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. 2019 Jun;68(6):1230-1239.
doi: 10.2337/db19-0072. Epub 2019 Apr 1.

Heterogeneity of the Human Pancreatic Islet

Michael P Dybala  1 , Manami Hara  2
Affiliations

Heterogeneity of the Human Pancreatic Islet

Michael P Dybala et al. Diabetes. 2019 Jun.

Abstract

Pancreatic β-cells play a pivotal role in maintaining normoglycemia. Recent studies have revealed that the β-cell is not a homogeneous cell population but, rather, is heterogeneous in a number of properties such as electrical activity, gene expression, and cell surface markers. Identification of specific β-cell subpopulations altered in diabetic conditions would open a new avenue to develop targeted therapeutic interventions. As intense studies of β-cell heterogeneity are anticipated in the next decade, it is important that heterogeneity of the islet be recognized. Many studies in the past were undertaken with a small sample of islets, which might overlook important individual variance. In this study, by systematic analyses of the human islet in two and three dimensions, we demonstrate islet heterogeneity in size, number, architecture, cellular composition, and capillary density. There is no stereotypic human islet, and thus, a sufficient number of islets should be examined to ensure study reproducibility.

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Figures

Figure 1
Figure 1
3D visualization of islet heterogeneity. A: (a) Large-scale image capture of a human pancreas tissue slice immunostained for insulin (green), glucagon (cyan), CD31 (red), and α-SMA (yellow). Scale bar: 1,000 μm. (b) 3D surface-rendered image of panel a. B: (a) Enlarged view of a cluster of various sizes of islets from the box in Aa. (b) 3D surface-rendered image of panel a without blood vessels. (c) Blood vessels with α-SMA. (d) Large (I), intermediate (II), and small (III) islets selected for enlarged views. Note that blood vessels are made transparent to reveal underlying structures. Scale bars: all 200 μm. C: I, II, and III with images showing intraislet capillaries. Scale bars: all 20 μm.
Figure 2
Figure 2
3D quantification of endocrine cell composition in the human islet. A: A large-scale capture of a tissue block immunostained for insulin (green), glucagon (cyan), somatostatin (blue), and a pan-endocrine cell surface marker (HPi1; red). Scale bar: 500 μm. B: Fluorescent signal processing of z-stack by binary conversion. (a) A representative slice of three islets (boxed in A) showing four channels merged. (b) Pan-endocrine. (c) Insulin. (d) Glucagon. (e) Somatostatin. C: Quantification of volume in 3D. (a) 3D surface rendering of pan-endocrine fluorescent binary signal used to identify islet boundary. 3D fluorescent signals for pan-endocrine (b), insulin (c), glucagon (d), and somatostatin (e). Scale bars: all 100 μm. D: (a–e) Optical slicing from top to bottom of islets showing pan-endocrine and three hormone fluorescent markers. E: Percentage of islet volume constituted by β-cells (insulin, green), α-cells (glucagon, cyan), and δ-cells (somatostatin, blue) was quantified. Five islets of different sizes were selected for each donor for quantification. yo, year-old.
Figure 3
Figure 3
Simulation of the limited selection of islets out of the whole human pancreas. A: Workflow for sampling islets. (a) A subset of islets (>40 μm in diameter) was sampled from the whole human pancreas analysis (21), and the average β-cell area from 1,000 times sampling was measured. (b) Simulation of islet subsets showing the mean β-cell area. (c) Distribution of β-cell composition by islet size. B: Simulation performed in human pancreatic samples from 10 donors. Insets: the total number of islets examined and subject information. C: Distribution of β-cell composition sorted into three diameter ranges. D: Difference from mean β-cell proportion of all islets by simulated islet sample size from each of 10 donors. yo, year-old.
Figure 4
Figure 4
No subunit formation of the mantle-core arrangement in the human islet. A: 2D images of islets immunostained for insulin (green), glucagon (red), and somatostatin (white). (a) Mouse islets. Scale bar: 50 μm. (b) Human islets of various sizes. Scale bar: 50 μm. (c) Large islet. Scale bar: 50 μm. (d) Large islets. Scale bar: 100 μm. B: α-Cell distribution in mouse islets (8-week-old C57BL/6J) and human islets from three different donors (I: 16-year-old [yo] girl, II: 59-year-old man, III: 62-year-old woman). (a–f) Serial optical z-slices from top to bottom of the islet. Fluorescent signal for glucagon after binary conversion is shown. Front view (g) and side view (h) of 3D-rendered α-cells. Scale bar: 50 μm for mouse in a–f, 30 μm for mouse in g and h, all 30 μm for I except 20 μm for g, and all 20 μm for II and III. Scale bars: 30 μm for I except 50 μm for g and h, all 50 μm for II, and 20 μm for III except 40 μm for g and h. C: Serial z-slices of a large islet depicting glucagon signal from top to bottom and 3D rendering. (a–f) Top to bottom serial z-slices of islet showing binary converted fluorescence. (g) Front view of 3D-rendered α-cells. (h) Side view of g. Scale bar: 80 μm for a–f, 70 μm for g, and 100 μm for h. See also Supplementary Figs. 1–4 and Supplementary Movies 1–7.
Figure 5
Figure 5
Islet architecture and capillary bed. A: (a–d) Sequential optical slices. Insulin (green), glucagon (cyan), somatostatin (blue), and CD31 (red). (e) 3D-reconstructed view of three islets and blood vessels. (f) Side view of e. Scale bars: all 50 μm. B: Intermediate size of islet (Feret diameter = 157 μm). (a) 3D-rendered view. Clusters of β-cells (b), α-cells (c), and δ-cells (d). (e) Endocrine cells only. (f) Blood vessels only. (g) β-Cells and α-cells. (h) α-Cells and δ-cells. Scale bars: all 40 μm. C: Large islet (Feret diameter = 404 μm). (a) 3D-rendered view. (b) Blood vessels made transparent. (c and d) Enlarged views. Scale bar: 50 μm for a and b, 30 μm for c, and 20 μm for d. D: Small islets. (a, c, and e) Solid 3D-rendered views. (b, d, and f) β-Cells made transparent. Scale bars: all 15 μm. E: A cluster of small islets. (a) 3D-rendered view. (b) β-Cells and α-cells. (c) α-Cells and δ-cells. (d) Blood vessels only. (e) 3D-reconstructed view with transparent blood vessels. (f) Side view of e. Scale bar: 100 μm for a–f, 40 μm for g–i, and 20 μm for j–l.
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