Human pancreatic neuro-insular network in health and fatty infiltration

Abstract

Aims/hypothesis Identification of a pancreatic neuro-insular network in mice suggests that a similar integration of islets and nerves may be present in the human pancreas. To characterise the neuro-insular network and the intra-pancreatic ganglia in a clinically related setting, we examined human pancreases in health and with fatty infiltration via 3-dimensional (3D) histology and compared the human pancreatic microenvironment with its counterpart in mice. Methods Human pancreatic specimens from individuals with normal BMI, high BMI (≥ 25) and type 2 diabetes were used to investigate the neuro-insular network. Transparent specimens were prepared by tissue clearing for transmitted light and deeptissue fluorescence imaging to simultaneously visualise infiltrated adipocytes, islets and neurovascular networks. Results High-definition images of human islets reveal that both the sympathetic and parasympathetic nerves enter the islet core and reside in the immediate microenvironment of islet cells. Around the islets, the neuro-insular network is visualised with 3D histology to identify the intra-pancreatic ganglia (peri-lobular and intra-parenchymal ganglia) and the islet-ganglionic association. In humans, but not in mice, pancreatic fatty infiltration (BMI dependent) features adipocytes infiltrating into the parenchyma and accumulating in the perilobular space, in which the peri-lobular ganglia also reside. We identified the formation of adipose-ganglionic complexes in the peri-lobular space and enlargement of ganglia around adipocytes. In the specimen from the individual with type 2 diabetes, an increase in the number of nerve projections from the intra-parenchymal ganglia is associated with severe fatty infiltration. Conclusions/interpretation We present new perspectives of human pancreas and islet innervation via 3D histology. Our results strongly suggest that fatty infiltration in the human pancreas creates a neurotrophic microenvironment and promotes remodelling of pancreatic innervation.

Islet Microvasculature Alterations With Loss of Beta-cells in Patients With Type 1 Diabetes

“…The islet microvasculature is organized into a glomerular-like network of highly fenestrated capillaries surrounded by a unique double basement membrane. [7][8][9][10][11][12][13] The islet microvasculature is required for normal endocrine cell development and serves a critical role in hormone secretion. 11,14,15 Pancreatic islets are well perfused, with an estimated blood perfusion rate of 5-15% of the entire organ despite representing only 1-2% of pancreatic volume.…”

Advances in Ex Situ Tissue Optical Clearing

“…Pancreas is yet another fragile and complex organ of the gastrointestinal system, with the structure determined by characteristic dual functions performed by exocrine and endocrine cells. Like for the intestines, the most comprehensive research on optically cleared pancreas comes from Tang and co‐workers, utilizing FocusClear and RapiClear as OCAs. In a series of studies, these commercial reagents were demonstrated to be suitable for rapid (90‐min long to overnight) clearing and immunostaining (taking 1–2 days) of 400 µm thick slices of both murine and human pancreas .…”

Diet‐induced obesity in young mice: Consequences on the pancreatic intrinsic nervous system control of insulin secretion

“…Obesity induces endocrine pancreatic dysfunction, such as impaired pulsatility and loss of first phase insulin secretion, both under nervous control involving the pancreatic intrinsic nervous system (PINS) . PINS is made of perilobular ganglia and ganglia scattered within the parenchyma (intraparenchymal ganglia) sometimes in close proximity to the islets, whose terminal axons supply the endocrine and exocrine parts of the pancreas, and new techniques of 3D panoramic histology with tissue clearing enabled to nicely visualize the neuro‐insular network in mice and humans . Although previous human islet imaging has suggested limited neural‐islet associations, particularly a lack of parasympathetic nerves in the islets, these improved high‐definition images revealed that the sympathetic and parasympathetic nerves enter the islet core and are located in the immediate microenvironment of islet cells in humans as well as in mice .…”

“…PINS is made of perilobular ganglia and ganglia scattered within the parenchyma (intraparenchymal ganglia) sometimes in close proximity to the islets, whose terminal axons supply the endocrine and exocrine parts of the pancreas, and new techniques of 3D panoramic histology with tissue clearing enabled to nicely visualize the neuro‐insular network in mice and humans . Although previous human islet imaging has suggested limited neural‐islet associations, particularly a lack of parasympathetic nerves in the islets, these improved high‐definition images revealed that the sympathetic and parasympathetic nerves enter the islet core and are located in the immediate microenvironment of islet cells in humans as well as in mice . PINS confers a functional autonomy to the pancreas as suggested by the spontaneous pulsatile insulin secretion displayed by ex vivo isolated pancreas and could be responsible for the synchronization and the amplitude modulation of the pulses of insulin secretion …”