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.

The search for putative precursor cells within the pancreas has been the focus of extensive research. Previously, we identified rare pancreas-derived multipotent precursor (PMP) cells in the mouse with the intriguing capacity to generate progeny in the pancreatic and neural lineages. Here, we establish the embryonic pancreas as the developmental source of PMPs through lineage-labeling experiments. We also show that PMPs express insulin and can contribute to multiple pancreatic and neural cell types in vivo. In addition, we have isolated PMPs from adult human islet tissue that are also capable of extensive proliferation, self-renewal, and generation of multiple differentiated pancreatic and neural cell types. Finally, both mouse and human PMP-derived cells ameliorated diabetes in transplanted mice. These findings demonstrate that the adult mammalian pancreas contains a population of insulin(+) multipotent stem cells and suggest that these cells may provide a promising line of investigation toward potential therapeutic benefit.

The neural mechanisms underlying the transition from a drug-nondependent to a drug-dependent state remain elusive. Chronic exposure to drugs has been shown to increase brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. BDNF infusions into the VTA potentiate several behavioral effects of drugs, including psychomotor sensitization and cue-induced drug seeking. We found that a single infusion of BDNF into the VTA promotes a shift from a dopamine-independent to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn. This shift involves a switch in the γ-aminobutyric acid type A (GABA A ) receptors of VTA GABAergic neurons, from inhibitory to excitatory signaling.The ventral tegmental area (VTA) serves as an anatomical locus controlling the switch from an opiate-nondependent to an opiate-dependent state (1,2). In nondependent rats, opiate reward is mediated by a dopamine-independent neural system, involving the brainstem tegmental pedunculopontine nucleus (TPP) (3). Once chronically exposed to opiates and in a state of withdrawal, opiate reward switches to a dopamine-dependent system (3). It has been observed that the switch between the two motivational systems is due to a switch in γ-aminobutyric acid type A (GABA A ) receptor functioning in VTA GABAergic neurons, from an inhibitory to an excitatory signaling state ( fig. S1) (2).Brain-derived neurotrophic factor (BDNF) is capable of producing this change in GABAergic response, from inhibitory to excitatory, as has been observed in the hippocampus during epileptic seizures (4) and in the spinal cord during neuropathic pain (5). BDNF is present in the VTA (6), and its TrkB receptors are present on both GABA ( fig. S2) and dopamine VTA neurons (7,8 enhance several behavioral effects of drugs, including psychomotor sensitization (6,9) and drug seeking (6,10). We hypothesized that, along with the changes in structural plasticity induced by BDNF in VTA dopaminergic neurons (11), increasing BDNF levels in the VTA would induce a switch to a drug-dependent motivational state in drug-nondependent rats due to the effects of BDNF on GABAergic neurons.First, we examined whether BDNF protein and mRNA levels in the VTA were increased in opiate-dependent rats. Sixteen hours after withdrawal from repeated daily exposure to heroin (0.5 mg/kg, subcutaneously) for 8 days [see supporting online material (SOM)], BDNF protein (F 3,37 = 7.63, P < 0.05) and BDNF mRNA (F 3,19 = 4.04, P < 0.05) levels in the VTA increased by 150% (P < 0.05) and 193%, respectively, of the control drug-naïve rats (P < 0.05). However, there were no increases in BDNF either when rats received a single injection of heroin (P > 0.05) or 15 days after withdrawal from repeated heroin exposure (P > 0.05) ( fig. S3).To explore whether BDNF alone was sufficient to cause a change in the neurobiological substrates mediating opiate reward, we next performed place conditioning procedures on rats after single bi...