The Human Islet: Mini-Organ With Mega-Impact

Abstract

This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.

Keywords: diabetes; glucagon; glucose; insulin; islet; α cell; β cell.

Graphical Abstract

Figure 1.

Timeline of key events, discoveries, and technologies related to human islet biology. The upper portion of the figure shows examples of data from the study of human pancreas, islets, or islet cells (described later). The middle portion of the figure shows a timeline of experimental approaches broadly categorized into 3 eras of discovery: 1) identity of islets or islet cells by morphological and histological features; 2) identity of islets or islet cells by antibodies (immunostaining) or ultrastructural features (electron microscopy); and 3) identity of islets or islet cells by genomic or transcriptional profiling leading to molecular signatures. The lower portion of the figure indicates the approximate timing of some important discoveries or events in the understanding of islet biology in each era. These discoveries are illustrated by images or data in the upper panel from some of the original publications positioned at the approximate time of discovery. These selected images and references do not recognize the important work by many scientists because of space limitations. Each image panel in the upper portion of the figure is denoted with a letter: A, A hand-drawn image shows hyaline degeneration in a human islet (likely representing amyloid deposition) in some forms of adult-onset diabetes (9). Differential stainings distinguish endocrine (red in the image) and exocrine (purple in image) areas of the pancreas section. Republished with permission of Rockefeller University Press, from “The Relation of Diabetes Mellitus to Lesions of the Pancreas, Hyaline Degeneration of the Islands of Langerhans,” Opie, The Journal of Experimental Medicine 5, 1901 (8); permission conveyed through Copyright Clearance Center, Inc. B, A hand-drawn image of a guinea pig islet showing 2 distinct islet cell types noted by differential staining with gentian violet and orange G following fixation with alcohol (referred to as α cells; purple cells in figure) or an aqueous chrome-sublimate (referred to as β cells; light orange cells in panel) (10). Republished with permission of John Wiley and Sons, from “The cytological characters of the areas of Langerhans,” Lane, American Journal of Anatomy 7, 1907 (5); permission conveyed through Copyright Clearance Center, Inc. C, A hand-drawn image of a human islet showing δ cells (light blue cells noted with black line) identified by Mallory-azan staining (11), republished with permission of John Wiley and Sons, from “A new type of granular. Cell in the islets of Langerhans of man,” Bloom, Anatomical Record 49, 1931 (12); permission conveyed through Copyright Clearance Center, Inc. D, Electron microscope image of a β cell showing insulin secretory granules in the figure inset (13), reprinted by permission from Springer Nature: Diabetologia, “A portrait of the pancreatic B-Cell,” Orci, 1974 (14); permission conveyed through Copyright Clearance Center, Inc. E, Lymphocytes in a human islet in type 1 diabetes (15), reprinted from The American Journal of Medicine 70, Gepts and Lecompte, “The pancreatic islets in diabetes,” p. 111, © 1981 by authors (16), with permission from Elsevier. Gepts originally described the presence of immune cells in an earlier publication (17). F, Confocal microscopy of an isolated human islet showing immunostaining for insulin (green), glucagon (red), and somatostatin (blue) and highlighting the difference in cell arrangement in human islets compared to rodent islets (18), Brissova, Fowler, Nicholson, et al, Journal of Histochemistry & Cytochemistry 35, p. 11, copyright © 2005 by authors (19); reprinted by permission of SAGE Publications, Inc. G, Panel illustrates the result of transcriptional profiling of single cells with human islets by sequencing the messenger RNA (mRNA) in an individual cell (single-cell RNA sequencing; more information in Table 4) followed by analysis and projection on a T-distributed stochastic neighbor embedding (t-SNE) plot. Colors correspond to cell clusters grouped by patterns of gene expression. Panel provided by review authors (unpublished).

Figure 2.

The pancreatic endocrine islet is a mini-organ that coordinates glucose homeostasis. The pancreas, which is broadly divided into head, body, and tail regions, lies behind the stomach in back of the abdominal cavity, with the head positioned in the curve of the duodenum and the tail extending toward the spleen. Most of the pancreatic mass is exocrine tissue, encompassing clusters of digestive enzyme-secreting cells arranged in acini that feed into a branched ductal system joining the common bile duct for secretion into the small intestine. Variations in cystic duct anatomy exist but the most common anatomy is shown here. Blood flow from the pancreas feeds into the portal vein and flows directly to the liver. Endocrine islets are dispersed throughout the gland; they are composed of α, β, δ, γ, and ε cells and also contain capillaries, nerve fibers, and resident immune cells (shown here: macrophages). Text labels refer to examples of anatomic and cellular features; both pancreatic duct and capillary in inset are schematized to show lumen but are lined by ductal epithelium and vascular endothelium, respectively. © 2021 Victoria B. Rogers.

Figure 3.

Models used to study the human pancreatic islet. Using a cadaveric donor organ, islets can be isolated from surrounding exocrine tissue or can be dispersed further into single cells. Additionally, pancreatic sections can be fixed and/or frozen for histological analysis or processed into “slices” to perform experiments ex vivo. As an alternative to primary tissue, β-like cells can be generated from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or other cell types, and immortalized β cell lines are also available. Cells from multiple sources can be (re)combined to form pseudoislets, and native islets or pseudoislets may also be transplanted into immune-deficient mice for in vivo physiological analysis. See Table 1 for detailed information about these model systems. © 2021 Victoria B. Rogers.

Figure 4.

