Sugar and Pathways to Disease: an excerpt from "Inflammation Mastery" and "Volume 1: Essential Knowledge in Functional Medicine"

Fructose is the most reactive of the reducing sugars, promoting hemoglobin glycosylation, protein cross-linking, and (lipid) peroxidation much more rapidly than does glucose. Glycosylated proteins can be further modified ultimately to advanced glycation end-products (AGE), which bind to DNA and also promote chronic pain and inflammation at least in part via interaction with the receptor for AGE (RAGE) which, as part of the innate immune system, is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic/sustained inflammation.[1] AGE levels are increased in patients who are diabetic, fibromyalgic, elderly, and those with renal insufficiency; readers should appreciate that AGE levels reflect endogenous production (obviously exacerbated by hyperglycemia) and exogenous consumption (consumption of a diet high in processed foods, especially aged/cooked milk products and baked items such as pastries). As expected, the use of heat to reduce the bacterial load of cow's milk greatly increases the quantity of amino sugars in comparison with non-heated milk; in this manner, pasteurization changes the way these milk proteins are digested and thereafter perceived/processed by the intestinal immune system in a manner that promotes allergic sensitization.[2] The clinical significance of RAGE activation is its vicious contribution to inflammation, as perfectly summarized by Lee and Parker[3], "Interestingly, unlike other receptors, expression of RAGE is positively regulated by its ligand stimulation, which means that increasing concentration of ligands leads to up-regulation of RAGE. So, RAGE signals are accelerated more and more by the accumulation of signal stimulants. RAGE is found on the cell surface of various immune cells, and most of its ligands are mainly secreted by immune cells, including macrophages and dendritic cells; therefore one of the major roles of RAGE is involved in inflammation. Stimulation of RAGE by its ligands activates the proinflammatory transcription factor nuclear factor kappa B (NFkB)..." AGEs are excreted by the kidneys, which are also damaged by AGEs; thus a vicious cycle of AGE exposure, intrarenal AGE retention, renal injury, upregulation of RAGE receptors can culminate in renal failure, particularly due to diabetic nephropathy.
 
The polyol pathway, also called the sorbitol-aldose reductase pathway, is implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves. From a clinical perspective, the conversion of glucose to sorbitol via aldose reductase is important due to the resulting osmotic and oxidative stresses (and possible AGE production via sorbitol-amino binding), while the formation of fructose from sorbitol via sorbitol dehydrogenase is less consequential. Because the retina, kidney, and nervous tissues are insulin-independent, glucose enters in a dose-dependent manner per serum glucose levels, which reflect the balance between glucose intake (i.e., diet) and peripheral glucose uptake. In a hyperglycemic state, the affinity of aldose reductase for glucose rises, causing an escalating/disproportionate accumulation of sorbitol while also causing an escalating/disproportionate depletion of NADPH, resulting in tissue-specific glucose-induced oxidative stress. In these ways (osmotic stress, oxidative stress, AGE formation, inhibition nitric oxide and thus vasodilation and mitochondrial biogenesis), the polyol pathway is a major contributor to hyperglycemia-induced cellular/tissue damage and oxidative stress seen with sustained hyperglycemia, leading to the classic complications of diabetes: cataract, renal injury, neuropathy[4], and -more rarely and to a lesser extent- diabetic cerebral edema.

Dietary activation and modulation of Toll-like receptors (TLR): Toll-like receptors (TLR), especially TLR-2 and TLR-4, are part of the innate immune system activated by microbial motifs (pathogen-associated molecular patterns, PAMPs) and saturated fatty acids (SFA) to induce inflammation generally via NFkB-mediated pathways. As components of the innate immune system, TLR and RAGE can be seen as pro-inflammatory receptors with somewhat of an outward and inward focus, respectively, and for which some overlap in activation is likely to exist; TLR-2/4 are sensitive to PAMPS (hence an outward focus on external invaders) and saturated fatty acids while RAGE are predominantly sensitive to endogenous physiological/metabolic insults (e.g., resulting from hyperglycemia) or inflammation (hence an inward focus on homeodynamic balance). TLR activation by microbes and saturated fatty acids is of particular relevance for the development of insulin resistance and diabetes mellitus type-2 and the associated problems of obesity, hypertension, and appetite insatiation. The most simple model for understanding the sequence of events is as follows; this model of "metabolic inflammation" will be developed further in a following section in this book. TLR activation is primarily abrogated by treatment of causative dysglycemia/diabetes, dysbiosis, and dietary recklessness, secondarily mitigated via olive oil and fish oil which modulate intracellular TLR signaling, and tertiarily modulated by phytonutritional NFkB inhibitors.

[1] Ibrahim et al. RAGE and TLRs: relatives, friends or neighbours? Mol Immunol. 2013 Dec;56(4):739-44

[2] Roth-Walter et al. Pasteurization of milk proteins promotes allergic sensitization by enhancing uptake through Peyer's patches. Allergy. 2008 Jul;63(7):882-90

[3] Lee EJ, Park JH. Receptor for Advanced Glycation Endproducts (RAGE), Its Ligands, and Soluble RAGE. Genomics Inform. 2013 Dec;11(4):224-9

[4] Chung et al. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S233-6

Overview (Part 1) of the Functional Inflammology Protocol

Dr Vasquez's "functional inflammology protocol", famously recalled by the FINDSEX ® acronym, is reviewed in this presentation for its application to the three general types of inflammatory diseases/responses: 1) metabolic inflammation, including glial activation and emphasizing the component of mitochondrial dysfunction, 2) allergic inflammation, including asthma and eczema, and 3) autoimmune inflammation, including rheumatoid arthritis, psoriasis, and the many other conditions that Dr Vasquez has detailed in his books starting in 2004 (Integrative Orthopedics) and 2006 (Integrative Rheumatology, now published as Inflammation Mastery, 4th Edition)

Dr Vasquez introduces the "Functional Inflammology Protocol" at the 2013 International Conference on Human Nutrition and Functional Medicine (PDF brochure)

Inflammation Mastery 4th Edition