Summary: cholesterol plays critical roles in cell membranes and steroid hormone production. This study associates low LDL cholesterol with worse cognitive performance. As expected, the effect is amplified by inflammation. Care should be taken to apply a balanced approach to cholesterol lowering therapies.

A truly fascinating study was just published in the journal Neurobiology of Aging investigating lipoproteins and loss of cognitive function. The authors state:

“The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation.”

They collected biological and cognitive data on 1003 persons ≥ 65 years of age over 6 years of follow-up, measuring cognition with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). High HDL was associiated with better memory performance, but their data seem to suggest the importance of sufficient LDL cholesterol in brain neuronal membranes:

“We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed.”

Not at all surprisingly they found that inflammation compounds the adverse effects of low LDL:

“Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance.”

And since high triglycerides are commonly provoked by the high insulin levels due to insulin resistance which also have deleterious effects on the brain…

“Also, high triglycerides were associated with lower memory performance in those with high inflammation.”

The authors conclude by suggesting that HDL, LDL and inflammatory indicators can be used as predictors of poor cognitive function:

“Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.”

This compels us to use caution and see the ‘big picture’ when designing strategies to manage lipids—care should be taken to not suppress LDL cholesterol to too low a level.

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Summary: Adjuvants are agents added to vaccines to heighten the immune system response to the primary antigen. The video below presents an excellent lecture by one of the world’s leading experts in autoimmunology. He explains how adjuvants can trigger autoimmune reactions that manifest, months or years later, as autoimmune diseases. His exposition, richly illustrated by published case studies, is valuable for all clinicians regardless of specialty. Practically any tissue in the body, including the brain and vascular system, can be a target for autoimmune attack.

Autoimmunity seems to be the medical issue of our time as environmental and other factors promote a loss of immune tolerance to chemicals, toxic and benign, and to self. The resulting chronic inflammation underlies many conditions beyond the strictly defined autoimmune diseases such as MS, SLE and rheumatoid arthritis. Autoimmune inflammation can play a major role in cardiovascular disease, depression, fibromyalgia and chronic fatigue, migraine, loss of normal apoptosis (leading to malignancy), etc.

Professor Shoenfeld Yehuda, MD, FRCP is head of the Zabludowicz Center for Autoimmune Diseases of Sheba Medical Center (affiliated with Tel-Aviv University), the incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel-Aviv University, editor-in-chief of the journal Autoimmunity Reviews, and co-editor of the Journal of Autoimmunity. While celebrating vaccination as one of the greatest gifts of medicine in modern times, he explains the mechanism by which adjuvants can trigger autoimmunity. Also in this fascinating lecture he discusses some of the environmental, genetic, endocrine and immune factors that create a susceptibility to autoimmunity in general.

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Summary: chronic inflammation due to immune system dysregulation, with or without a diagnosed autoimmune disease, plays a fundamental role in chronic depression. This offers sustainable and evidence-based treatments for depression and brain health.

The authors of an important paper published in Current Immunology Reviews state:

…current antidepressants do not effectively target all of the pathological processes that are responsible for the major symptoms of depression…However, in recent years greater attention has been directed to the inter-relationship between the brain and peripheral organs (the” body-mind” connection) in which changes in the endocrine and immune systems play a major role in the pathological changes that occur in depression. Thus inflammation is beginning to emerge as a major contributing factor not only to depression and other major psychiatric disorders…”

Two major ways that immune dysfunction promotes depression are emphasized: the direct effect of inflammation on the brain, and the brain effects of the hormonal response to inflammation. Regarding the former:

“…in the past 30 years or so that clinical and experimental evidence has been obtained clearly demonstrating that aspects of both cellular and humoral immunity were dysfunctional in major depression…in particular the pro- and anti-inflammatory cytokines…Such clinical observations suggest that proinflammatory cytokines contribute to the major symptoms of depression and now forms the basis of the inflammation, cytokine or inflammatory response hypothesis of depression.”

