Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 103 (7), 2334-9

The Unique Cytoarchitecture of Human Pancreatic Islets Has Implications for Islet Cell Function

Affiliations

The Unique Cytoarchitecture of Human Pancreatic Islets Has Implications for Islet Cell Function

Over Cabrera et al. Proc Natl Acad Sci U S A.

Abstract

The cytoarchitecture of human islets has been examined, focusing on cellular associations that provide the anatomical framework for paracrine interactions. By using confocal microscopy and multiple immunofluorescence, we found that, contrary to descriptions of prototypical islets in textbooks and in the literature, human islets did not show anatomical subdivisions. Insulin-immunoreactive beta cells, glucagon-immunoreactive alpha cells, and somatostatin-containing delta cells were found scattered throughout the human islet. Human beta cells were not clustered, and most (71%) showed associations with other endocrine cells, suggesting unique paracrine interactions in human islets. Human islets contained proportionally fewer beta cells and more alpha cells than did mouse islets. In human islets, most beta, alpha, and delta cells were aligned along blood vessels with no particular order or arrangement, indicating that islet microcirculation likely does not determine the order of paracrine interactions. We further investigated whether the unique human islet cytoarchitecture had functional implications. Applying imaging of cytoplasmic free Ca2+ concentration, [Ca2+]i, we found that beta cell oscillatory activity was not coordinated throughout the human islet as it was in mouse islets. Furthermore, human islets responded with an increase in [Ca2+]i when lowering the glucose concentration to 1 mM, which can be attributed to the large contribution of alpha cells to the islet composition. We conclude that the unique cellular arrangement of human islets has functional implications for islet cell function.

Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Islets of Langerhans show striking interspecies differences. (AD) Confocal micrographs (1-μm optical sections), showing representative immunostained pancreatic sections containing islets of Langerhans from human (A), monkey (B), mouse (C), and pig (D). Insulin-immunoreactive (red), glucagon-immunoreactive (green), and somatostatin-immunoreactive (blue) cells were all found randomly distributed in human and monkey islets. By contrast, insulin-containing cells were located in the core, and glucagon- and somatostatin-containing cells in the mantle of mouse islets. Pig islets seemed to be formed of smaller units (three, in this case) showing a core–mantle organization. (Scale bar, 50 μm). (E) Quantitative enumeration of the contribution of insulin-, glucagon-, and somatostatin-immunoreactive cells to the composition of islets in four different regions of the human pancreas (n = 5 subjects; mean ± SEM). (F) Comparison of the cell composition of human islets with that of mouse islets. Human islets had more glucagon-immunoreactive cells and fewer insulin-immunoreactive cells (n = 3 mice and 5 humans; mean ± SEM).
Fig. 2.
Fig. 2.
Confocal micrographs (1-μm optical sections) of two series of five consecutive human pancreatic sections (10 μm apart), showing that the cytoarchitecture did not change within a given islet. Similar proportions of insulin- (red), glucagon- (green), and somatostatin- (blue) immunoreactive cells could be seen in all sections. Two islets are shown; the equatorial plane for A is shown third from the left and, for B, fourth from the left. (Scale bar, 50 μm.)
Fig. 3.
Fig. 3.
Endocrine cells in human islets were closely but randomly associated with vascular cells. Most insulin- (red), glucagon- (green), and somatostatin- (cyan) immunoreactive cells were in close proximity to vascular cells immunoreactive for both smooth muscle cell actin (vascular smooth muscle cells, blue) and CD34 (endothelial cells, blue). Note that many blood vessels were cut along their main axis, allowing for inspection of long tracts (BD and FH). Endocrine cells were aligned along the blood vessels in a random order; insulin-immunoreactive cells were bordered on both sides by glucagon- (BD) or somatostatin- (FH) immunoreactive cells and vice versa. Cells from different cell types were seen facing each other across the lumen of the blood vessel. The image shown in C is a higher magnification of a region in A; the image shown in H is a higher magnification of a region in E. (Scale bars, 50 μm.)
Fig. 4.
Fig. 4.
Human, monkey, and mouse islets showed functional differences that correlated with structural differences. Different contributions of glucagon-immunoreactive cells were seen for the three species; in human islets (A), the contribution was ≈38%, in monkey islets (B), ≈25%, and, in mouse islets (C), ≈18%. (Scale bar, 50 μm.) [Ca2+]i responses (Fura 2-AM) elicited by low glucose (1 mM, 1), high glucose (11 mM, 11), and high KCl (30 mM, KCl) showed that human (D) and monkey islets (E), but not mouse islets (F) responded to low glucose. Bars under the traces indicate the duration of the stimulus. The peak amplitudes of these responses were quantified for human (G), monkey (H), and mouse (I) islets (n ≥ 10 islets).
Fig. 5.
Fig. 5.
[Ca2+]i responses of β cells were not synchronized in human islets. Oscillations in the [Ca2+]i response to high glucose (11 mM) could be readily detected when recording from whole mouse islets (A) (n = 6 islets). By contrast, oscillatory responses could not be seen when recording from whole human islets (B) (representative trace of ≥70 islets from 10 preparations). Oscillations in the [Ca2+]i response were discernible only in small areas of the islet that corresponded in size to single cells or small groups of cells (C). (D) A magnification of C. Isolated human β cells showed oscillatory [Ca2+]i responses to high glucose concentrations (E) (11 mM; n = 48 of 66 cells from four preparations). The time scale in A also applies to B and C. Arrows indicate the time point when the bath solution was switched from 3 mM to 11 mM glucose.

Similar articles

See all similar articles

Cited by 364 PubMed Central articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback