The Different Faces of the Pancreatic Islet

Abstract

Type 1 diabetes (T1D) patients who receive pancreatic islet transplant experience significant improvement in their quality-of-life. This comes primarily through improved control of blood sugar levels, restored awareness of hypoglycemia, and prevention of serious and potentially life-threatening diabetes-associated complications, such as kidney failure, heart and vascular disease, stroke, nerve damage, and blindness. Therefore, beta cell replacement through transplantation of isolated islets is an important option in the treatment of T1D. However, lasting success of this promising therapy depends on durable survival and efficacy of the transplanted islets, which are directly influenced by the islet isolation procedures. Thus, isolating pancreatic islets with consistent and reliable quality is critical in the clinical application of islet transplantation.Quality of isolated islets is important in pre-clinical studies as well, as efforts to advance and improve clinical outcomes of islet transplant therapy have relied heavily on animal models ranging from rodents, to pigs, to nonhuman primates. As a result, pancreatic islets have been isolated from these and other species and used in a variety of in vitro or in vivo applications for this and other research purposes. Protocols for islet isolation have been somewhat similar across species, especially, in mammals. However, given the increasing evidence about the distinct structural and functional features of human and mouse islets, using similar methods of islet isolation may contribute to inconsistencies in the islet quality, immunogenicity, and experimental outcomes. This may also contribute to the discrepancies commonly observed between pre-clinical findings and clinical outcomes. Therefore, it is prudent to consider the particular features of pancreatic islets from different species when optimizing islet isolation protocols.In this chapter, we explore the structural and functional features of pancreatic islets from mice, pigs, nonhuman primates, and humans because of their prevalent use in nonclinical, preclinical, and clinical applications.

Keywords: ATP; Autocrine signaling; Basement membrane; Endocrine cells; Endocrine pancreas; GABA; Glucagon; Glutamate; Insulin; Islet cytoarchitecture; Islet innervation; Islet isolation; Islet microcirculation; Islet transplantation; Islet vasculature; Neurotransmitter; Paracrine signaling; Parasympathetic; Signaling hierarchy; Somatostatin; Sympathetic; T1D; T2D; Type 1 diabetes; Type 2 diabetes.

Fig. 2.1

Cytoarchitecture of the human, mouse, monkey, and pig islets. Immunostaining for insulin (red), glucagon (green), and somatostatin (blue) in fixed pancreatic sections obtained from (a) human, (b) mouse, (c) monkey, and (d) pig. Scale bar = 50 μm

Fig. 2.2

Sympathetic innervation patterns in the human and mouse endocrine and exocrine pancreas. (a, b) Immunostaining for the sympathetic nerve marker tyrosine hydroxylase (TH; green) and smooth muscle actin (SMA; red) in the (a) human and (b) mouse endocrine pancreas (blue: DAPI nuclear counterstain). (c, d) Immunostaining for the same marker in (c) human and (d) and mouse exocrine tissue. Scale bar = 50 μm

Fig. 2.3

Human islets have abundant smooth muscle actin in association with blood vessels. Immunostaining for smooth muscle actin (SMA; red) and the sympathetic nerve marker tyrosine hydroxylase (TH; green) in a human pancreatic islet shown in (a) a single confocal plane and (b) as maximum projection of a z-stack of multiple confocal images (blue: DAPI nuclear counterstain). Scale bar = 25 μm

Fig. 2.4

Human and mouse pancreatic islets have different patterns of parasympathetic innervation. Immunostaining for the parasympathetic nerve marker vesicular acetylcholine esterase (VAchT; green) and glucagon (red) in a (a) human and (b) mouse islet (blue: DAPI nuclear counterstain). Scale bar = 50 μm