It’s now known that peripherally derived inflammatory cytokines have access to the brain, including areas involved in depression…

“Once in the brain, the proinflammatory cytokines activated both neuronal and non-neuronal (for example, the microglia, astrocytes and oligodendroglia) cells via the nuclear factor-kappa-beta (NF-kB) cascade in a similar manner to that occurring in the peripheral inflammatory response…

Also, the production of serotonin and dopamine is adversely affected by inflammation:

“Recently much attention has been paid to the activation of the tryptophan-kynurenine pathway by these cytokines whereby tryptophan is shunted from the synthesis of serotonin to that of kynurenine…clearly this is an important mechanism whereby serotonergic function is decreased in depression. The activity of the dopaminergic system is also reduced in response to inflammation. For example, IFN reduces the synthesis of dopamine by decreasing the concentration of the co-factor tetrahydrobiopterin (BH4)…As IFN increases the synthesis of nitric oxide by activating the BH4 dependent enzyme nitric oxide synthase in the microglia it seems likely that the reduction in dopaminergic function is linked to the increase in nitric oxide. This gaseous neurotransmitter is known to activate the glutamatergic system which, when this exceeds physiologically limits, enhances apoptosis and neurodegeneration.”

In other words, an increase in inflammatory cytokines derails the production of serotonin and dopamine, and activates the excitatory (glutamatergic) system to the point of cell death.

Additionally, proinflammatory cytokines activate the HPA (hypothalamo-pituitary-adrenal) axis causing excessive cortisol production which is lethal to brain cells at high levels…

“In addition to the modulation of neurotransmitter function, proinflammatory cytokines contribute to the major symptoms of depression by activating the HPA axis by increasing the release of CRF, thereby contributing to hypercortisolaemia, a feature of major depression. The mechanism whereby the cytokines induce hypercortisolaemia involves a decreased sensitivity of the glucocorticoid receptors thereby leading to glucocorticoid resistance…”

The inflammation model also sheds light on the role of stress in depression:

“…as major depression is often accompanied by inflammatory diseases (such as irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders) that can activate the peripheral and central inflammatory response, it is possible that such inflammatory disorders initiate the inflammatory changes that precipitate depression….[But] it is evident that inflammation also occurs in depressed patients who are not suffering from concurrent inflammatory disorders. Thus the increased vulnerability of depressed patients to psychosocial stress is probably the key factor that leads to the activation of the immune and endocrine axes in depression. It is known, for example, that even the relatively mild acute stress of public speaking causes an increase in NF-kB activity, a key element in the induction of the inflammatory cascade. In this regard, it is also known that patients with major depression frequently show an enhanced responsiveness of IL-6 and NF-kB to an antigen challenge…such changes appear to be associated with activation of the microglia thereby suggestion that the inflammatory changes are also occurring in the brain.”

In other words, patients with major depression have a more pronounced inflammatory response to substances to which they are sensitized or allergic to (antigens). This is in addition to an increased immune and hormonal response to psychosocial stress.

Of special significance for the use of heart rate variability analysis for evaluation of the autonomic nervous system and therapies that increase parasympathetic tone…

“The mechanism whereby psychological stress influences both the peripheral and central inflammatory cascade is co-ordinated by the autonomic nervous system. Thus the release of noradrenaline and adrenaline following the activation of the sympathetic system results in the activation of both alpha and beta adrenoceptors on immune cells thereby initiating the release of proinflammatory cytokines, via the activation of the NF-kB cascade, particularly on macrophages and monocytes in peripheral blood…Conversely stimulation of the parasympathetic system has the opposite effect on the stress induced inflammatory response…It is possible that the anti-depressant-like action of vagal nerve stimulation, occasionally used to treat resistant depression, is associated with such an anti-inflammatory action.”

