Insulin Can Be Irresistible.
Although it’s an understatement to say many are recommending sugar restriction as a means to improving health, evidence – relating to inflammatory conditions like insulin resistance, obesity and diabetes – indicates that this approach is unsafe, and can end up becoming a powerful driver of worsening inflammation and disease.
A good way to understand how this might happen, is to look at how exposure to stress, in combination with lack of sugar availability, can inhibit metabolic function, and promote factors which increase biochemical stress. Many of these factors are central to the progression of the inflammatory blood sugar and insulin dysregulated conditions. Problems relating to digestion, tend to be more relevant than most realize.
“Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients…an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently…obesity, T2D, and CVD [cardiovascular disease] share a metabolic milieu characterized by insulin resistance and chronic subacute inflammation.” (Shoelson SE, et al., 2006)
“The present study examined the relationships between cortisol and related parameters of IR…possible pathophysiological mechanisms for the association between…stress and IR or diabetes involve hyper-stimulation of the HPA axis due to stress…chronic stress was associated with IR and may contribute to the development of IR.” (Yan YX, et al., 2016)
“Central to metabolic diseases is insulin resistance associated with a low-grade inflammatory status…we looked for a molecule involved early in the cascade of inflammation and identified LPS (bacterial endotoxin)…LPS is a strong stimulatory of the release of several cytokines that are key inducers of insulin resistance.” (Patrice D. Cani, et al., 2007)
When stress is high and sugar intake is restricted, glycogen stores are fast depleted, and the stress hormones, cortisol and adrenaline, will generally rise, as part of a process which is designed to provide alternative sources of fuel.
Adrenaline helps get the remaining glycogen out of storage and releases fat from tissue, in the form of free fatty acids. Cortisol breaks down muscle and other tissue, so that it can be used for the provision of more energy. The stress substances are crucial for survival, however when they are chronically or excessively raised, they promote degeneration and disease.
If the fatty acids released out of storage into circulation as a result of stress, are made up of high levels of the polyunsaturated fats (PUFAs), they can have a long term negative impact upon numerous biological processes, known to be involved in the progression of insulin related problems.
PUFAs and their breakdown products, are able to promote the development of a chronic inflammatory stress state, responsible for encouraging insulin dysfunction (and many related metabolic issues), in a manner which can become self-perpetuating, and difficult to reverse. The PUFAs are highly unstable, and can easily and rapidly break down inside the body.
“Increased MDA [Malondialdehyde, breakdown product of PUFAs]…was a risk factor for non-alcoholic steatohepatitis…insulin resistance in NAFLD correlates with enhanced oxidative stress. Histopathological disease severity significantly correlated with oxidative stress parameters…” (Köroğlu E, et al., 2016)
“…lipogenic enzyme mRNAs were markedly reduced with increasing dietary corn oil in a dose dependent fashion…PUFA-mediated suppression of the mRNA…was partially restored by pioglitazone treatment…effects…seem to be due to increased insulin sensitivity.” (Iritani N, Fukuda H. 1995)
“Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus…c-Jun amino-terminal kinases (JNKs) can interfere with insulin action…and are activated by inflammatory cytokines and free fatty acids, molecules…implicated in the development of type 2 diabetes.” (Hirosumi J, et al., 2002)
“…accumulation of PUFA from (n-6) and (n-3) series elicited an intracellular oxidative stress, resulting in the activation of oxidative stress-responsive transcription factors such as AP1 and NFkappaB.” (Mazière C, et al., 1999)
The greater the exposure to the stress promoting inflammatory byproducts of the degradation of PUFAs, the more this is likely to interfere with insulin function and proper blood sugar regulation. This then causes further stress, inflammation, and overall damage to metabolism. Intestinal bacterial issues are intertwined with these kinds of metabolic problems. Sugar is protective against stress. Salt and magnesium are also very important.
The byproducts of the PUFAs, stimulate the release of the stress substances (including cortisol, adrenaline, serotonin, nitric oxide and estrogen) and powerfully inhibit thyroid performance, suppressing mitochondrial energy metabolism. A slow metabolism, with increasing exposure to the PUFAs, tends to impede digestion. Sugar increases metabolism and inhibits polyunsaturated free fatty acid release.
A sub-optimal thyroid metabolism and digestive system, allows for bacteria to feed and grow in quantity, moving further up into the small intestine where it is not intended for them to be, promoting exposure to harmful and inflammatory bacterial toxins like endotoxin (LPS). Endotoxin causes serotonin production to be increased.
