The Mouse That Roared: Connecting the Nervous System to Diabetes

With a clarion-like pronouncement that would do Gabriel proud and which brings tears to the eyes of basic science researchers seeking their day in the sun with a medical breakthrough, researchers from the Hospital for Sick Children in Toronto proclaimed a link between the nervous system and diabetes. In a paper published in the basic sciences journal Cell, Razavi and her colleagues stated: "Our observations open new avenues for therapeutic strategies, raising the possibility that sensory nerve dysfunction may contribute to prediabetes initiation and progression in diabetes-prone humans."¹

How did these basic researchers reach such Olympian heights? As is true for the most effective research that uncovers a mechanism of disease, they turned to animals (think Louis Pasteur and the development of a rabies vaccine, first tested on dogs). In particular, they chose a strain of mice developed at the renowned Jackson Laboratory in Bar Harbor, Maine - where yours truly actually spent one of his most productive summers in research some time ago. These mice (strain NOD) are prone to both insulitis (inflammation and the ultimate destruction of the islets of Langerhans in the pancreas) and diabetes.

Keep in mind that type 1 diabetes has been found to be an autoimmune disease characterized by glucose intolerance due to insulin deficiency. It results from a cascade of reactions in prediabetes, in which there is a progressive lymphoid infiltration surrounding and ultimately inside the pancreatic islets of Langerhans. Eventually, insulin-producing beta cells are destroyed by autoreactive T lymphocytes.²

A key component of this cascade is the expression of antigens recognized by the T cells with this pathogenic potential. But what are these antigens? A clue might be offered from a group of sensory neurons that express what is called a transient receptor potential vanilloid-1 (TRPV1) protein, which has been identified as the receptor for capsaicin.^3,4 The final pieces of this puzzle for building the hypothesis come from the observations that (1) TRPV1+ neurons are known to be important in proinflammatory reactions,⁵ and (2) islets-infiltrating lymphocytes express receptors for neuropeptides.⁶ The connection is made even tighter by the fact that the TRPVI+ nerve terminals express insulin receptors, while insulin both sensitizes and lowers the activation threshold of TRPV1 channels.⁷ Bundling all these threads together, the research team from the Hospital for Sick Children asked: Do the sensory neurons TRPVI+ play a role in type 1 diabetes?

By exposing neonatal NOD mice to capsaicin, TRPVI+ neurons were effectively removed from the equation by means of having their receptor sites occupied. Lack of reactivity of the TRPV1+ protein can be shown by both immunofluorescence and Western blot analysis. What results is that these mice fail to develop either insulitis or diabetes.¹

But it gets better, much better. Because capsaicin has shut down these two indicators of diabetes, the researchers hypothesized that the release of neuropeptides from sensory neuron terminals may be depressed in these mice. It turns out that substance P [sP]⁵ is elevated in the dorsal root ganglia of NOD mice as compared to other strains. The suggestion here is that this accumulation signals that the release of sP has been reduced in these mice. So, by injecting additional sP via the pancreatic artery, Razavi and her colleagues were able to show that within two days after the treatment, 80 percent of the islets in the pancreas were free of the T-cell infiltration that ultimately would lead to diabetes. To complete the picture, both blood glucose levels and insulin sensitivity migrated toward normal levels in the treated mice. In essence, these animals were freed of diabetes with the beneficial effects of a single sP injection lasting as long as four months!

To supplement these findings with genetic data, the Canadian researchers mapped the TRPV1 protein to a specific site on chromosome #11 on the mouse. If this locus in the NOD mouse was replaced with the homologous genome from a normal [B6] strain, both insulitis and diabetes were absent. And elsewhere T-cell pools that were systemic, rather than pancreatic, were shown not to have been affected by the capsaicin treatments. Finally, the authors demonstrated that the level and functionality of the TRPV1 protein in NOD mice were lower than in other strains. This led the authors to suspect that their original hypothesis was supported - that abnormal TRPV1 function could affect beta-cell function in the pancreas, leading to diabetes; and that the effective removal of this aberrant neuropeptide could block the expression of both insulitis and diabetes.

What does all this mean? A neuropeptide is intimately connected to a hormonal defect leading to diabetes. In addition to suggesting further research leading to a possible new means of treating this debilitating and fatal disease, it tells us in no uncertain terms that the nervous and hormonal systems are intertwined. This obviously leads to the question of neural integrity and chiropractic. It offers more than a modicum of support to the very sparse observations in anything but the established front-line refereed medical journals that manipulation seems to have a palliative effect in diabetic patients:

1. One very preliminary observation tells us that in two patients undergoing a neurovascular technique, such complications as vision deterioration or development of foot ulcers seen in diabetic patients did not occur.⁸
2. In another observation that was only barely more robust, using markers that are far more objective and reliable, Kfoury demonstrated that in a single patient, both glucose and glycosylated hemoglobin levels returned to normal after chiropractic adjustments.⁹

Granted that these two factoids may be equated by some to reading tea leaves, they still provide food for thought when coupled with the thorough and groundbreaking findings of Razavi and her colleagues.¹ This entire story emphasizes on no uncertain terms how basic research can uncover such key information to understanding the processes of disease and degeneration. It is the only way in which future productive clinical trials can be designed. And even though the chiropractic community can bask in the glory of having its central premise of chiropractic (the connection between neural integrity and health) supported in this research, it must learn from this key investigation to never lose sight of the basic sciences in being able to justify its means of health care delivery.

References

1. Razavi R, Chan Y, Afifiyan FN, et al. TRPVI+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell, 2006;127(6):1123-1135.
2. Anderson MS, Blueston JA. The NOD mouse: A model of immune dysregulation. Annual Review of Immunology, 2005;23:447-485.
3. Caterina MJ, Julius D. The vanilloid receptor: A molecular gateway to the pain pathway. Annual Review of Neuroscience, 2001;24:487-517.
4. Prescott ED, Julius D. A molecular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science, 2003;300:1284-1288.
5. O'Connor TM, O'Connell J, O'Brien DI, et al. The role of substance P in inflammatory disease. Journal of Cell Physiology, 2004;201:167-180.
6. Persson-Sjogren S, Lejon K, Holmberg D, Forsgren S. Expression of the NK-1 receptor on islet cells and invading immune cells in the non-obese diabetic mouse. Journal of Autoimmunity, 2005;24:269-279.
7. Van Buren JJ, Bhat S, Rotello R, Pauza ME, Premkumar LS. Sensitization and translocation of TRPV1 by insulin and IGF-1. Molecular Pain, 2005;1:17.
8. Nelson WA. Diabetes mellitus: two case reports. Chiropractic Technique, 1989;1(2):37-40.
9. Kfoury PW. Chiropractic and holistic management of type II diabetes mellitus. Digest of Chiropractic Economics, 1995;37(4):37-40.