Vagus nerve regulates inflammation and metabolism

Vagus and inflammation, metabolismVagus nerve (cranial nerve X) function, a key regulator of inflammation and metabolism, is under assault in the modern environment. An excellent paper published in Nature Reviews Endocrinology presents a lucid review of the clinically important vagal inflammatory reflex, the role of impaired vagal function in type 2 diabetes and obesity, with therapeutic implications for reducing inflammation and regulating appetite. The authors state:

“The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus.”

The vagus inflammatory reflex

Functional anatomy of the vagal inflammatory reflexThe vagal inflammatory reflex is a crucial factor in the brain’s regulation of inflammation…

Communication between the immune system and the brain is vital for controlling inflammation. The inflammatory reflex is a centrally integrated physiological mechanism in which afferent vagus nerve signaling, activated by cytokines or pathogen-derived products, is functionally associated with efferent vagus nerve-mediated output to regulate proinflammatory cytokine production and inflammation. The absence of this inflammatory reflex…results in excessive innate immune responses and cytokine toxicity.”

Vagal cholinergic control of inflammationWhen cytokines or pathogen-derived products activate the vagus nerve, it acts to regulate proinflammatory cytokine production and inflammation. When function of the inflammatory reflex is diminished there is excessive innate immune inflammatory activity. Disrupted immune regulation results in persistent pro-inflammatory cytokine activity and chronic inflammation.

“This state underlies the pathogenesis of a range of disease syndromes, including sepsis, rheumatoid arthritis, inflammatory bowel disease and other inflammatory and autoimmune disorders.”

Vagal output is a crucial mechanism for calming inflammation in the digestive tract and throughout the body.

Association with metabolism and obesity

Metabolic and immune dysregulation both contribute to chronic inflammation, and vagal stimulation can help remediate both.

“Chronic inflammation as a result of immune and metabolic dysregulation is a characteristic feature in patients with obesity and is causally linked with insulin resistance and other metabolic complications. Decreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.

Importantly, the vagus nerve also acts to control appetite and feeding.

“Vagus nerve afferent and efferent signalling has an important role in the regulation of feeding behaviour and metabolic homeostasis. This finely tuned regulation is aimed at preserving energy balance and preventing fluctuations in body weight and metabolism that can be detrimental to the individual.”

It sends functional and metabolic information from the digestive and hepatic systems to the brain, and instructions from brain in return:

“Vagus nerve afferents innervating the gastrointestinal tract and liver are major constituents of a sensory system that detects changes in micronutrient and metabolic molecules. These nerve fibres transmit information detected by associated mechanoreceptors, chemoreceptors and specific metabolite receptors in the gut and hepatic portal system concerning levels of lipids, cholecystokinin, leptin, peptide YY, insulin and glucose to the brain…Vagus nerve efferents, on the other hand, provide brain-derived output to the gastrointestinal tract, liver and pancreas.”

Morever, vagal stimulation is necessary to maintain the gut barrier:

“…truncal vagotomy is associated with increased bacterial trans location across the intestinal mucosa, which suggests a tonic vagus nerve control of intestinal permeability and postprandial endotoxaemia.”

Vagal dysregulation in the inflammation of obesity

Inflammation is characteristic of obesity, associated with impaired vagal function…

“Disruption in metabolic and immune homeostasis in obesity is associated with hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. This cluster of conditions characterizes the metabolic syndrome. Moreover, levels of proinflammatory cytokines and acute-phase proteins such as CRP are increased in individuals with obesity, indicating chronic inflammation. This inflammatory state is considered to be an essential pathophysiological constituent in obesity, underlying its adverse consequences and linking it to the other components of the metabolic syndrome. Several lines of evidence indicate that vagus nerve activity could be impaired in obesity, and enhancing cholinergic signaling within the inflammatory reflex can suppress obesity-associated inflammation and its adverse implications.”

There are numerous mechanisms by which obesity promotes systemic inflammation i association with disturbed vagal function.

Autonomic dysfunction and diminished vagus nerve activity occur frequently in individuals with obesity and type 2 diabetes mellitus. A 15-year follow-up study has revealed a strong relationship between autonomic dysfunction and insufficient vagus nerve activity (revealed by impaired heart rate recovery following exercise cessation), impaired glucose homeostasis and development of type 2 diabetes mellitus. Together, these preclinical and clinical findings support the hypothesis that diminished vagus nerve signaling in obesity could lead to enhanced inflammation and metabolic complications.”