Brain inflammation associated with depression actually causes the death of brain cells (apoptosis):

“Thus in major depression, the prolonged activation of the inflammatory network in the brain results in a decrease in neurotrophins, leading to reduced neuronal repair, a decrease in neurogenesis, and an increased activation of the glutamatergic pathway that contributes to neuronal apoptosis, oxidative stress and the induction of apoptosis in astrocytes and oligodendrocytes.”

On top of all this, inflammation causes the biochemical pathway that produces serotonin from tryptophan to converted to the production of neurotoxins instead through the tryptophan-kynurenine pathway and the production of quinolinic acid.

“As both the cytokines and cortisol are raised in major depression, it is not surprising to find that the tryptophan-kynurenine pathway is increased….Kynurenine hydroxylase metabolises kynurenine first to 3-hydroxykynurenine and then to 3-hydroxyanthranilic acid and quinolinic acid. This pathway is increased in depression and dementia…In chronic depression…the activated microglia produce an excess of the neurotoxin…Furthermore quinolinic acid can cause apoptosis of the astrocytes. This results in a reduction in the metabolic and physical buffer to the neurons that is usually provided by the astrocytes and thereby further exposes the neurons to the neurodegenerative actions of quinolinic acid.”

Inflammation in the brain over the long term causes neurodegeneration that appear as brain shrinkage:

“The structural changes observed in the brain of patients with chronic depression lends support to the neurodegenerative hypothesis of depression. It is known that there is a shrinkage of the hippocampus in patients with major depression and a decrease in the number of astrocytes and a neuronal loss in the prefrontal cortex and in the striatum. Such changes could be the consequence of chronic low grade inflammation in which the proinflammatory cytokines, nitric oxide, prostaglandin E2 and other inflammatory mediators play key roles; the cytokines are known to induce the cyclo-oxygenase and nitric oxide sythase pathways in the brain and thereby increase the inflammatory insult. The inhibition of neurotrophin synthesis in the brain by glucocorticoids, and the neurotoxic action of quinolinic acid, add further to the impact of the inflammatory changes.”

There are indications that patients who respond poorly to neurotransmitter-manipulating medications have markers for increased inflammation:

“Further evidence for the relationship between inflammation and depression is provided by the observation that depressed patients with a history of partial or lack of response to antidepressant treatments have elevated plasma concentrations of IL-6 and acute phase proteins that persist despite antidepressant treatment. It has been suggested that patients who are resistant to conventional antidepressant treatment possess abnormal alleles of the IL-1 and TNF genes, and possibly for T-cell function.”

Moreover, even when there is some relief from a depressed mood or anxiety with these medications…

“…there is abundant clinical evidence that the available antidepressants…are far less effective in treating the memory and cognitive dysfunction (fatigue, psychomotor retardation) that commonly affect middle aged and elderly depressed patients.”

There is mounting evidence that modulating inflammation can improve the inflammatory response:

“There are already indications from the clinical literature that TNF antagonists…reduce the symptoms of depression in a variety of patients with autoimmune diseases…the mood state of the patients improving before the signs of improvement of the autoimmune disorder…IL-10, and insulin-like growth factor that has prominent anti-inflammatory activity, have been shown to attenuate the depressive-like behaviour in rodents induced by an inflammatory challenge.”

IL-10 is increased by correcting suboptimal levels of vitamin D.

“Perhaps the most obvious step to the reduction of inflammation both centrally and peripherally is to reduce the activity of the prostenoid pathway and thereby reduce the synthesis of inflammatory prostaglandins such as PGE2.”

This is exactly what is accomplished by correcting an omega-3 fatty acid deficiency with a low 3:6 ratio.

The best chance for a sustainable program for helping depression by treating the inflammation is to determine with the appropriate tests why the excessive inflammation is happening in the first place. Then physiological and sustainable treatments can address those underlying causes properly. That brings up the very large topic of the functional management of autoimmune disease and chronic inflammation, a subject of many posts here and deserving of a weighty textbook. See posts forthcoming in the next week on the role of gastrointestinal inflammation as a contributing cause and treatment target for depression and the effectiveness of the omega-3 fatty acid EPA as a PGE2 reducer for depression.

