Paracrine and autocrine interactions in the human islet: more than meets the eye

Abstract

The pancreatic islet secretes the hormones insulin and glucagon to regulate glucose metabolism. To generate an adequate secretory response, islet endocrine cells must receive multiple regulatory signals relaying information about changes in the internal and external environments. Islet cells also need to be made aware about the functional status of neighboring cells through paracrine interactions. All this information is used to orchestrate a hormonal response that contributes to glucose homeostasis. Several neurotransmitters have been proposed to work as paracrine signals in the islet. Most of these, however, have yet to meet the criteria to be considered bona fide paracrine signals, in particular in human islets. Here, we review recent findings describing autocrine and paracrine signaling mechanisms in human islets. These recent results are showing an increasingly complex picture of paracrine interactions in the human islet and emphasize that results from other species cannot be readily extrapolated to the human context. Investigators are unveiling new signaling mechanisms or finding new roles for known paracrine signals in human islets. While it is too early to provide a synthesis, the field of islet research is defining the paracrine and autocrine components that will be used to generate models about how islet function is regulated. Meanwhile, the identified signaling pathways can be proposed as therapeutic targets for treating diabetes, a devastating disease affecting millions worldwide.

Figure 1. Cellular composition of pancreatic islets

A, Confocal image of a human pancreatic section containing an islet immunostained for insulin (red, beta cells), glucagon (green, alpha cells), and somatostatin (blue, delta cells). These endocrine cells are distributed throughout the islet. Scale bar = 20 μm. B, Schematic diagram depicting endocrine cells (colors as in A), vascular cells (pink), and sympathetic axons (yellow) in the human islet. The vasculature in the human islet possesses numerous vascular smooth muscle cells embedded deep within the islet. These vascular cells are the main targets for sympathetic axons. The endocrine cells are aligned along the vessel without apparent order.

Figure 2. The cellular organization of human and rodent islets is strikingly different

A, B, Confocal images of pancreatic islets from a human (A) and a mouse (B), immunostained for insulin (red), glucagon (green), and somatostatin (blue). Notice the species differences in cell composition and cytoarchitecture. In particular, mouse beta cells (red) mostly appose other beta cells, whereas human beta cells almost always are in contact with alpha cells (green), or delta cells (blue), or both. Scale bar = 50 μm. C, Confocal images of human islets stained as in A showing alignment of endocrine cells along blood vessels (seen as dark spaces). There is no apparent order or segregation of different endocrine cells to distinct regions within the islet. Scale bar = 10 μm.

Figure 3. Schematic diagram depicting cholinergic signaling in pancreatic islets

Whereas muscarinic signaling may be similar in human (left) and mouse (right) beta cells, acetylcholine originates from alpha cells in human islets and from parasympathetic axons in mouse islets.

Figure 4. Schematic diagram depicting putative paracrine and autocrine pathways in human pancreatic islets

Arrows indicate the origin and target of a particular paracrine signal. Black arrows denote excitatory signaling, white arrows indicate inhibition.