Reducing obesity-associated inflammation with vagal support

Vagal cholinergic stimulation can alleviate the inflammation and metabolic complications of obesity:

“Targeting cholinergic mechanisms in the inflammatory reflex using α7nAChR agonists or a centrally-acting acetylcholinesterase inhibitor could alleviate inflammation and metabolic complications in obesity.”

Type 2 diabetes and cardiovascular risk can both be ameliorated by reducing inflammation through vagal support.

“The chronic inflammatory state associated with obesity is one such common step that could be targeted. Some anti-inflammatory approaches have already been explored in the treatment of obesity-linked disorders in preclinical and clinical scenarios. For example, patients with type 2 diabetes mellitus who were treated with a recombinant human IL-1 receptor antagonist (anakinra) experienced reductions in levels of IL-6 and CRP. Additionally, HbA1c levels in these patients were reduced and their pancreatic β-cell secretory function improved. Administration of salicylate—a known IKK inhibitor in rodents, which propagates proinflammatory signals—significantly improved glucose homeostasis, reduced free fatty acid levels and increased adiponectin levels in patients with type 2 diabetes mellitus.”

Therapeutic Considerations

In addition to stimulation of the vagus by devices and pharmacotherapy, there are numerous ‘hands-on’ therapies that stimulate the CNS from the periphery (chiropractic, cranial therapy, auriculotherapy, acupuncture, etc.) that, when properly rendered, increase parasympathetic (vagal) activity. The authors conclude:

“The inflammatory reflex mediated by the vagus nerve has been successfully exploited therapeutically in preclinical models of diseases with aetiologies characterized by excessive inflammatory responses. Insufficient efferent vagus nerve cholinergic output might have a causative role in the dysfunctional immune and metabolic regulation observed in obesity, as selective activation of the efferent cholinergic arm of the inflammatory reflex attenuates both inflammation and metabolic derangements. Although cholinergic suppression of inflammation can contribute specifically to alleviating metabolic complications, direct cholinergic effects on metabolic pathways could also have a role in alleviating symptoms associated with the metabolic syndrome and type 2 diabetes mellitus. These complex interactions and the contribution of central and peripheral mechanisms in this regulation are topics of ongoing study. Additionally, intracellular mechanisms by which cholinergic signals control obesity-associated inflammation and modulate insulin signaling are under investigation…The use of cholinergic modalities in combination with existing or new therapeutic approaches to target neural, endocrine and immune functions for therapeutic benefit in patients with obesity-related disorders should also be considered.”

They offer a summary by way of these key points:

  • The inflammatory reflex is a physiological mechanism through which the vagus nerve regulates immune function and inhibits excessive proinflammatory cytokine production
  • Vagus nerve signaling has an important role in the regulation of feeding behaviour and metabolic homeostasis
  • Disruption of metabolic and immune regulation in obesity results in inflammation, which mediates insulin resistance and the development of type 2 diabetes mellitus as well as other debilitating and life-threatening conditions
  • Activation of cholinergic signaling in the efferent arm of the inflammatory reflex alleviates obesity-associated inflammation and metabolic derangements
  • The inflammatory reflex can potentially be exploited for treatment of the metabolic syndrome, type 2 diabetes mellitus and other obesity-driven disorders

Readers may also be interested in how vagal activity regulates the brain-immune relationship.

CKD (chronic kidney disease) expected for 50% over age 30

American Journal of Kidney DiseasesChronic kidney disease (CKD) is rising steeply and projected to affect more than half of those aged 30 to 64 years in the coming twenty years according to a study just published in the American Journal of Kidney Diseases. The authors state:

“Awareness of chronic kidney disease (CKD), defined by kidney damage or reduced glomerular filtration rate, remains low in the United States, and few estimates of its future burden exist…We used the CKD Health Policy Model to simulate the residual lifetime incidence of CKD and project the prevalence of CKD in 2020 and 2030. The simulation sample was based on nationally representative data from the 1999 to 2010 National Health and Nutrition Examination Surveys.”

