Research using NOD/ShiLtJ mouse suggests novel therapies for type 1 diabetes
In 2006, a study (Razavi et al. 2006) using the NOD/ShiLtJ (001976; NOD) mice, formally NOD/LtJ, proposed new pathophysiological mechanisms and therapies for insulin-dependent diabetes mellitus (IDDM) or type 1 diabetes (T1D). People with T1D produce inadequate or no insulin because insulin-producing beta cells in the pancreas' islets of Langerhans are destroyed by auto-reactive T cells. T1D accounts for 5-10% of diabetes cases in America. The research team conducting the study was led by Dr. Hans Michael Dosch at The Hospital for Sick Children (SickKids), and included scientists from the University of Calgary along with colleagues David Serreze, Ph.D., and John Driver, Ph.D., of The Jackson Laboratory (SickKids 2006).
The SickKids team took a different approach than many previous type 1 diabetes researchers had taken. Instead of investigating links between irregularities in the immune system and T1D, they investigated links between the immune system, the nervous system and the pancreatic islets. They discovered what they believe to be a control circuit between insulin-producing pancreatic islet cells and their associated sensory or pain neurons. According to the team, the proper functioning of the control circuit depends on the integrity of a protein called transient receptor potential vanilloid-1 (TRPV1), a non-specific cation known to be the receptor for capsaicin. TRPV1 is expressed on sensory neurons that play an important role in proinflammatory reactions. A subset of these neurons innervates the islets of Langerhans.
The SickKids research team found that, in NOD mice, TRPV1 is defective, resulting in the inability of the pancreatic nerve terminals to produce sufficient quantities of a neuropeptide called substance P. The researchers were able to prevent, and even reverse, type 1 diabetes in NOD mice by inactivating (with capsaicin) the neurons that express the defective TRPV1, transiently normalizing the defective TRPV1 by acute local injections of substance P, or replacing the defective Trpv1 gene with the wild-type Trpv1 allele. Hence, the Trpv1 gene was proposed as a candidate for the diabetes susceptibility Idd4.1 locus on chromosome 11.
Based on their results, the team suggested that the critical control circuit works as follows: the neuron subset that innervates the islets of Langerhans responds to the local insulin environment by releasing substance P, which in turn inhibits cytopathic T cell proliferation and survival while sustaining normal insulin secretion and beta cell physiology. In the NOD mice, TRPV1 hypofunction disrupts the control circuit, and leads to insulin resistance, hyperinsulinism and beta cell stress and destruction by infiltrating autoreactive T cells. Inactivating the defective TRPV1 neurons or administering substance P neuropeptides normalizes the circuit.
Although interactions among autoimmunity, inflammation and the nervous system proposed by the SickKids team must be investigated further (Bour-Jordan and Bluestone 2006), the team's research may lead to therapies that prevent (and perhaps reverse) type 1 diabetes without the severe, toxic and immunosuppressive side effects of traditional T1D therapies.
Bour-Jordan H, Bluestone JA. 2006. Sensory neurons link the nervous system and autoimmune diabetes. Cell 127:1097-9.
Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, Tsui H, Tang L, Tsai S, Santamaria P, Driver JP, Serreze D, Salter MW, Dosch HM. 2006. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 127:1123-35.
SickKids. 2006. Discovery of a critical role for sensory nerves in diabetes opens door to new treatment strategies. www.sickkids.ca. Dec 14.