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Summary: chronic low-grade inflammation is both a damaging result of and a fundamental cause promoting obesity. Management of both weight loss programs and the medical complications of obesity should address the inflammatory component.

An important paper was recently published in the Journal of Clinical Investigation that discusses the role of inflammation in obesity, obesity-related disorders, and metabolic dysfunction. The chronic inflammatory response associated with obesity is has been termed metainflammation:

“Over the past decade, the search for a potential unifying mechanism behind the pathogenesis of obesity-associated diseases has revealed a close relationship between nutrient excess and derangements in the cellular and molecular mediators of immunity and inflammation. This has given birth to the concept of “metainflammation” to describe the chronic low-grade inflammatory response to obesity.”

The authors describe characteristics of the metainflammation of obesity:

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time. Childhood obesity may place individuals at risk for lifelong metainflammation, since inflammatory markers are elevated in obese children as young as 3 years old. Superimposed on this chronic inflammation are recurrent acute episodes of nutrition-related immune activation induced by nutrient availability (fasting or high-fat meals)…Non-biased assessments of gene expression networks in adipose tissue identify a robust pattern of overexpressed inflammatory genes associated with obesity and metabolic disease and enriched for macrophage genes…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Importantly, inflammation itself induces insulin resistance that further promotes obesity:

“Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines, decreases in protective factors (e.g., adiponectin), and communication between inflammatory and metabolic cells. For example, direct and paracrine signals from M1 classically activated macrophages can impair insulin signaling and adipogenesis in adipocytes…Similar effects on adipocyte inflammation and glucose transport are generated by signals from activated conventional T cells such as IFN-γ. In parallel, dysregulated macrophage-myocyte and macrophage-hepatocyte signaling can influence insulin sensitivity.”

They discuss the fascinating observation that obesity is associated with an imbalance of immune regulation characterized by the dominance of Th1 (cell-mediated, with a classical proinflammatory macrophage activation state = M1) over Th2 (antibod-mediated, M2) immune inflammatory activity:

“While ATMs [adipose tissue macrophages] likely assume a number of states along the M1/M2 spectrum depending on fat depot location and nutritional status, increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate.”

Most importantly there are a number points where we may intervene to ‘perturb the system’ in the direction of more balanced immune function, thus reducing inflammation and supporting weight loss:

“…maintaining metabolic homeostasis requires a balanced immune response and an integrated network of multiple cell types. Adipose tissue also contains potent tolerogenic CD4+ Tregs that are downregulated by obesity, a potential initiating event in metainflammation. Likewise, there appear to be innate systems by which nutrient signals are utilized to self-limit inflammation. For example, the obesity-induced increase in expression of GPR120, an omega-3 fatty acid (FA) receptor on macrophages capable of attenuating M1 macrophage activation and increasing M2 gene expression, limits inflammation…”

Also of great interest is the role of brain inflammation in promoting obesity:

“The effects of brain inflammation on the metabolic function of peripheral tissues are broad. Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension. Many of these effects are generated by signals from the sympathetic nervous system, which is also capable of inducing inflammatory changes in adipose tissue in response to neuronal injury…The dynamic interplay between hypothalamic inflammation and obesity suggest additional targets for antiinflammatory therapies in obesity. A key extension of these observations is the potential that antiinflammatory pathways may counteract these CNS inflammatory events and improve leptin sensitivity.”

Obesity must be understood as an active agent, both as cause and result, in the web of chronic inflammation. The greatest clinical success in managing weight loss and chronic inflammatory disorders comes from determining and treating the pro-inflammatory factors involved according to each individual case.

