Islet sympathetic innervation and islet neuropathology in patients with type 1 diabetes

Abstract

Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac β-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.

Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases

“…These data suggest the possibility that the exocrine compartment influences beta cell function, including beta cell susceptibility to autoimmunity in T1D and beta cell failure in T2D. In addition to changes in acinar mass, alterations in the islet vasculature have been reported in T1D; however, vessels in the peri-islet region were not different between controls and T1D patients 84–86 . In addition, neuroplasticity of sympathetic innervation was observed in inflammatory conditions of the exocrine pancreas 86–88 .…”

“…[84][85][86] In addition, neuroplasticity of sympathetic innervation was observed in inflammatory conditions of the exocrine pancreas. [86][87][88] The development of diabetes after recurrent AP or CP indicates another condition in which inflammation of the exocrine pancreas decreases beta cell insulin secretion. Finally, subjects with diabetes associated with an exocrine pancreatopathy have decreased pancreas weight or volume with histological findings of increased interacinar fibrosis and acinar atrophy.…”

“…In addition to changes in acinar mass, alterations in the islet vasculature have been reported in T1D; however, vessels in the peri-islet region were not different between controls and T1D patients. [84][85][86] In addition, neuroplasticity of sympathetic innervation was observed in inflammatory conditions of the exocrine pancreas. [86][87][88] The development of diabetes after recurrent AP or CP indicates another condition in which inflammation of the exocrine pancreas decreases beta cell insulin secretion.…”

“…139 The ability to study complex interactions between islets and the surrounding acellular components of the environment as well as the nonendocrine cells that contribute to the islet niche has begun to provide a better understanding of islet physiology and pathophysiology. 140 Because living tissue slices retain islets in the native 3D tissue, other cell types and signals contributing to islet physiology can also be studied, including nerves, 86 vasculature, 141 pancreatic ductal cells, 142 exocrine cells, 143 ECM, 144 and immune cells. [145][146][147] Furthermore, slices make it possible to monitor islet and immune cell behavior in the pancreas parenchyma under pathophysiological states such as T1D, which result in compromised islet morphology and thus make isolation of whole islets challenging.…”

The Sympathetic‐Immune Milieu in Metabolic Health and Diseases: Insights from Pancreas, Liver, Intestine, and Adipose Tissues

“…reported altered adrenergic signaling and loss of sympathetic innervation in individuals with non‐diabetic islet autoantibody‐positive, but not in T1D individuals. [ 3a,21 ] In a study utilizing the rat insulin promoter‐lymphocytic choriomeningitis virus‐glycoprotein (RIP‐LCMV‐GP) mouse model of T1D, Christoffersson et al. demonstrated a remarkable infiltration of CD8 + T cells in conjunction with the depletion of islet‐specific tyrosine hydroxylase‐positive (TH + ) sympathetic nerves.…”