-weaning maturation of beta cells is characterised by the re-balancing of the AMPK/mTOR energy-sensing pathways and their interaction with circadian clock entrainment. Both of these elements further interact with the canonical triggering and metabolic amplification pathways of GSIS involving NADP-mediated glutathione redox cycling. The feedback between these metabolic and nutrient-sensitive control points also trigger/respond to transcriptional shifts of maturation-associated genes, microRNA regulation and epigenetic signatures in beta cells. Dotted arrows with ‘?’ symbols denote indirect or mechanistically unknown pathways of regulation. GSH, glutathione; S-AMP, adenylosuccinate. This figure is available as part of a downloadable slideset

Fig. 2

Proposed glucose-sensitive metabolic cycles in functionally mature beta cells. The metabolic processing of glucose into TCA cycle intermediates with the resultant oxidative phosphorylation pathway is a core component of canonical GSIS. However, the processing of TCA-derived metabolites throughout a multitude of mitochondrial–cytosolic cycling reactions have also been shown to be a component of mature beta cell function. Genes that form core components of each cycle are shown in boxes outlined in the colour of the relevant cycle. Glycolytic intermediates may also act in the regulation of glucose-sensitive metabolism, together with interactions with elements of cellular energy-sensing machinery. F-1,6-BP, fructose 1,6-bisphosphate; DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate; αKG, α-ketoglutarate. This figure is available as part of a downloadable slideset