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More evidence that dairy foods contain agents with antiinflammatory and antioxidant properties is presented in a study published recently in The American Journal of Clinical Nutrition showing reductions in damaging inflammatory biomarkers. The authors state:

“Oxidative and inflammatory stress are elevated in obesity and are further augmented in metabolic syndrome. We showed previously that dairy components suppress the adipocyte- and macrophage-mediated generation of reactive oxygen species and inflammatory cytokines and systemic oxidative and inflammatory biomarkers in obesity…The objective of this study was to determine the early (7 d) and sustained (4 and 12 wk) effects of adequate-dairy (AD) compared with low-dairy (LD) diets in subjects with metabolic syndrome.”

Their forty overweight or obese subjects with metabolic syndrome were randomly assigned to receive either an ‘adequate dairy diet’ (defined as 3.5 daily servings) or ‘low dairy diet’ (less than half a daily serving) form of weight-maintenance diet for 12 weeks. They measured oxidative and inflammatory biomarkers at the start and after 1, 4, and 12 weeks as primary outcomes, along with body weight and composition to start and after 4, and 12 weeks as secondary outcomes. Their data showed a dramatic difference for the ‘adequate dairy’ diet:

“AD decreased malondialdehyde and oxidized LDL at 7 d (35% and 11%, respectively), with further decreases by 12 wk. Inflammatory markers were suppressed with intake of AD, with decreases in tumor necrosis factor-α at 7 d and further reductions through 12 wk (35%); decreases in interleukin-6 (21%) and monocyte chemoattractant protein 1 (14% decrease at 4 wk, 24% decrease at 12 wk); and a corresponding 55% increase in adiponectin at 12 wk. LD exerted no effect on oxidative or inflammatory markers. Diet had no effect on body weight; however, AD significantly reduced waist circumference and trunk fat, and LD exerted no effect.”

While these findings don’t obviate the need to attend to the possibility of dairy allergies or the quality of dairy foods consumed, this is strong evidence that there agents in an ‘adequate dairy’ diet that can do more than a low dairy diet even when the same amount of weight is lost.

“Data from this study show that an increase in dairy intake from suboptimal to adequate levels (≈3.5 servings/d) significantly attenuates both oxidative and inflammatory stress in metabolic syndrome. Notably, although these effects may result, in part, from reductions in adiposity on higher dairy diets, the rapid onset (within the first 7 d of dietary change) suggest that there is an adiposity-independent effect as well. This is further supported by our previous evidence that showed direct effects of dairy components on adipocyte cytokine expression and secretion.”

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Most readers here are well aware that osteoporosis results from a failure to maintain the resilient protein matrix (web, or ‘scaffolding’) of bone tissue, and that chronic inflammation is a prime contributor. A paper just published in Current Opinion in Endocrinology, Diabetes and Obesity examines the role of autoimmunity, now so widespread, in skeletal disease in general and osteoporosis in particular. The authors state:

“There is an increased risk of osteoporotic fractures and osteonecrosis often at a young age among patients with certain systemic autoimmune diseases. The loss of bone mineral density and bone integrity seen with these diseases often cannot be explained by traditional risk factors alone…”

The review studies that document that in rheumatoid arthritis the risk of osteoporosis is doubled, the risk for hip fracture is doubled or tripled, and there is a two to six-fold risk of vertebral fracture.

“Reduction in bone mineral density in RA may be influenced by immobility, inflammation associated with osteoclast activation, and medications used to treat the disease such as corticosteroids.”

In the case of lupus…

“Risk factors for osteoporosis in patients with SLE include high disease activity, vitamin D deficiency, renal disease, corticosteroid use, and premature ovarian failure from cytotoxic medications…”

The include a review of vitamin D in skeletal health and note that besides its well-known role in bone metabolism…

“…vitamin D is thought to have an immunomodulatory function, with deficient levels associated with impaired innate immune function and overexuberant adaptive immune function. Markers of inflammation have been associated with increased bone turnover and bone loss, a factor that is thought to be particularly at play among patients with inflammatory diseases. Consequently, low vitamin D levels can lead to accelerated bone loss among patients with inflammatory diseases. Put together, these observations move us beyond the calcitropic effects of vitamin D deficiency among patients with inflammatory diseases, and argue in favor of higher serum levels than are currently accepted.“