More than half of people aged 30 to 64 years likely to be affected

The authors’ data showed that…

For US adults aged 30 to 49, 50 to 64, and 65 years or older with no CKD at baseline, the residual lifetime incidences of CKD are 54%, 52%, and 42%, respectively. The prevalence of CKD in adults 30 years or older is projected to increase from 13.2% currently to 14.4% in 2020 and 16.7% in 2030.”

Currently one in seven adults is affected by chronic kidney disease. The public health consequences are enormous. The authors conclude:

“For an individual, lifetime risk of CKD is high, with more than half the US adults aged 30 to 64 years likely to develop CKD. Knowing the lifetime incidence of CKD may raise individuals’ awareness and encourage them to take steps to prevent CKD.”

Prevention: Metabolic syndrome and chronic kidney disease

Current Opinion in Nephrology and HypertensionComponents of metabolic syndrome (MetS) including insulin resistance, hypertension, dyslipidemia and inflammation are particularly rough on the kidneys. A review published in Current Opinion in Nephrology and Hypertension highlights the connection:

“The association of the metabolic syndrome (MetS) with cardiovascular risk, mortality, type 2 diabetes mellitus, stroke, nonfatty liver disease and gout is well known. However, the association of the MetS with chronic kidney disease (CKD) is now emerging…Studies show that patients with MetS have a 2.5-fold higher risk of developing CKD. The risk of microalbuminuria is also increased two-fold in the MetS. Renal dysfunction becomes apparent long before the appearance of hypertension or diabetes in MetS. Compared with healthy controls, patients with MetS have increased microvascular disease-tubular atrophy, interstitial fibrosis, arterial sclerosis and global and segmental sclerosis.”

Clinicians should especially note that metabolic syndrome is contributing to chronic kidney disease well before it evolves into diabetes and the development of hypertension. Regarding potential mechanisms:

“Studies suggest that the renal fibrosis seen in MetS might be caused by a constellation of insulin resistance, hypertension, dyslipidemias and inflammation, and result in a heightened expression of adipocytokines, angiotensin and inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha.”

World Journal of NephrologyThe author of a paper published in the World Journal of Nephrology states:

“Despite the ambiguous definition of MetS, it has been clearly associated with chronic kidney disease markers including reduced glomerular filtration rate, proteinuria and/or microalbuminuria, and histopathological markers such as tubular atrophy and interstitial fibrosis. However, the etiological role of MetS in chronic kidney disease (CKD) is less clear. The relationship between MetS and CKD is complex and bidirectional, and so is best understood when CKD is viewed as a common progressive illness along the course of which MetS, another common disease, may intervene and contribute. Possible mechanisms of renal injury include insulin resistance and oxidative stress, increased proinflammatory cytokine production, increased connective tissue growth and profibrotic factor production, increased microvascular injury, and renal ischemia.

PLOS ONEThe authors of a study published in PLOS One on the relation between metabolic syndrome and chronic kidney disease in an adult Korean population came to the conclusion:

“The strength of association between MS [metabolic syndrome] and the development of CKD increase as the number of components increased from 1 to 5. In sub-analysis by men and women, MS and its each components were a significant determinant for CKDMS and its individual components can predict the risk of prevalent CKD for men and women.”

Moreover, they excluded patients with diabetes to more clearly isolate contribution of metabolic syndrome to CKD.

Cardiology Research and PracticeCommenting on the link between metabolic syndrome and chronic kidney disease in the development of cardiovascular disease in a paper published in Cardiology Research and Practice the authors note:

Microalbuminuria has been described as the earliest manifestation of MetS-associated kidney damage and diabetic nephropathy, and it is associated with insulin resistance independent of diabetes. MetS is often accompanied by increased plasma renin activity, angiotensinogen, angiotensin-converting enzyme activity, and angiotensin II (renin-angiotensin-aldosterone system) and with renal sympathetic activity. Hyperinsulinemia, insulin resistance, and increased plasma angiotensin II levels are potent activators of expression of transforming growth factor-β1, a fibrogenic cytokine that contributes to glomerular injury.”

Insulin resistance, of course, spurs chronic inflammation:

“The hallmark of MetS is insulin resistance. Inflammatory mediators, including tumor necrosis factor (TNF)-α, have been shown to mediate insulin resistance. Adipokines, including TNF-α, IL-6, and resistin, are cytokines secreted by adipose tissue, and their plasma concentrations are elevated in patients with MetS, whereas their plasma adiponectin levels are reduced. These findings may contribute to insulin resistance, and insulin resistance promotes chronic inflammation.”

