Deletion of the insulin receptor in sensory neurons increases pancreatic insulin levels

Abstract

Insulin is known to have neurotrophic properties and loss of insulin support to sensory neurons may contribute to peripheral diabetic neuropathy (PDN). Here, genetically-modified mice were generated in which peripheral sensory neurons lacked the insulin receptor (SNIRKO mice) to determine whether disrupted sensory neuron insulin signaling plays a crucial role in the development of PDN and whether SNIRKO mice develop symptoms of PDN due to reduced insulin neurotrophic support. Our results revealed that SNIRKO mice were euglycemic and never displayed significant changes in a wide range of sensorimotor behaviors, nerve conduction velocity or intraepidermal nerve fiber density. However, SNIRKO mice displayed elevated serum insulin levels, glucose intolerance, and increased insulin content in the islets of Langerhans of the pancreas. These results contribute to the growing idea that sensory innervation of pancreatic islets is key to regulating islet function and that a negative feedback loop of sensory neuron insulin signaling keeps this regulation in balance. Our results suggest that a loss of insulin receptors in sensory neurons does not lead to peripheral nerve dysfunction. The SNIRKO mice will be a powerful tool to investigate sensory neuron insulin signaling and may give a unique insight into the role that sensory neurons play in modifying islet physiology.

Insulin Confers Differing Effects on Neurite Outgrowth in Separate Populations of Cultured Dorsal Root Ganglion Neurons: The Role of the Insulin Receptor

“…This assumption is supported by the apparent insensitivity to insulin’s neurite outgrowth promoting effect of the IB4-positive neurons which lack both the InsR and sensitivity to NGF. Furthermore, novel findings in sensory neuron InsR knockout mice suggested that not the InsR itself, but an interaction between insulin, TRPV1 and/or neuropeptides, such as CGRP is crucial in the development of dysfunctions of insulin signaling in DRG neurons ( Grote et al, 2018 ). However, the results demonstrate a significantly higher expression rate of the InsR in TRPV1- and CGRP-IR DRG neurons as compared to the IB4-positive population.…”

Modulation of Sensory Nerve Function by Insulin: Possible Relevance to Pain, Inflammation and Axon Growth

“…These studies suggested the importance of sensory neurons expressing the TRPV1 receptor in the mediation of pancreatic pathologies. Recently, loss of InsRs expressed by pancreatic sensory nerves has been shown to result in elevated insulin levels and reduced glucose tolerance in sensory neuron insulin receptor knock out (SNIRKO) mice [96].…”

“…It has also been shown that chronic administration of fructose, which induces insulin resistance, and neuropathic pain, reduced InsR protein expression in DRGs and sciatic nerve [123]. However, it has also been revealed that SNIRKO mice do not show any physiological, morphological or behavioral signs of diabetic peripheral neuropathy [96].…”

IGF2 enhanced the osteo‐/dentinogenic and neurogenic differentiation potentials of stem cells from apical papilla

“…INS is a critical component of metabolic regulation and is known to have neurotrophic properties. 61,62 HMGB1 is a nuclear protein with extracellular inflammatory cytokine activity and is released passively during cell injury and necrosis, and secreted actively by immune cells. 63 Recent findings indicate that HMGB1 had an important role in non-infectious inflammation, such as autoimmunity, cancer, trauma and ischaemia reperfusion injury.…”

“…Further bioinformatic analysis identified INS, BMP2, HMGB1, IGFBP3 and HSPA13 were the most important proteins by signal‐net analysis. INS is a critical component of metabolic regulation and is known to have neurotrophic properties 61,62. HMGB1 is a nuclear protein with extracellular inflammatory cytokine activity and is released passively during cell injury and necrosis, and secreted actively by immune cells 63.…”