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Review
. 2018 Jul;61(1):R43-R60.
doi: 10.1530/JME-18-0011. Epub 2018 Apr 16.

The role of beta cell heterogeneity in islet function and insulin release

Daniela Nasteska  1   2   3 , David J Hodson  4   2   3
Affiliations
Review

The role of beta cell heterogeneity in islet function and insulin release

Daniela Nasteska et al. J Mol Endocrinol. 2018 Jul.

Abstract

It is becoming increasingly apparent that not all insulin-secreting beta cells are equal. Subtle differences exist at the transcriptomic and protein expression levels, with repercussions for beta cell survival/proliferation, calcium signalling and insulin release. Notably, beta cell heterogeneity displays plasticity during development, metabolic stress and type 2 diabetes mellitus (T2DM). Thus, heterogeneity or lack thereof may be an important contributor to beta cell failure during T2DM in both rodents and humans. The present review will discuss the molecular and cellular features of beta cell heterogeneity at both the single-cell and islet level, explore how this influences islet function and insulin release and look into the alterations that may occur during obesity and T2DM.

Keywords: diabetes II; insulin secretion; metabolism; pancreatic beta cell.

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Figures

Figure 1
Figure 1
Beta cell communication and insulin release: (A) Gap junctions comprising connexin 36 allow beta cells to coordinate their activities within the intact islet. Gap junction signalling is reduced during obesity and ageing, as well as in individuals harbouring risk alleles for T2DM (SNP). (B) Beta cells in human islet mount coordinated responses to incretins such as glucagon-like peptide 1 (GLP-1), facilitating insulin release. (C) During obesity, a reduction in gap junction signalling leads to loss of coordinated beta cell activity, impairing GLP-1-stimulated insulin secretion. (D) Insulin secretion is polarised toward the vasculature and in rodent models of obesity and T2DM, a reduction in the number of actively secreting beta cells is detected. In humans, some beta cells and beta cell clusters contribute to insulin secretion more than others. (E) Islets display a large functional reserve, with only a handful of first responders supporting glucose-stimulated insulin secretion. Figures were adapted from Servier Medical Art under a CC-BY3.0 licence (https://creativecommons.org/licenses/by/3.0/).
Figure 2
Figure 2
Beta cell heterogeneity and islet function. (A) Optogenetic silencing of less mature and metabolically‑adapted beta cells, termed hubs, leads to a loss of coordinated population activity (eNpHR3.0; halorhodopsin3.0, a yellow light-activated Cl− pump). (B) Optogenetic activation of cells with high but not low NAD(P)H levels leads to activation across the islet (ChR2, channel rhodopsin 2, a blue light-activated Na+ channel). (C) Insulin secretion is impaired following silencing of hubs, but not other single beta cells. (D) Hubs are targeted by cytokines to mimic the pro-inflammatory milieu associated with T2DM. (E) Hubs are stable for a few hours, but their fate is not known over longer time periods. Possibilities include: (1) remaining a hub; (2) becoming a non-hub beta cell or (3) transdifferentiation into another cell type. Figures were adapted from Servier Medical Art under a CC-BY3.0 licence (https://creativecommons.org/licenses/by/3.0/).
Figure 3
Figure 3
Future technologies for interrogating beta cell heterogeneity. (A) Photopharmacology uses light-activated drugs to turn receptors and ion channels into endogenous photoswitches. (B) Tethered pharmacology combines the precision of genetics with pharmacology to selectively target specific cell and receptor populations, and even organelles. (C) Single-cell metabolomics subjects cytoplasm extracted from specific cells to capillary electrophoresis-mass spectrometry, potentially delineating differences in metabolite abundances between subpopulations. (D) TIVA-tag affords optical control over mRNA capture in single cells using a photocleavable poly-U-oligo, which hybridises the corresponding poly-A-tail. (E) Two-photon imaging of islets transplanted into the anterior chamber of the eye allows beta cell heterogeneity to be visualised in a setting where vascular and neural supplies re-wire. Figures were adapted from Servier Medical Art under a CC-BY3.0 licence (https://creativecommons.org/licenses/by/3.0/).
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