Sugar versus salt in hypertension and chronic kidney disease

Open HeartA striking paper just published in the journal Open Heart (British Cardiovascular Society) identifying sugar as a worse culprit than salt for hypertension and cardiometabolic disease further links metabolic syndrome and chronic kidney disease. The authors note:

“Cardiovascular disease is the leading cause of premature mortality in the developed world, and hypertension is its most important risk factor. Controlling hypertension is a major focus of public health initiatives, and dietary approaches have historically focused on sodium. While the potential benefits of sodium-reduction strategies are debatable, one fact about which there is little debate is that the predominant sources of sodium in the diet are industrially processed foods.”

But processed foods are high in sugar as well as salt, and it may be unwise to aggressively change sodium consumption…

‘Strategies to lower dietary sodium intake focus (implicitly if not explicitly) on reducing consumption of processed foods: the predominant sources of sodium in the diet…Nonetheless, the mean intake of sodium in Western populations is approximately 3.5–4 g/day. Five decades worth of data indicates that sodium intake has not changed from this level across diverse populations and eating habits, despite population-wide sodium-reduction efforts and changes in the food supply.Such stability in intake suggests tight physiologic control, which if indeed the case, could mean that lowering sodium levels in the food supply could have unintended consequences. Because processed foods are the principal source of dietary sodium, if these foods became less salty, there could be a compensatory increase in their consumption to obtain the sodium that physiology demands.

Highly refined carbohydrates, the fuel for metabolic syndrome, worse than salt

This includes fructose:

“Coincidentally, processed foods happen to be major sources of not just sodium but of highly refined carbohydrates: that is, various sugars, and the simple starches that give rise to them through digestion. Compelling evidence from basic science, population studies, and clinical trials implicates sugars, and particularly the monosaccharide fructose, as playing a major role in the development of hypertension. Moreover, evidence suggests that sugars in general, and fructose in particular, may contribute to overall cardiovascular risk through a variety of mechanisms. Lowering sodium levels in processed foods could lead to an increased consumption of starches and sugars and thereby increase in hypertension and overall cardiometabolic disease.”

Hypertensive mechanisms of fructose. NO, nitric oxide; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROS, reactive oxygen species.

Hypertensive mechanisms of fructose. NO, nitric oxide; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROS, reactive oxygen species.

 “Although high intakes of either fructose alone or sucrose may lead to insulin resistance, it is fructose that has been implicated as the sugar responsible for reducing sensitivity of adipose tissue to insulin.Insulin stimulates the SNS and hyperinsulinaemia may lead to hypertension, with the degree of insulin resistance in peripheral tissues directly correlated with hypertension severity. Reducing insulin resistance may lead to a reduction in blood pressure, and hyperinsulinaemia seems more related to fructose than glucose.”

The authors make a distinction between fructose added to foods and that found naturally in whole fruit as stated in their conclusion:

“While naturally occurring sugars in the form of whole foods like fruit are of no concern, epidemiological and experimental evidence suggest that added sugars (particularly those engineered to be high in fructose) are a problem and should be targeted more explicitly in dietary guidelines to support cardiometabolic and general health…Evidence from epidemiological studies and experimental trials in animals and humans suggests that added sugars, particularly fructose, may increase blood pressure and blood pressure variability, increase heart rate and myocardial oxygen demand, and contribute to inflammation, insulin resistance and broader metabolic dysfunction. Thus, while there is no argument that recommendations to reduce consumption of processed foods are highly appropriate and advisable, the arguments in this review are that the benefits of such recommendations might have less to do with sodium—minimally related to blood pressure and perhaps even inversely related to cardiovascular risk—and more to do with highly-refined carbohydrates. It is time for guideline committees to shift focus away from salt and focus greater attention to the likely more-consequential food additive: sugar.”

Quoted in Medscape Medical News, Richard Krasuski, MD, from the Cleveland Clinic in Ohio commented on the study:

“”It is a little bit frightening that we have been focusing on salt for so long.”…The conclusion that sugar represents a greater danger to the heart than salt, Dr Krasuski said, was an “eye opener.” He acknowledged, though, that he should have anticipated it. He and other cardiologists have noticed that the recommendations to increasingly lower salt intake have not resulted in the expected positive cardiovascular outcomes.”