“…the gut microbiota plays a key role in promoting levels of colon and blood 5-HT (serotonin)…select microbes and their metabolic products can be used to promote endogenous, localized 5-HT biosynthesis…” (Yano JM, et al., 2015)
Increased circulating serotonin levels, have been shown to be an important factor involved in the promotion of blood sugar dysregulation and insulin issues, which often lead to obesity and diabetes.
“Recent studies revealed that peripheral 5-HT [serotonin] plays an important role in metabolic regulation in peripheral tissues, where it suppresses adaptive thermogenesis in brown adipose tissue…suppressing 5-HT signaling might represent a new target for anti-obesity treatment by increasing energy expenditure and improving insulin resistance.” (Oh CM, et al., 2016)
Serotonin and endotoxin, have both been demonstrated to promote inflammation, and to inhibit mitochondrial energy metabolism, leading to further stress and circulation of PUFAs, interfering with the proper use of sugar. Examining ways to improve digestion, in order to minimize bacterial issues, makes a lot of sense in the context of inflammatory conditions which rise under stress, and are associated with insulin resistance.
“Latest evidence suggests…bacterial LPS (endotoxin) deriving from the gut microbiota may trigger inflammation and oxidative stress in response to diets…This “metabolic endotoxemia” has been shown to initiate or promote obesity, insulin resistance, metabolic syndrome, and finally diabetes.” (Pussinen PJ, et al., 2011)
“A striking inflammatory response is septic shock. We tested the hypothesis that non-neuronal serotonin enhances this neutrophil-driven disorder…Indeed, Tph1-/- mice were protected from lethal LPS-induced septic shock…The release of serotonin is yet another way by which platelets enhance inflammatory responses. Excessive neutrophil recruitment may thus also become a target of antiserotonergic treatment strategies.” (Duerschmied D, et al., 2013)
Contrary to popular beliefs, there is good evidence showing that rising serotonin is a central element involved in the progression of depression and anxiety. Endotoxin and inflammation are also closely connected to mental dysregulation, and depression, anxiety, and diabetes often go hand in hand.
“…endotoxaemia and inflammation owing to increased intestinal 5-HT may underpin the depression and diabetes association, where the risk of the latter pathology becomes particularly preeminent after the onset of depression…” (Pomytkin IA, et al., 2015)
Stress and lack of sugar, combined with mineral and nutrient deficiencies, and excessive exposure to PUFAs, can powerfully suppress thyroid energy metabolism and digestive function, also impacting upon intestinal barrier capabilities. Interference with the gut barrier, is more dangerous when bacterial issues exist, as more of the toxic bacterial byproducts, like endotoxin, have the opportunity to pass through to the liver. Serotonin excess has been shown to promote intestinal permeability.
If the liver becomes stressed and overloaded, this interferes with detoxification functions, which means that harmful substances produced in the intestine (such as bacterial endotoxin and serotonin) pass into the main system in greater quantities, where they promote further inflammation, aggravating problems associated with insulin function and diabetes. The combination of the PUFAs, high serotonin, and endotoxin, is inflammatory and anti-metabolic. Apart from their diabetogenic effects, all these things can be involved in the progression of nonalcoholic fatty liver disease (NAFLD), obesity, and heart disease.
“…high-fat feeding dramatically increased intestinal permeability…gut bacteria are involved in the control of intestinal permeability and furthermore in the occurrence of metabolic endotoxemia.” (Patrice D. Cani, et al., 2008)
“Compelling evidence supports the concepts that gut microbiota actively promotes weight gain and fat accumulation and sustains, indirectly, a condition of low-grade inflammation, thus enhancing the cardiovascular risk.” (Manco M, et al., 2010)
“Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD…treatment…caused a reduction of elevated serotonin levels… resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation.” (Haub S, et al., 2011)
The liver is responsible for preparing estrogen for excretion. Excess estrogen interferes with liver function, inhibits thyroid performance, and promotes serotonin levels, and these conditions can provoke stress and rising cortisol and adrenaline levels, and can encourage a general state of metabolic suppression, nervous system and immune dysfunction, and blood sugar dysregulation.
When stress and inflammation is high, estrogen is more likely to get trapped inside tissue. Actual levels of estrogen in the body, are not accurately reflected in blood test results, encouraging misleading (although very popular) ideas with regards to ‘estrogen deficiencies’ as a cause of illness, when it is excess estrogen that is the real problem. Prolactin (a substance which is connected to stress and inflammation), promotes cortisol release, and is associated with insulin resistance, and prolactin levels are known to be an accurate measure of tissue estrogen status.
