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The core physiological issue underlying diabetes and insulin resistance has been linked to impaired afferent vagal function.¹ Disruption of vagal afferent fibers by toxicity or surgical activates the glucocorticoid induction of diabetes and hypertension.² Other researchers have shown that intact vagal afferent fibers are required for glucocorticoid-induced glucose intolerance.^2-4

The vagus nerve derives its name from the Latin word for wanderer, to explain the meandering anatomic distribution of the vagus nerve, which has been documented to suppress inflammation,⁵ inhibit seizure activity⁶ and depression,⁷ and establish a regulatory circuit between the liver and central nervous system that can have a positive effect in insulin metabolismand blood pressure.⁴

Diabetes and metabolic syndrome due to insulin resistance cause aberrations in visceral-abdominal fat that generate a cluster of physiological abnormalities: high triglycerides, high blood pressure, high fasting blood sugar, and low HDL cholesterol. While insulin injections help control diabetes, they do not address the afferent vagal deficit and this leads to elevated risks of severe neurological and vascular complications, primarily due to autoimmune destruction of the insulin-producing beta cells. When the body lacks insulin, cells starve and glucose levels soar, causing blindness, kidney failure, and a wide spectrum of other diseases. No treatment on the market has been proven to correct insulin resistance by addressing neural mechanisms underlying the death of pancreatic beta cells.

Excessive abdominal fat is a strong predictor of heart attacks in young men, chronic heart failure in older people, and high blood pressure, and is even implicated in the development of Alzheimer's disease, colon cancer, gallstones, ovarian cystic disease, breast cancer, and sleep apnea. Unlike other kinds of body fat, visceral-abdominal fat can become dysfunctional and produce a stew of menacing molecules that can expand to the point of rupturing. Ruptured fat cells trigger immune cells (macrophages), interleukin-6 (IL-6) and tumor necrosis factor-alpha, which adhere to the endothelium of the blood vessels causing atherosclerosis. Indeed, elevated levels of IL-6 and C-reactive protein (CRP) predict the development of type 2 diabetes and support the role for inflammation in diabetogenesis. Baseline levels of CRP and IL-6 were significantly higher in 188 diabetic women versus 362 matched "normal" controls. And large-scale studies (the Physician's Health Study and the Women's Health Study) revealed high CRP levels to be a risk predictor of myocardial infarction or stroke in men,⁸ cardiovascular events in women,⁹ and cardiovascular events in patients with the metabolic syndrome.^10,11 A cross-sectional study revealed that CRP levels were related to insulin resistance, obesity, endothelial dysfunction, hypertension and diabetes,^12-15 and excessive visceral-abdominal fat,^16,17 all of which have been linked to impaired afferent vagal function.^1-7 These studies raise the prospect that doctors might forestall autoimmune disease by restoring afferent vagal function, which in turn will restore immune function and glucose metabolism.

The vagus afferent-efferent physiology provides a two-way highway of communication between the brain and the liver, duodenum, stomach, and pancreas that regulates digestion, detoxification, steroidogenesis, glucose metabolism, and immunological function. Studies have shown that the afferent-specific neurotoxin capsaicin increased the levels of circulating glucose and triglycerides and negated the actions of insulin on these and free fatty acids and ketone bodies.^18-19

In summary, alternative medicine needs to address the efferent cholinergic anti-inflammatory pathway and the afferent vagus, as these are central mechanisms behind excessive inflammatory responses and diabetes. The involvement of vagus efferent neurons in neuroimmunomodulation provides a protective role against prolonged inflammation via the cholinergic anti-inflammatory pathway.^20,21 Thus, being "holistic" requires that we nourish and support the reciprocal afferent-efferent vagus function, as this is undoubtedly is a missing link in current natural protocols for diabetes, which, for the first time, fully explains the aberrant physiology underlying diabetes.

Notes
1. Tougas G et al. Evidence of impaired afferent vagal function in patients with diabetes gastroparesis. Pacing Clin Electrophysiol. 1992;15:1597–1602.
2. Carlos Bernal-Mizrachi et al. An afferent vagal nerve pathway links hepatic PPARa activation to glucocorticoid-induced insulin resistance and hypertension. Cell Metab. 2007;5:2,91–102.
3. Walls EK et al. Selective vagal rhizotomies: a new dorsal surgical approach used for intestinal deafferentations. Am J Physiol Regulatory Integrative Comp Physiol. 1995;269:1279–1288.
4. Uno K et al. Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science. 2006;312:1656–1659.
5. Borovikova LV et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462.
6. Uthman, BM et al. Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Neurology. 2004;63:1124–1126.
7. Nahas Z et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psych. 2005;66:1097–1104.
8. Ridker PM et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. NEJM. 1997;336:973–979.
9. Ridker PM et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. NEJM. 2000;342:836–843.
10. Ridker PM et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. NEJM. 2002;347: 1557–1565.
11. Ridker PM et al. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. Circulation. 2003;107: 391–397.
12. Yudkin JS et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction. ATVG. 1999;19:972–978.
13. Aruna D et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–334.
14. Hu FB, Meigs JB, Li TY, Nader R, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004;53:693–700.
15. Sesso HD et al. C-reactive protein and the risk of developing hypertension JAMA. 2003;290:2945–2951.
16. Pitombo C et al. Amelioration of diet-induced diabetes mellitus by removal of visceral fat J. Endocrinol. 191(3):699–706.
17. Goodpaster BH et al. Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. Arch Int Med. April 11, 2005;165(7):777–783.
18. Warne JP et al. Afferent signalling through the common hepatic branch of the vagus inhibits voluntary lard intake and modifies plasma metabolite levels in rats. J Physiol. 2007;583(2):455–467.
19. Warne JP, Foster MT, Horneman HF, et al. Hepatic branch vagotomy, like insulin replacement, promotes voluntary lard intake in streptozotocin-diabetic rats. Endocrinology. 2007, 148, 3288–298.
20. Blalock JE. Harnessing a neural-immune circuit to control inflammation and shock. J Exp Med. 2002;195:F25–28.
21. Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003;May–Aug;9(5–8):125–134.

Paul Yanick Jr., PhD
www.aaqm.org