Bottom line for chronic kidney disease

CKD incidence is rising steeply and projected to affect half the population aged 30 to 64. Key causal factors are metabolic syndrome with insulin resistance and hypertension. These are made worse by added sugars than by salt. Appropriate diet, objective determination of individual genetic and circumstantial needs for supplementation, regular exercise, not smoking, stress management and addressing sleep disordered breathing are common sense preventive and remedial measures.

Low-normal thyroid function and cardiometabolic disorders

European Journal of Clinical InvestigationLow-normal thyroid function commonly shows up in lab results in my general practice, mostly due to the diffuse autoimmune phenomena so widespread now, but it seems to be often overlooked. A study just published in the European Journal of Clinical Investigation offers more evidence that low-normal thyroid function should be respected as a risk factor, in this case for cardiovascular and metabolic disorders. The authors state:

“Subclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid [‘normal’] reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD).”

The authors surveyed a range of reviews and meta-analyses derived from clinical and basic research papers, obtained published up to November 2014 and found:

Low-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far.”

See earlier posts for studies reporting additional adverse effects from low-normal thyroid and low-normal free T3. Practitioners should be alert to anti-thyroid antibodies indicating a pre-Hashimoto’s state and test for iodine insufficiency (by 24 hour urine collection) when indicated. The authors conclude:

“Observational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain.”

Nuts reduce inflammation and all-cause mortality

Asia Pacific Journal of Clinical NutritionNuts have been shown to confer multiple health benefits, so it’s disconcerting to see  some apparently popular paleo diet plans that forbid them. In the absence of a nut allergy it’s a shame to forgo the benefit of such a healthful and convenient food. The intent of the paleo diet is to reduce inflammation, so it’s worth considering a paper published in the Asia Pacific Journal of Clinical Nutrition offering evidence that nuts reduce inflammation. The authors note:

“Several large epidemiological studies have associated the frequency of nut consumption with reduced risk of coronary heart disease (CHD), CVD, myocardial infarction, sudden death, and all causes of mortality, Type 2 diabetes (T2D) and other chronic disease.

Nuts are anti-inflammatory

Key inflammatory markers including CRP and IL-6 are reduced by nut consumption:

“Epidemiological and clinical studies suggest that some dietary factors, such as n–3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.”

Nuts also benefit cholesterol and lipids

“In the last two decades, a considerable number of clinical trials have consistently demonstrated beneficial effects on blood lipids and lipoproteins, primarily a decrease in Low-density lipoprotein (LDL) cholesterol, a classical CHD risk factor. This effect has been demonstrated consistently in different population groups, using different types of nuts (walnuts, hazelnuts, almonds, pecan, pistachio and macadamia nuts) and study designs. The favourable effects of tree nuts or tree nut oils on plasma lipid and lipoprotein profiles is a mechanism that appears to account for some of the cardio protective effects observed in the epidemiological studies.”

Nuts and olive oil are a great combination for cardiovascular risk:

“…in a cross-sectional study we evaluated the association between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects with high risk of cardiovascular disease. Subjects with the highest consumption of nuts and virgin olive oil showed the lowest concentrations of VCAM-1, ICAM-1, IL-6 and CRP; although this difference was statistically significant for ICAM-1 only in the case of nuts and for VCAM-1 in the case of olive oil.”

After reviewing several other studies documenting improvements in inflammation and endothelial function the authors conclude:

“In conclusion, nuts are complex food matrices containing diverse nutrients and other chemical constituents that may favourably influence human physiology. These sub- stances may inhibit the activation of the innate immune system, probably by decreasing the production of proinflammatory cytokines such as CRP, IL-6, TNF-α or IL-18, and increase the production of antiinflammatory cytokines such as adiponectin. This may improve the proinflammatory milieu, which in turn ameliorates endothelial dysfunction at the vascular level, and ultimately decreases the risk of insulin resistance, type 2 diabetes and coronary heart disease. The capacity of nuts to modulate inflammation may explain at least in part why frequent nut consumption is associated with reduced risk of diabetes and cardiovascular disease in epidemiological studies.”

Nut consumption reduces total and cause-specific mortality

New England Journal of MedicineA paper published earlier this year in The New England Journal of Medicine add more extensive data presenting evidence that eating nuts reduces death from cancer, heart disease, respiratory disease and ‘all causes’.