As estrogen levels go up, and liver function is increasingly interfered with, thyroid hormone is less able to be converted into the metabolically active form (T3), further adding to stress and the suppression of energy system function, leading to greater release of the polyunsaturated free fatty acids, and worsening inflammation and insulin resistance.
Rising levels of endotoxin, serotonin, and estrogen, in combination with high levels of exposure to the PUFAs, seem to go together with rising stress, causing a worsening of inflammation and insulin resistance, and an exacerbation of bacterial issues. All this increases the occurrence of obesity, diabetes, and cardiovascular disease, and other inflammatory conditions.
“…evidence suggests that changes in intestinal microbial composition could be responsible for increased endotoxemia in response to a high-fat diet, which in turn would trigger the development of obesity and diabetes.” (Patrice D. Cani, et al., 2008)
“Experiments…have shown that endotoxin is associated with cardiometabolic abnormalities including obesity, insulin resistance, and diabetes….Importantly, a high-fat diet increased the proportion of…LPS-containing microbiota in the gut.” (Pussinen PJ, et al., 2011)
“In vivo experiments have demonstrated that injections of bacterial endotoxins induce systemic inflammation, which is accompanied by the appearance of insulin resistance…serum LPS [endotoxin] activity is inversely correlated with insulin sensitivity both in diabetic and nondiabetic cohorts.” (Lassenius MI, et al., 2011)
Bacterial endotoxin is directly inflammatory, and both endotoxin and inflammation can promote a rise in levels of the stress substance nitric oxide, which suppresses thyroid energy metabolism, and is another factor in the development of insulin resistance and related metabolic issues.
“Increased nitric oxide (NO) production, especially as a consequence of inducible nitric oxide synthase (iNOS), has also been implicated in insulin resistance, especially in the context of obesity…iNOS is markedly increased in macrophages and other inflammatory cells stimulated by proinflammatory cytokines.” (Evans JL, Goldfine ID., 2013)
“LPS [endotoxin] and the accompanying inflammatory stress markedly impair insulin stimulated muscle glucose uptake as well as induce cardiovascular dysfunction…an increase in NO availability alone in the absence of an inflammatory stress markedly impaired insulin-stimulated MGU [muscle glucose uptake]…” (Lawrence M. House II, et al., 2015)
“Considering the hyperactivity of the inducible NO synthase in MS [metabolic syndrome], these data confirm the altered redox and inflammatory status that characterizes the MS and suggest a link between lipid peroxidation, inflammation, and insulin resistance…examination…shows… in particular, a significant positive association between NOx and the degree of insulin resistance.” (Caimi G, et al., 2014)
Stress and the suppression of oxidative metabolism, causes lactate levels to go up, encouraging insulin resistance, and increasing diabetes risk. Lactate has also been shown to be a driver of cancer, and evidence suggests that high lactate is one of the reasons for the link between cancer and diabetes. Low blood sugar promotes lactate.
“Accumulative evidence indicates a high incidence and mortality for a variety of malignancies in patients with diabetes…Diabetes and cancer interact with each other in a vicious cycle, where lactate plays a pivotal role in this mutual interaction. Insulin resistance/diabetes and cancer conditions produce high levels of lactate and conversely high lactate promotes diabetes and cancer development and progression…” (Wu Y, et al., 2016)
Depending on individual metabolic circumstances, sugar restriction (especially when used to help with existing problems), can be just the thing needed to set in motion a cascade of interrelated, often synergistic, stressful, and inflammatory changes, popularly blamed on the consumption of too much sugar.
Lack of sugar increases cortisol, adrenaline, and free fatty acids, which inhibits thyroid function and digestion, promoting bacterial endotoxin. Endotoxin increases inflammation, and can cause estrogen, serotonin and nitric oxide to rise, stressing the liver. Low sugar also reduces liver function, allowing for systemic inflammatory issues to rise. Endotoxin, nitric oxide, serotonin, and estrogen, suppress oxidative metabolism, increasing lactate. These things promote each other, and further fuel the inflammatory response, increasing stress and insulin resistance, creating a self-feeding downward spiral. Stress and high cortisol from sugar restriction, magnifies the inflammatory response to endotoxin.
“…transient elevation of in vivo cortisol concentrations to levels that are observed during major systemic stress enhanced a subsequent, delayed in vivo inflammatory response to endotoxin. This appeared to be a dose-dependent effect that was more prominent at intermediate concentrations of cortisol than at higher concentrations of cortisol.” (Yeager MP, et al., 2009)
Carbohydrate consumption (in particular the difficult to digest starchy, fibrous foods) can also promote bacterial overgrowth and endotoxemia, although this is far more likely to be true in combination with consumption of PUFAs, when stress is high, when minerals and vitamins are deficient, and when metabolism and digestion are already less than optimal.
