Rodent models, the mouse in particular, have been and remain critical for advancing our understanding of islet biology and disease. Nonetheless, caution is required when translating mouse-derived data to human islet physiology. This caution is predicated on specific differences between mouse and human islets, which, as a group, underscore the importance of research on human islets.43
Architecture and cell ratios
Multiple species differences have been observed in islet morphology and function. In the
mouse, β cells regularly constitute close to 80% of the endocrine cells in each islet, and they are tightly grouped in the interior of the islet structure. The other cell types, especially α cells, are arranged in a “mantle” around the β cell core (Figure 9A). In human islets, however, the spatial arrangement of cell types is highly heterogeneous, with α cells frequently penetrating the islet core (Figure 9B). In addition, the ratio of cell types varies greatly in human islets, with α cells
Figure 9. Islet morphology and composition varies between mice and humans. (A) Mouse and (B) human islets labeled for insulin (green), glucagon (red), and somatostatin (blue). Images exemplify the heterogeneous arrangement of cell types in the human islet, compared to the define beta cell
“core” and alpha cell “mantle” of the mouse islet. Percent of each cell type in (C) mouse islets, n=28, and (D) human islets, n=32, quantified from optical sections taken at various depths throughout the islet. Human islet composition was significantly different (p<0.0001) for all endocrine cell populations examined.
Horizontal bar shows the mean value for each cell type. Image adapted from Brissova et al., 2005.26
representing a much larger percent of islet cells (Figure 9C). This has implications, for example, for whole islet transcription data, where there is an assumed ratio of cell types in the mouse that is not appropriate for human islets.44,45
Gene expression and insulin secretion
The expression of certain critical β cell genes is highly glucose-responsive in mouse islets, but not in human. As published previously,46 48-72 hour treatment with high glucose does not increase gene expression of glucose-sensing genes, transcription factors, or insulin itself in human islets, as it does in mouse islets (Figure10 A-D). As is mentioned earlier in this chapter, MAFB expression is maintained in human adult β cells, whereas its expression is restricted to α cells in adult mouse islets. The insulin secretory profiles of mouse and human islets also vary. When directly compared, human islets secrete more basal insulin, but the fold increase in secretion upon stimulation with high glucose is smaller in human than in mouse (Figure 10E-F), and insulin content experiences a smaller fold increase in human islets than mouse, after 24 hour treatment with high glucose.46
Proliferative capacity and expansion of β cell mass
The establishment of β cell mass and the general proliferative frequency of β cells also differs between species. In the adult mouse, basal β cell proliferation is approximately 2-5%, but the ability of mouse β cells to proliferate in response to obesity, pregnancy, and other conditions of increased insulin demand has been clearly documented.47,48 Some studies suggest that mouse β cell mass more than doubles in pregnancy. Most therapeutically intriguing have been studies suggesting that mouse β cell regeneration can resolve diabetes.49
Figure 10. Differences in glucose-responsive gene expression and glucose-stimulated insulin secretion in human and mouse islets. Human (A) and mouse (B) expression of glucose-sensing genes and islet secreted factors after culture in 5 mM (black bars) or 11mM (white bars) glucose. Human (C) and mouse (D) transcription factor expression after culture in 5 mM (black bars) or 11mM (white bars) glucose. Islet perifusion profiles of human (E) and C57Bl/6 mouse (F) isolated islets, showing that human islets secrete more insulin basally (at 5.6 mM glucose) but have a smaller fold increase in secretion upon stimulation with 16.7 mM glucose. Images from Dai et al. (2012).46
Figure 11. Levels of human β cell proliferation across life periods.
Graphical representation of peak human β cell proliferation during the neonatal period, with β cell proliferation dropping to or below 1% during childhood. Gray points are derived from individual donor pancreata, red points are the mean values in each time category, with the dashed curve representing the change trend between the average value in each life period. Image from Gregg et al.
(2012).50
In human islets, there is a transient burst of β cell proliferation in the postnatal period, but rates drop precipitously and remain very low (0.1-0.5%, by most estimates) during adulthood.50 Although autopsy studies provide evidence that increased body mass index (BMI) correlates with greater β cell mass,51 the lack of longitudinal studies precludes the conclusion that this is due to β cell mass expansion in individual patients, and it seems that β cell mass adaptation in human pregnancy is minor, compared to that in mice.52
The cyclins and cyclin-dependent kinases (cdks) responsible for both mouse and human β cell progression through the cell cycle have been well, if not completely, defined.53,54 As a result, there has been great therapeutic interest in defining mouse and human β cell mitogens, with the end goal of increasing or replacing β cell mass and alleviating diabetes.55 However, due to the relatively modest proliferative response of human β cells to stimuli, it remains unclear whether it will be feasible to address human diabetes with the stimulation of human β cell proliferation.