Common cellular imaging techniques used to study human islets. A, Cleared tissue imaged for 3-dimensional reconstruction is instrumental to understanding intricate structures such as nerves and vasculature. Labeling of the human pancreas for PGP9.5 (islets and nerves; green), CD31 (blood vessels; red), and D2-40 (lymphatic vessels; blue). Image provided by Shiue-Cheng Tang, PhD (National Tsing Hua University, Hsinchu, Taiwan) and is related to reference (108). B and C, Multiplexed immunohistochemistry provides information of overall tissue architecture, cell identity, and cell heterogeneity, accomplished by using antibodies conjugated to oligonucleotide barcodes (B, co-detection by indexing, CODEX; or C, metal isotopes; imaging mass cytometry. B shows an islet labeled for C-peptide (β cells; green), glucagon (α cells; cyan), somatostatin (δ cells; magenta), CD31 (capillaries; red), IBA1 (macrophages; yellow), collagen IV (extracellular matrix; purple), and DAPI (4′ 6‐diamidino‐2‐phenylindole; dark blue); image provided by review authors (unpublished). C shows an islet labeled for C-peptide (β cells; chartreuse), glucagon (α cells; cyan), somatostatin (δ cells; light blue), pancreatic polypeptide (γ cells; red), CD8 (medium blue), CD56 (light orange), CD68 (green), collagen (purple), and nuclear factor κB (dark orange). Image from the Human Pancreas Analysis Program (hpap.pmacs.upenn.edu) (65, 129). D, Imaging mass spectrometry maps spatial distribution of proteins and metabolites. Panel is from a 20-μm image of human pancreas analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS); m/z 703.6 (green) is likely sphingomyelin and m/z 758.6 (magenta) is likely phosphatidylcholine (34:2). Image provided by Boone M. Prentice, PhD (University of Florida, Gainesville, Florida, USA), and is related to reference (119). E, To probe islet ultrastructure, electron microscopy provides enhanced resolution that highlights intracellular components with macromolecular resolution. Image from Nanotomy database (www.nanotomy.org/OA/nPOD), associated with references (124, 130).

Figure 5.

The human islet microenvironment contains a diversity of cells that are intricately connected. Schematic depiction of endocrine cells (β, dark green; α, blue; δ, purple), islet vasculature (red), neuronal processes (yellow), macrophages (pink), and pericytes (pale green). Ligands are colored according to the predominant cell type(s) that produce them or to show they are primarily delivered to the islet via the systemic blood flow; in addition to acting as ligands, some nutrients can also be metabolized (glucose, amino acids [ΑA], free fatty acids [FFA]). Lines depict local action on islet cells through major receptor categories. Key signaling molecules and receptors are shown; see text for discussion of several of these ligands and their effects on α and β cells. The authors emphasize the complex nature of signaling within the islet microenvironment but note that many pathways are necessarily excluded in this depiction because of space constraints. © 2021 Victoria B. Rogers.

Figure 6.

Intracellular mechanisms controlling insulin and glucagon secretion from β and α cells. Perifusion traces depict endocrine cell function and associated schematics of insulin secretion from A and B, β cells, and C and D, glucagon secretion from α cells. Exposure to high glucose (pink), a 3′,5′-cyclic adenosine 5′-monophosphate (cAMP)-potentiator (IBMX; purple), low glucose and epinephrine (teal), and direct depolarization (KCl; orange) represent the standardized protocol used by the Human Pancreas Phenotyping Program (HIPP) to evaluate human islet preparations distributed through IIDP and the Alberta IsletCore; traces shown are from 7 nondiabetic donors, ages 17 to 49 years, analyzed through HPAP (hpap.pmacs.upenn.edu). Schematics of the B, β cell, and D, α cell, highlight major signaling pathways controlling hormone secretion; in the α cell these pathways are less well defined and so the pathways shown are presumptive. Key components within the cell are color coordinated with the corresponding perifusion stimuli to conceptualize how the intracellular pathways result in the secretion dynamics shown in A and C. © 2021 Victoria B. Rogers.

Figure 7.

Age- and disease-related changes to islet structure and function. A, Schematic showing alterations to islet architecture and composition from birth to aging, based on cross-sectional histological evidence. At birth, islets contain a higher proportion of δ cells and lower proportion of β cells compared to adulthood. Additionally, β cells are located primarily in the islet core, whereas α and δ cells are primarily in the islet periphery. By childhood, endocrine cells are intermingled and β cells outnumber α and δ cells. In response to certain metabolic stressors such as insulin resistance/obesity or pregnancy, some studies have indicated slightly increased β cell mass. Aging is marked by epigenetic and molecular changes but maintenance of endocrine mass. B, Schematics showing development of type 1 (left) and type 2 (right) diabetes. In the type 1 diabetes (T1D) model, a yet-to-be-defined “triggering event” or multiple events are thought to initiate an autoimmune process, development of islet autoantibodies, and progressive loss of β cell mass. While this schematic depicts an islet containing only α and δ cells, the degree of β cell loss varies in individuals and with disease progression, and some β cells can still be detected in the pancreas of individuals with T1D. In the type 2 diabetes (T2D) model, progressively insufficient insulin secretion to meet (potentially elevated) insulin demand may be characterized by glucose and lipid toxicity and/or inflammation. In some cases, islet capillaries increase in size, macrophages infiltrate the islet, and/or amyloid deposits disrupt islet architecture. While curves showing changes in β cell mass are smooth, it is likely that the loss of functional β cell mass may stop and restart. © 2021 Victoria B. Rogers.

Figure 8.

Clinical strategies to restore functional β cell mass. Exogenous β cell replacement approaches (left panel) include transplantation of cadaveric islet (human or xenograft) or of stem cell-derived β-like cells. Endogenous approaches (right panel) can be categorized into those that 1) protect β cells from immune or metabolic stress, 2) increase β cell mass through proliferation, neogenesis, or transdifferentiation, and 3) improve β cell function. Modulation of these strategies may require use of β cell or islet-targeting approaches such as antibodies, aptamers or adeno-associated viruses. © 2021 Victoria B. Rogers.