Importantly, the mechanisms by which inflammation disrupts skeletal are becoming known:

“Several studies have found an association between pro-inflammatory cytokines which play a role in bone resorption, such as TNF-α, IL-1 and IL-6, and the development of osteoporosis. Epidemiologic studies have shown levels of systemic inflammation to predict bone loss and future fracture. It is becoming clear that T cells play a pivotal role in regulating bone homeostasis through direct interactions with bone marrow, stromal cells and osteoblasts. Once activated, these T cells release osteoclastogenic cytokines and Wnt ligands.”

And it appears that steroid treatment does not undo the skeletal effects of inflammation:

“Among a cohort of 20 patients with SLE who had never been on steroids, osteocalcin levels were significantly lower, the urinary excretion of cross-links were significantly higher than in a non-SLE cohort, suggesting that there is decreased bone formation and increased bone resorption among steroid-naive SLE patients. Although these findings were attributed to the underlying disease, comparable results were detected among a steroid-treated cohort implying that steroid treatment does not undo the skeletal effects of inflammation in SLE as was speculated by some researchers.”

Summing up the studies linking osteoporosis to SLE, the authors state:

“These findings suggest that patients with more active inflammation are at greater risk for bone loss.“

Concerning the importance of vitamin D and autoimmunity, they comment:

“In light of the alarming prevalence of vitamin D deficiency seen worldwide, all patients with autoimmune disease should have at least a baseline screening 25-hydroxyvitamin level to screen for vitamin D deficiency. The only laboratory test usually required to ascertain the patient’s status is the 25-hydroxyvitamin D level with a goal of at least greater than 30 ng/ml.”

Their conclusion is heightened in significance by the sharp increase in autoimmune disorders in recent years:

“Bone loss and damage commonly occurs in patients with systemic autoimmune diseases. We are improving in our ability to diagnose and treat autoimmune diseases and their complications; yet osteoporosis and osteonecrosis remain growing comorbid conditions.”

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A study published in the Archives of General Psychiatry illustrates an important aspect of the biological component of depression. The authors set out to…

“…test the hypothesis that reduced hippocampal volume precedes and therefore may be implicated in the onset of depression.”

The hippocampus is the ‘seat’ of short-term memory and regulates the adrenal rhythm of cortisol. It’s well known that the hippocampal shrinkage occurs due to damage from high levels of cortisol that can occur in reaction to inflammation (autoimmune and allergic), blood sugar dysregulation and other stress demands. The authors examined 55 girls aged 9-15 years with voxel-based morphometry brain matter density estimates and traced hippocampal volume (MRI), 23 were high risk because of a maternal history of depression. What did the data show?

“Voxel-based morphometry analyses indicated that individuals at high risk of depression had significantly less gray matter density in clusters in the bilateral hippocampus than low-risk participants. Tracing yielded a volumetric reduction in the left hippocampus in the high-risk participants.”

This is why factors that have an adverse effect on hippocampal integrity always considered in the functional approach to depression as noted in the Parents’ Guide to Brain Health. The authors conclude:

“Compared with individuals at low familial risk of the development of depression, high-risk individuals have reduced hippocampal volume, indicating that neuroanatomic anomalies associated with depression may precede the onset of a depressive episode and influence the development and course of this disorder.”

The most dependable way to know whether there are abnormalities in the regulation of cortisol amplitude and rhythm that may be associated with hippocampal damage is by easily measuring the free-fraction (bioactive) cortisol levels in four saliva samples easily collected over the day.

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While insulin resistance and pre-diabetic but elevated glucose levels are widely recognized as  contributors to cardiovascular disease, it is less well-known that hypoglycemia also damages the cardiovascular system. A study just published in the journal Diabetic Medicine reports on one of the mechanisms:

“Intensive glycaemic control increases the incidence of hypoglycaemia. We sought to define the effects of hypoglycaemia on aldosterone, a hormone involved in cardiovascular injury and baroreflex impairment.”