“Observational and intervention studies of nut consumption have also shown reductions in various mediators of chronic diseases, including oxidative stress, inflammation, visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction. In prospective cohort studies, increased nut intake has been associated with reduced risks of type 2 diabetes mellitus, the metabolic syndrome, colon cancer, hypertension, gallstone disease, diverticulitis, and death from inflammatory diseases.”

To extend the data to encompass the effects of eating nuts and all causes of death the authors:

“…examined the association of nut consumption with total and cause-specific mortality in two large, independent cohort studies of nurses and other health professionals. These studies provide repeated measures of diet (including separate data on peanuts and tree nuts), extensive data on known or suspected confounding variables, 30 years of follow-up, and data on more than 27,000 deaths for analysis.”

Their data suggest that nuts are among the healthiest foods to eat:

“In two large prospective U.S. cohorts, we found a significant, dose-dependent inverse association between nut consumption and total mortality, after adjusting for potential confounders. As compared with participants who did not eat nuts, those who consumed nuts seven or more times per week had a 20% lower death rate. Inverse associations were observed for most major causes of death, including heart disease, cancer, and respiratory diseases. Results were similar for peanuts and tree nuts, and the inverse association persisted across all subgroups.”

Some nuts every day was the best:

“Our results are consistent with the findings in previous, smaller studies. The Adventist Health Study showed that, as compared with nut consumption less than once per week, consumption five or more times per week was associated with reduced total mortality among whites, blacks, and elderly persons, with hazard ratios ranging from 0.56 to 0.82. Similarly, a study of a U.K. cohort, the Iowa Women’s Health Study, the Netherlands Cohort Study, and an earlier analysis of the NHS all showed significant inverse associations between nut intake and total mortality. Finally, in a recent secondary analysis within the PREDIMED (Prevención con Dieta Mediterránea) trial, a hazard ratio for death of 0.61 (95% CI, 0.45 to 0.83) was found for consumption of more than three servings of nuts per week, as compared with no nut consumption.”

Bottom line: ‘paleo’ and ‘autoimmune’ paleo diets can be fine healing diets for many, but like everything else should not be applied dogmatically or in a ‘rubber stamp’, ‘one-size-fits-all’ manner. In the absence of allergy, the evidence supports the consumption of nuts as wholesome foods with anti-inflammatory and metabolic benefits, exactly what paleo diets intend to accomplish.

Prediabetes increases cancer risk

DiabetologiaPrediabetes, elevated levels of blood sugar that are still ‘within’ the normal range, increases cancer risk among its mob of other afflictions as further validated by a meta-analysis just published in Diabetologia. The authors state:

Prediabetes is a general term that refers to an intermediate stage between normoglycaemia and overt diabetes mellitus. It includes individuals with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or a combination of the two. In 2003, the ADA redefined the range of fasting plasma glucose (FPG) concentration for diagnosing IFG from 6.1– 6.9 mmol/l to 5.6–6.9 mmol/l [101-124 mg/dL] in order to better identify individuals at risk of developing diabetes.”

Because this lower range has been disputed with inconsistencies in previous studies, the authors set out to…

“…to evaluate the putative association between different definitions of prediabetes and risk of cancer.”

Their data adds yet more weight to the vital clinical importance of regulating blood sugar and insulin:

“In this meta-analysis of 16 prospective cohort studies comprising more than 890,000 individuals, we found that the presence of prediabetes at baseline was significantly associated with increased risks of cancer in the general population, particularly for liver cancer and stomach or colorectal cancer. The risks were increased when a lower FPG value of 5.6– 6.9 mmol/l [101-124 mg/dL] was used, according to the current ADA definition of IFG, as well as in participants with IGT. The results were consistent across cancer endpoints, age, study characteristics, follow-up duration and ethnicity.”

Much has been written here about the importance of glucose and insulin regulation for a wide range of conditions. The authors echo these themes in comments about likely mechanisms:

Hyperglycemia, advanced glycation end-products and oxidative damage

“First, chronic hyperglycaemia and its related conditions, such as chronic oxidative stress and the accumulation of advanced glycation end-products, may act as carcinogenic factors. It has been reported that diabetes is associated with an increased production of reactive oxygen species and greater oxidative damage to DNA. Recently, it has also been reported that the overall frequency of DNA damage and cytotoxicity correlates with the level of HbA1c in people with prediabetes.”

