Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes

Abstract

Human and rodent islets differ substantially in several features, including architecture, cell composition, gene expression and some aspects of insulin secretion. Mouse pancreatic islets are highly vascularized with interactions between islet endothelial and endocrine cells being important for islet cell differentiation and function. To determine whether human islets have a similar high degree of vascularization and whether this is altered with diabetes, we examined the vascularization of islets from normal human subjects, subjects with type 2 diabetes (T2D), and normal mice. Using an integrated morphometry approach to quantify intra-islet capillary density in human and mouse pancreatic sections, we found that human islets have five-fold fewer vessels per islet area than mouse islets. Islets in pancreatic sections from T2D subjects showed capillary thickening, some capillary fragmentation and had increased vessel density as compared with non-diabetic controls. These changes in islet vasculature in T2D islets appeared to be associated with amyloid deposition, which was noted in islets from 8/9 T2D subjects (and occupied 14% ± 4% of islet area), especially around the intra-islet capillaries. The physiological implications of the differences in the angioarchitecture of mouse and human islets are not known. Islet vascular changes in T2D may exacerbate β cell/islet dysfunction and β cell loss.

Keywords: amyloid; diabetes; islet; pancreas; vasculature.

Figure 1.

Human islets are less vascularized than mouse islets. (A) Vasculature in mouse islets was visualized by endothelium-binding lectin-FITC. Brackets in A and B denote an islet (i). (B) Human pancreatic sections from normal autopsy specimens were labeled with endothelial cell marker CD34. (C) Area of individual islets was similar in the mouse (n=6) and human (n=8). p=0.97. (D) Human islets (n=8) had a lower capillary density as compared with that of the mouse (n=6). ****p<0.0001. Scale, 100 μm.

Figure 2.

Human type 2 diabetes (T2D) islets have abnormal capillary morphology. (A–C) Representative images of normal human islets with uniformly labeled CD34⁺ capillaries. (D–F) Representative images of CD34 staining in T2D human islets. (D) A small fraction of T2D islets had uniform CD34 staining, similar to the controls. (E) The majority of T2D islets had capillaries of irregular appearance, with a diffuse CD34 staining pattern. (F) Some T2D islets displayed partial or near complete loss of hematoxylin-positive nuclei (area marked by asterisk). Brackets in A–F denote an islet (i). Intra-islet capillaries in T2D islets were frequently thicker as compared with control islets (arrowheads). (G) Area of individual islets was similar in normal (n=8) and T2D pancreatic tissues (n=9). p=0.55. (H) Islets in T2D subjects (n=9) had higher capillary density as compared with controls (n=8). ***p<0.001. Scale, 100 μm.

Figure 3.

Alterations in type 2 diabetes (T2D) islet capillary morphology are associated with amyloid deposition. (A–C) β cells and islet amyloid deposition in normal and T2DM pancreas are visualized by fluorescence labeling for insulin (Ins; red) and thioflavin S (green), respectively. (Aʹ–Cʹ) Insets show higher magnification images of vascular regions in panels A–C, as marked by arrowheads. (D–F) Islet capillaries in adjacent sections are visualized by CD34 labeling (brown). (Dʹ–Fʹ) Insets show higher magnification images of vascular regions in panels D–F, as marked by arrowheads. Staining in panels B, C, E and F reveals that amyloid deposits in T2D islets coincide with perivascular location (arrowheads). Brackets in D–F denote an islet (i). Scale (A–F), 100 μm (A’-F’), 50 µm.