I’m not a doctor or a nutritionist, and this is not medical, health or dietary advice, but my experience has shown me that at times like this, it is even more important to experiment with ways to ensure that sugar and protein and other nutrients, can be supplied in a manner which is as easy as possible for digestion. High fat, high carb meals, especially those which are high in PUFAs and starches, can be inflammatory, and can add to bacterial, insulin, and blood sugar issues.
“HFHC (high PUFA high carb) meal…induces an increase in plasma LPS (endotoxin)…relevant to the pathogenesis of postprandial oxidative and inflammatory stress, insulin resistance, and atherosclerosis…” (Ghanim H, et al., 2009)
Orange juice – as well as white sugar, or sugar from fruit in general – with plenty of salt, can powerfully protect against stress, lowering exposure to endotoxin, estrogen, serotonin, nitric oxide, lactate, cortisol, and adrenaline. From this perspective, sugar can be seen as an anti-inflammatory, anti-diabetes, pro-metabolism food.
“The combination of glucose…and the HFHC meal induced oxidative and inflammatory stress and an increase in…endotoxin….orange juice intake with the HFHC meal prevented meal-induced oxidative and inflammatory stress…” (Ghanim H, et al., 2010)
It’s true that the consumption of any kind of fat can cause a temporary insulin resistant state, but it is the PUFAs which are known to stimulate chronic inflammation, and which can prevent the return to normal function, after stress is lowered or when sugar for fuel becomes available. One of the benefits of the highly saturated fats, like coconut oil for instance, is that they are anti-inflammatory, and have anti-bacterial properties.
“Our findings provide evidence for early biological adaptations to high fat feeding that proceed and possibly lead to insulin resistance…our study is the first to demonstrate that circulating endotoxin concentrations are increased following 5 days of an isocaloric, HFD [30% carbohydrate, 15% protein, and 55% fat (25% SFA)] in healthy humans.” (Anderson AS, et al., 2015)
Another possible advantage of a lower fat (and very low PUFAs), moderate protein, high carb diet, is that excess sugar will either be stored as glycogen for later use, or converted into predominantly saturated fats, which are anti-inflammatory, and can be used as fuel during times of stress, without causing harm to metabolism.
A diet avoiding the PUFAs, and with enough protein from milk, cheese, meat and gelatin, with plenty of sugar from easily digestible sweet ripe fruits, fruit juice, white sugar, and honey, is one way to help protect against stress, promote thyroid function and energy metabolism, and limit the blood sugar dysregulating, insulin interfering, inflammatory effects of excess exposure to endotoxin and other toxic things.
“Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites…Endotoxin caused a less severe change in permeability index in…EFAD (essential fatty acid deficient) rats than in normal rats…” (Li EJ, et al., 1990)
When enough sugar is provided (in the context of a nutrient/mineral dense, easy to digest diet) and stress is lowered, polyunsaturated fats still in storage, can be safely eliminated, leading to less exposure to the stress substances (including cortisol, serotonin, nitric oxide, estrogen and lactate). Together, this can allow for a gradual lowering of inflammatory issues, and an improvement in blood sugar regulation, and overall metabolic performance.
The ease of digestion of a pro-metabolic high sugar, high salt, low PUFAs diet, reduces stress, inhibits bacterial issues, improves gut barrier function, lowers endotoxin circulation, improves insulin sensitivity, and can protect against obesity, diabetes, heart disease, cancer, and metabolic issues in general. In this sense sugar is powerfully anti-bacterial, and not the villain it is made out to be.
“…gut bacteria are involved in…metabolic endotoxemia…inflammation, and metabolic disorders. This effect could be mediated by a mechanism that could increase gut permeability and enhance LPS absorption. Antibiotic treatment significantly lowers plasma LPS levels, gut permeability, and the occurrence of…inflammation, oxidative stress…and metabolic disorders.” (Patrice D. Cani, et al., 2008)
Some other things which are pro-metabolism and have the potential to protect against bacterial issues and improve insulin function, include magnesium, biotin, riboflavin, B6, coffee and caffeine, activated charcoal, coconut oil, niacinamide, thyroid hormone, aspirin, glycine, cascara, taurine, minocycline and some other antibiotics, certain antihistamines like cyproheptadine and famotidine, and pregnenolone.
The antibiotic, anti-microbial effects, of a daily raw carrot salad and some occasional well cooked mushrooms, can also help protect against bacterial overgrowth and related insulin dysregulating effects.
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Image: FoodsMatter: “Probiotics – the ‘friendly’ bacteria:” John Scott