Insulin resistance

“Second, insulin resistance is a core defect responsible for the development of diabetes, and is established in individuals with prediabetes. The compensatory hyperinsulinaemia and increased level of bioavailable IGF 1 related to insulin resistance may promote the proliferation of cancer cells and may also relate to worsened cancer outcomes.”

Genetics

Third, genetic ‘interferences’ may also play an important role in the development of cancer in prediabetic individuals. A recent study has suggested that nuclear receptor coactivator 5 is a haploinsufficient tumour suppressor, and that a deficiency of nuclear receptor coactivator 5 increases susceptibility to both glucose intolerance and hepatocellular carcinoma, partially by increasing IL-6 expression.”

The public health implications of their results are enormous:

“These findings have important clinical and public health implications. In the US population aged ≥18 years, the age- adjusted prevalence of prediabetes increased from 29.2% in 1999–2002 to 36.2% in 2007–2010. Considering the high prevalence of prediabetes, as well as the robust and significant association between prediabetes and cancer dem- onstrated in our study, successful intervention in this large population could have a major public health impact. The ADA suggest that lifestyle intervention is the mainstay of treatment for prediabetes in the general population, and metformin is recommended for delaying progression to overt diabetes if individuals present with other related risk factors, such as a BMI ≥35 kg/m2, dyslipidaemia, hypertension, a family history of diabetes or an HbA1c >6% (42 mmol/mol)]. It should be noted that metformin is now considered as having some ‘protective’ anticancer properties. Notably, metformin mediates an approximately 30% reduction in the lifetime risk of cancer in diabetic patients. However, whether this is true in prediabetic individuals is not yet known. Long-term, large- scale studies of high-risk individuals, especially those with IGT or a combination of IGT and IFG, are urgently needed…”

Of course, functional practitioners have a number of resources besides metformin to help recover insulin sensitivity and restore healthier blood glucose regulation. The authors conclude:

“Overall, prediabetes was associated with an increased risk of cancer, especially liver, endometrial and stomach/colorectal cancer.’

Inflammation and diabetes

Diabetes Research and Clinical PracticeConsidering that chronic inflammation is a key common denominator in diabetes, prediabetes (metabolic syndrome) and cancer, it’s edifying to reflect on a paper published recently in Diabetes Research and Clinical Practice:

“It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes.”

Breast cancer and glucose intolerance

PLOS ONEBreast cancer, insulin resistance and blood sugar dysregulation are associated, and more evidence for the breast cancer link with glucose intolerance is presented in a study just published in PLOS ONE (Public Library of Science). The authors used oral glucose tolerance tests (OGTT) to assess breast cancer patients at their initial diagnosis and during chemotherapy and found a persistent association:

“The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5%, 50.6% and 28.1%, and 25.3% and 33.3%, respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT.”

It is fundamentally important to regulate blood glucose and insulin in oncologic case management since high glycation and insulin promote disease progression. The authors conclude:

Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.”

Thyroid in heart, metabolism, brain, kidney; vital importance of T3

The American Journal of MedicineNote: Scroll to the bottom of this post for an ‘executive summary.’

Thyroid disorders have widespread impact and although subclinical hypothyroidism and low triiodothyronine (T3) syndrome are common they are frequently overlooked in practice.

Thyroid function is very important for cardiovascular health. The authors of freshly published paper in The American Journal of Medicine remind readers:

Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists.”

The authors apparently rely on TSH as do many others, but in my opinion and as subsequent papers illustrate, this can result in many missed diagnoses…

“As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease.”

This includes the…

“…potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases.”

 

The Annals Of Thoracic SurgeryMore inspiration to  not overlook the widespread occurrence and clinical importance of low T3 (triiodothyronine, the ‘active’ thyroid hormone) is offered in a study just published in The Annals of Thoracic Surgery differentiates low triiodothyronine syndrome from gross hypothyroid in the context of coronary artery disease.

“There is strong clinical and experimental evidence that altered thyroid homeostasis negatively affects survival in cardiac patients, but a negative effect of the low triiodothyronine (T3) syndrome on the outcome of coronary artery bypass grafting (CABG) has not been demonstrated. This study was designed to evaluate the prognostic significance of low T3 syndrome in patients undergoing CABG.”

