TRPV1+ Sensory Neurons Control Beta Cell Stress and Islet Inflammation in Autoimmune Diabetes

Cell. 2006 Dec 15;127(6):1123-35. doi: 10.1016/j.cell.2006.10.038.

Abstract

In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1(+) neurons are eliminated. TRPV1(NOD), localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1(-/-) mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity
  • Capsaicin / pharmacology
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / physiopathology*
  • Female
  • Inflammation*
  • Insulin Resistance
  • Insulin-Secreting Cells / pathology
  • Insulin-Secreting Cells / physiology*
  • Islets of Langerhans / innervation*
  • Islets of Langerhans / pathology
  • Islets of Langerhans / physiopathology
  • Male
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / physiology*
  • Substance P / pharmacology
  • T-Lymphocytes / immunology
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / physiology*

Substances

  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Substance P
  • Capsaicin