The authors examined the effects of hypoglycaemia and normal blood sugar (euglycemia) on aldosterone and plasma renin activity through the use of the hypoglycaemic hyperinsulinaemic clamp protocol in which the glucose is dropped in a controlled fashion with insulin. What did the data show?

“In Study 1, aldosterone increased approximately 2.5-fold during hypoglycaemic hyperinsulinaemia but did not rise with euglycaemic hyperinsulinaemia. In Study 2, aldosterone increased significantly at glucose levels of 2.8 mmol/l; this increase was amplified with glucose of 2.2 mmol/l. Aldosterone increases paralleled those of ACTH.”

Parallel increases of ACTH (adrenacorticotropic hormone) show that the aldosterone increase is part of the hypothalamus-pituitary-adrenal  axis reaction to hypoglycemia. Regarding the signficance for cardiovascular disease, the authors state in conclusion:

“Hypoglycaemia increases aldosterone in a dose-dependent fashion…Because aldosterone activation of the mineralocorticoid receptor is implicated in the pathophysiology of cardiovascular injury, including vascular dysfunction, inflammation, baroreflex impairment and cardiac arrhythmias, these findings may be of relevance in individuals who experience hypoglycaemia.”

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There has been a lot of interesting science, some of it reported here, documenting the benefits of resveratrol for factors contributing to inflammation, insulin resistance, obesity, diabetes and longevity. A paper just published in the American Journal of Clinical Nutrition offers evidence that the valuable phenolic compound quercitin may be even more effective than resveratrol for reducing the inflammation associated with insulin resistance and diabetes. The authors state:

“Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes…The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes [fat cells] treated with tumor necrosis factor-{alpha} (TNF-{alpha})—an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.”

They stimulated fat cells with TNF-{alpha} to promote inflammation after pretreatment with quercetin and trans-RSV, then measured gene and protein markers of inflammation and insulin resistance. What did the data show?

Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-{alpha}–induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1… Quercetin, but not trans-RSV, decreased TNF-{alpha}–induced nuclear factor-{kappa}B transcriptional activity. Quercetin and trans-RSV attenuated the TNF-{alpha}–mediated suppression of peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}) and PPAR{gamma} target genes and of PPAR{gamma} protein concentrations and transcriptional activity….”

Quercitin is known to be helpful for gut inflammation associated with food allergies, and I have found it to be a surprisingly helpful palliative for airborne allergies. In light of this the authors’ conclusion is not a surprise:

“These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-–mediated inflammation and insulin resistance in primary human adipocytes.”

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Magnesium is important for a multitude of functions and functional deficiencies of magnesium are extremely common. A study just published in the journal Diabetes Care illuminates the role of magnesium in the chronic inflammation associated with insulin resistance and diabetes. The authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

They examined 4,497 Americans, aged 18-30 years and without diabetes, for magnesium intake and the subsequent onset of diabetes; along with key inflammatory markers (high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen) and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“During 20-year follow-up, 330 incident diabetic cases were identified. Magnesium intake was inversely associated with incidence of diabetes [those with the lowest magnesium had 53% more chance of developing diabetes]…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

The association between magnesium and the inflammation markers hs-CRP, IL-6 and fibrinogen is significant for more than diabetes because chronic inflammation is a hallmark of most chronic diseases including cardiovascular disease and cancer. The same goes for insulin resistance as indicated by HOMA-IR. Serum magnesium is not a sensitive indicator of deficiency. Measuring magnesium concentration in the red blood cells is a more accurate representation. Urinary organic acids can also indicate when key metabolic pathways are impaired due to magnesium deficiency. Muscle cramps at rest are very often associated with magnesium deficiency and clear up when magnesium sufficiency has been restored.

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