Innervation Patterns of Autonomic Axons in the Human Endocrine Pancreas

Abstract

SUMMARY The autonomic nervous system regulates hormone secretion from the endocrine pancreas, the islets of Langerhans, and thus impacts glucose metabolism. The parasympathetic and sympathetic nerves innervate the pancreatic islet, but the precise innervation patterns are not known, particularly in human islets. Here we demonstrate that the innervation of human islets is different from that of mouse islets and that it does not conform to existing models of autonomic control of islet function. By visualizing axons in three dimensions and quantifying axonal densities and contacts within pancreatic islets, we found that, in contrast to mouse endocrine cells, human endocrine cells are sparsely contacted by autonomic axons. Few parasympathetic cholinergic axons penetrate the human islet and the invading sympathetic fibers preferentially innervate smooth muscle cells of blood vessels located within the islet. Thus, rather than modulating endocrine cell function directly, sympathetic nerves may regulate hormone secretion in human islets by controlling local blood flow or by acting on islet regions located downstream.

3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury

“…Our results differ from previous observations made by Rodriguez-Diaz et al of the mouse islet sympathetic innervation: we reveal intra-islet TH + axons and varicosities and their connection/ elongation in space and contacts with capillaries, which are absent in the mouse islet images presented previously [23]. Because Rodriguez-Diaz et al found sympathetic neurovascular contacts in human islets, they proceeded to emphasise species differences in innervation patterns.…”

“…The potential reason for the discrepancy between the intra-islet TH + sympathetic innervation reported in this study and the lack of TH + signals inside mouse islets in the observations from Rodriguez-Diaz et al [23] might be due to the different optical properties of the islets used in the two studies. The transparent mouse islets that we prepared by optical clearing account for the detection of the TH + neurovascular complex in the islet core, whereas the untreated islets used in the study of Rodriguez-Diaz et al study are prone to losing fluorescent signals because of scattering in the tissue.…”

“…The revealed neurovascular morphology in the current study supports the following three mechanisms, which may be used individually or in combination to influence islet hormone secretion in mice: (1) neurotransmitters are released and dispersed into the islet circulation through vascularly attached varicosities to regulate downstream endocrine cells in response to activation of sympathetic nerves (chemical stimulation/inhibition: indirect route); (2) while passing through the arteriole, the volume of islet blood flow is controlled by encircling sympathetic nerves to regulate the islet hormones flowing into the body circulation (mechanical modulation); and (3) because the peri-islet sympathetic axons are close to the mouse alpha cells (Figs 2b and c) [35], the sympathetic discharge could directly stimulate glucagon secretion, as suggested by Rodriguez-Diaz et al (chemical stimulation: direct route) [23].…”

“…use of the immersion solution to reduce scattering as light travels in the specimen [18][19][20]) to allow for deeptissue microscopy. Here, in islet imaging, we employed the same penetrative 3-D microscopy with vessel painting (perfusion of blood vessels with fluorescent probes) [13,21] and islet histology [7,8,22,23] to provide a global and integral view of the islet sympathetic neurovascular complex.…”

Tuning to the right signal

“…In this issue of Diabetologia, Carol Yang, Quin Wills and Jim Johnson systematically evaluate the beta cell-protective properties of an extensive panel of over 200 factors on primary mouse beta cells [4]. These factors were selected on the basis of the expression of their cognate receptors in mouse or human islets, derived from prior work by the authors [5] among many others [6][7][8][9][10]. Recognising that beta cell stress in diabetes can occur in many different shapes and forms [3], each factor was systematically evaluated in five distinct islet cell culture conditions, reflective of different type 1 or type 2 diabetes-associated stresses.…”