Type 2 Diabetes and Endotoxemia

by Maelán Fontes

Currently there’s an epidemic of type 2 diabetes (T2D) worldwide, especially in Westernized countries. T2D is characterized by persistent elevated glucose levels due to disrupted insulin action or an alteration in pancreatic insulin production1.

It was estimated that 171 million people were suffering from T2D in 2001, with a total overall population prevalence of 6%. More alarming is the fact that in Caucasian adolescents 4% suffer from T2D and 25% are glucose intolerant1. However, T2D prevalence in hunter-gatherer societies is low2-6, and even nonexistent in the island of Kitava in Trobiand Islands in Papua New Guinea3.

Genetics does not seem to explain the difference, because when these populations are Westernized they suffer even more from diseases of civilization such as T2D, obesity, myocardial infarction and stroke among others7-10 than original Western populations. Furthermore, there’s evidence showing that hunter-gatherer populations can reverse T2D when they are resettled in their ancient habitat8, a fact that has been demonstrated in two recent clinical trials conducted on Western populations11, 12.

Insulin resistance seems to be one of the factors involved in T2D which is caused, by low-grade chronic inflammation13-15 among other factors. Interestingly, low-grade chronic inflammation is a hallmark16-19 in T2D patients.

Considering these factors, it seems plausible that the nutrition introduced with the agricultural revolution 10,000 years ago played an important role in the current diabetes epidemic in Westernized populations. Western foods are overload with antinutrients, namely lectins, saponins and gliadin, which may explain the great disparity between paleolithic and modern Western food when it comes to metabolic syndrome (a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes). There is evidence showing that antinutrients act as endocrine disrupting substances, promoting metabolic syndrome20. On the other hand, antinutrients may elicit their negative health effects through increased intestinal permeability21. However, scant evidence exists regarding the role of antinutrients in the aetiology of Western diseases.

Gliadin and increased intestinal permeability

One of the most studied foods in the recent years is wheat, which contains a protein called gliadin, and is part of the gluten protein family22. Gliadin increases gut permeability by means of Zonulin production (a protein that regulates in tight junctions between cells in the wall of the digestive tract) in the gut enterocytes (epithelial cells found in the small intestines and colon). Zonulin binds the CXCR3 chemokine receptor leading to intracellular signalling cascades, mediated by protein kinase C (PKC), which ultimately causes disruption of the tight junction proteins which maintain the gut barrier function, and lead to increased gut permeability23, 24.

In addition, when intestinal permeability is increased, gliadin - which is resistant to heat and digestive enzymes - is able to interact with gut associated lymphoid tissue (GALT) stimulating the innate immune system, leading to low-grade chronic inflammation22, 24. Several studies have demonstrated that gliadin induces the production of pro-inflammatory cytokines (a small protein released by cells that has a specific effect on the interactions between cells, communications between cells or the behavior of cells), independent of one’s genetic predisposition to celiac disease – which is virtually everyone23, 25, 26.

Lectins and increased gut permeability

Lectins are a family of glycoproteins (a complex protein containing a carbohydrate combined with a simple protein) found in the plant kingdom, including grains, legumes and solanacous plants (tomatoes, potatoes, eggplants and peppers)21, 27. Lectins also have the ability to bind sugar containing molecules. They were first studied for their ability to agglutinate (cause to adhere) red blood cells by binding to their cell membranes. Many lectins present in other foods are harmless, but some lectins found in grains, legumes and solanaceous plants have been shown to be harmful to human physiology28. Lectins are resistant to heat (unless cooked by pressure cooking)29 and digestive enzymes38, and therefore arrive intact when they reach the intestinal epithelium, passing through the intestinal barrier into peripheral circulation. Lectins are able to bind peripheral tissues, producing many deleterious health effects21. Furthermore, lectins disrupt intestinal barrier and immunological function when they bind surface glycans (a carbohydrate polymer containing simple sugars) on gut epithelial cells, causing cellular disruption and increasing gut permeability. Lectins also facilitate the growth of certain bacteria strains, stimulate T-cell proliferation, increase intercellular adhesion molecules (ICAM), stimulate production of pro-inflammatory cytokines (IL-1, TNF-alpha, etc.), and amplify HLA class II molecules expression, among other effects21.

Saponins and increased gut permeability

Saponins are glycoalkaloids (a family of poisons commonly found in the plant species Solanum dulcamara - nightshades) produced by plants, technically known as steroid glycosides or triterpenoids, are formed by a sugar compound (glucuronic acid, glucose or galactose, among others) and aglycone (non-sugar molecule) portion30-32. The aglycone portion binds the cholesterol molecule on gut cell membranes. When certain amounts of saponins bind cell membrane cholesterol molecules of the intestinal epithelial cells at a 1:1 ratio, the sugar portion of the saponins bind together, resulting in a complex molecule consisting of cholesterol and saponins. This new molecule disrupts the gut barrier and increases intestinal permeability. This has been shown in humans who consume a diet rich in alpha-solanine and alpha-chaconine - two of the saponins found in potatoes31.

On the other hand, saponins have adjuvant-like activity, which means that they are able to affect the immune system leading to pro-inflammatory cytokine production33, 34, ultimately inducing insulin resistance.

Intestinal permeability and endotoxemia

Intestinal epithelia act as a physical barrier between the outside and the inside of the body, meaning that the intestinal lumen is technically outside the organism. When the intestinal barrier is disrupted, it allows increased passage of gut luminal antigens derived from food, bacteria and viruses into the organism21. In case of bacteria derived antigens, lipopolysaccharide (LPS) is the most commonly studied and utilized antigen to induce acute immune stimulation, this is known as endotoxemia (the presence of endotoxins - a toxin that forms an integral part of the cell wall of certain bacteria - in the blood which may cause hemorrhages, necrosis of the kidneys, and shock)35. In addition, endotoxemia is associated with low-grade chronic inflammation, insulin resistance and T2D13, 18, 36. In a recent human study it was demonstrated that LPS induced low-grade chronic inflammation in adipose tissue in T2D36 humans.

LPS-TLR4 interaction and low-grade chronic inflammation

The innate immune system is localised in the GALT. When luminal antigens pass through the intestinal barrier, they are phagocited (consumed) by dendritic cells or macrophagues, key components of the innate immune system. Dendritic cells or macrophagues recognize antigens through a family of receptors known as Toll-like receptors (TLR). The best studied and known antigens from gram negative bacteria are LPS which interact with toll-like receptors-4 (TLR4), inducing the production of pro-inflammatory cytokines and ultimately insulin resistance and T2D35. Interestingly, a recently published study demonstrated increased TLR4 expression in T2D humans, contributing to an increased inflammatory state37.

In summary, antinutrients introduced with the agricultural revolution 10,000 years ago may be one of the causal factors in the epidemic of obesity, (as well as T2D) in Western countries. Lectins, saponins and gliadin increase intestinal permeability and allow increased passage of gut bacteria from intestinal lumen to peripheral circulation. LPS - an antigen found in gram-negative bacteria cell membranes - interacts with TLR-4, leading to inflammatory cytokine production and low-grade chronic inflammation, which is at the root of insulin resistance. Insulin resistance is recognised to induce the metabolic syndrome, including T2D. Endotoxemia-induced insulin resistance in T2D patients may be exacerbated, in part, by antinutrients.

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