Islet vasculature. The islet is richly vascularized (Figure 5.3); while islets comprise only ∼2% of pancreas volume, they receive approximately 15% of the blood flow . Arterioles enter the islet and branch into tortuous capillaries, which have been suggested to contact almost every endocrine cell in the islet. These then converge on collecting venules outside the islet . Blood flow through the islet is thought to occur in two distinct patterns: first, arterioles penetrate the islet core and blood flow then emanates from the center of the islet outward. Second, blood flow can also proceed from one side of the islet to the other. These two patterns of blood flow appear to occur in islets from the same pancreas, with the former pattern being more frequent [31,32]. The concept that islet blood flows predominantly from the center to the mantle of the islet suggests that β cells are perfused first . Thus, α cells are exposed to high concentrations of insulin as they lie downstream of β cells in the islet vasculature, which tonically inhibit glucagon secretion. δ Cells are thought to be downstream of both β and α cells, consistent with the notion that somatostatin’s effects to inhibit insulin and glucagon secretion occur in a paracrine, rather than endocrine manner. While the distribution of endocrine cells within nonhuman primate or human islets differs from that of rodents, it is likely that the same directional vascular supply exists [34,35].
Interestingly, there are differences in islet vascular density among species. Rodent islets contain a dense network of small capillaries [30,31], while human islets appear to contain fewer, larger capillaries (Hull, Brissova, Powers, unpublished observation) . However, the functional consequence of this difference in capillary density is unknown. Islet capillaries are lined by a highly fenestrated endothelium, with islet endothelial cells containing around 10 times more fenestrae than capillaries in the neighboring exocrine pancreas . This fenestration allows rapid exchange of nutrients and oxygen between blood and islet cells. However, in contrast to the liver which contains open fenestrae in its endothelium, islet endothelial fenestrae are gated; that is, covered by a glycocalyx, a semipermeable layer composed predominantly of the polysaccharide heparan sulfate . This suggests some selectivity exists with respect to the molecules that can readily pass in and out of the islet capillary, although this is poorly understood. While the islet vasculature is critically important for providing adequate blood flow, supplying nutrients to islet cells and facilitating delivery of islet hormones to peripheral tissues, islet capillaries also provide important signals for normal islet endocrine growth and survival [39–41]. Finally, a vascular basement membrane, a specialized form of extracellular matrix, exists between islet capillaries and endocrine cells [36,37,40,42–44]. While this extracellular matrix comprises predominantly collagen IV and laminins, it also contains a complex array of other proteins and proteoglycans including heparan sulfate proteoglycans, nidogens and hyaluronan which provide both structural support along with critical signals to both islet endothelial cells and endocrine cells, and participates in maintenance of normal function and proliferation of islet cells [40,45,46].
Islet innervation.The islet receives extensive autonomic input, via both sympathetic and parasympathetic branches of the autonomic nervous system . These nerves do not form classical synapses with islet endocrine (or other) cells, but form terminals that release neurotransmitters in close proximity to islet cells which in turn act as important regulators of islet endocrine hormone release . Islet innervation and its functional consequences are reviewed in detail in Chapter 9. Morphologically, islet innervation mirrors that of vascularization, with nerve fibers running parallel to islet capillaries . Accordingly, rodent islets containing numerous, fine nerve fibers , while in contrast, human islets contain fewer, larger nerve fibers  (Figure 5.4).
Interactions among islet cell types. This highly ordered distribution of islet cell types has functional consequences. Islet cell types interact with one another by a number of different mechanisms including direct cell–cell contact, release of paracrine signals or via the extracellular matrix. For example, signaling via gap junctions is important for coordinating insulin release , while autocrine and paracrine signals such as GABA or somatostatin can enhance or suppress islet hormone release from neighboring endocrine cells [22,51,52]. Exposure of islets to neurotransmitters (reviewed in Chapter 9) or endothelial-derived factors such as hepatocyte growth factor, laminin or thrombospondin-1 can stimulate β-cell secretory function and/or replication [41,45,53]. Conversely, β cells produce factors such as vascular endothelial growth factor, which are essential for islet endothelial cell viability and function [40,41]. Culture of β cells on extracellular matrix has profound effects to enhance islet cell proliferation, survival and function, suggesting another mechanism by which endocrine cells can be influenced by the islet vasculature [40,54]. Thus, changes in the abundance or organization of any one of the multiple islet cell types, or in exocrine pancreatic viability and function, likely has significant consequences for islet health and function and ultimately for glucose homeostasis.
Islet beta-cell regenerative potential
As discussed in Chapter 4, development and organization of islet endocrine cells occurs during embryogenesis and the early post-natal period . In rodents, continued β-cell expansion can occur into adulthood . However, the ability of rodent β cells to replicate is severely limited with increasing age . In humans, there is some plasticity in islet volume, particularly in very young individuals , but there is very limited regenerative potential of β cells in adults [57,58]. Physiologic stimuli such as insulin resistance, obesity, and pregnancy have been reported to result in increased β-cell mass in humans and rodents [59–62]; however, pancreatectomy, which is known to stimulate β-cell regeneration in young rodents [56,63], does not result in increased β-cell replication in older rodents  or adult humans . Altering islet volume appears to be an exquisitely regulated process; in line with the requirement for maintenance of the organization of islet cell types, β-cell replication in rodents during pregnancy is preceded by islet angiogenesis (expansion of islet capillaries), suggesting that expansion of the islet vascular supply is required to allow expansion of the endocrine cell population . Maintenance of the appropriate proportions and organization of islet endocrine cell populations in the face of islet expansion also occurs in response to high fat feeding in mice . Islet innervation is also increased under conditions of high fat feeding and insulin resistance [66,67]. However, despite the ability of the islet cell population to expand in response to some physiologic stimuli, the limited capacity for β-cell expansion, especially with age, becomes a major problem in disease states where β cells are targeted for destruction.