The authors evaluated 806 consecutive CABG patients for any effect of baseline free T3 (fT3) concentration and of preoperative low T3 syndrome (fT3 <2.23 pmol/L) on the risk of low cardiac output (CO) and death, finding a significant association:

“There were 19 (2.3%) deaths, and 64 (7.8%) patients experienced major complications. After univariate analysis, fT3, low T3, New York Heart Association class greater than II, low left ventricular ejection fraction (LVEF), and emergency were associated with low CO and hospital death…At multivariate analysis, only fT3, low T3, emergency, and LVEF were associated with low CO, and fT3 and LVEF were the only independent predictors of death.”

They summarize these striking results in their conclusion:

“Our study demonstrates that low T3 is a strong predictor of death and low CO in CABG patients. For this reason, the thyroid profile should be evaluated before CABG, and patients with low T3 should be considered at higher risk and treated accordingly.”

 

Acta CardiologicaIn this vein a very interesting paper was published in the journal Acta Cardiologica (Official Journal of the Belgian Society of Cardiology) that identifies low free (bioactive) T3 as a contributor to the development of cardiac dysfunction. The authors outline their intent:

“A low T3 syndrome was described in patients with heart failure (HF), and it appears to be associated with adverse outcome, representing an independent predictor of mortality. However, it is not known if low T3 levels contribute to the pathophysiology of HF. On the other hand, it has been seen that an elevation of brain natriuretic peptides (BNP and NT-proBNP) may represent a warning signal for future cardiovascular disease and may be an early marker of diastolic dysfunction. Therefore we tested the hypothesis that low levels of free-triiodothyronine (FT3) are sufficient to determine an increased concentration of the amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), as the result of an initial and asymptomatic cardiac impairment.”

They evaluated thyroid function and measured NT-proBNP in 52 consecutive non-cardiac patients. Dividing them into a low T3 group (19 patients) and a normal T3 group (33 patients) they found…

“The median NT-proBNP concentration of patients with low T3 syndrome was significantly higher than in those with normal FT3 (370 vs. 120 pg/ml). There is a strong and inverse correlation between FT3 and Log NT-proBNP (R = -0.47); this relation persists in a multivariable regression analysis, after adjustment for other potentially confounding variables.”

The authors articulate the clinical significance in their conclusion:

“In absence of overt cardiovascular disease, patients with low T3 syndrome present an increased concentration of NT-proBNP. These data suggest that low FT3 levels may be a contributing factor for the development of cardiac dysfunction.”

 

European Journal of Clinical InvestigationThe same syndrome of subclinical low thyroid manifesting as low T3 applies to stroke as well according to a study published in the European Journal of Clinical Investigation. The authors state:

Low triiodothyronine (T3) has been associated with increased short-term mortality in intensive care unit patients and long-term mortality in patients with heart disease. The objective of this study was to investigate possible associations of thyroid hormone status with clinical outcome in patients admitted for acute stroke.”

Considering T3 values ≤ 78 ng dL (1·2 nmol L as ‘low T3’ and T4 values ≤ 4·66 µg dL (60 nmol L) were as ‘low T4′, they examined data for 737 consecutive patients with acute first ever stroke within 24 hours of onset. They measured total T3, thyroxin (T4) and thyroid-stimulating hormone (TSH) levels and evaluated the basic clinical characteristics, stroke risk factors, and brain imaging. Low thyroid (T3) turned out to be a significant predictor:

“Four hundred and seventeen (56%) patients had T3 values ≤ 78 ng dL−1 and 320 had normal T3 values. The 1-year mortality was 27·34% for low T3 and 19·37% for normal T3 cases. A smaller percentage of patients with low T3 values were independent at 1 year compared to those with normal T3 values [54·2% vs. 68·7%, odds ratio (OR) = 0·53]. Cox regression analysis revealed that increased age, haemorrhagic stroke, low Scandinavian Stroke Scale score, increased glucose and low T3 values (hazards ratio 0·69) were significant predictors of 1-year mortality.”

Clinicians should bear in mind the authors’ conclusion about low T3 thyroid syndrome and stroke:

“A high proportion of patients with acute stroke were found soon after the event with low T3 values. The low-T3 syndrome is an independent predictor of early and late survival in patients with acute stroke, and predicts handicap at 1 year.”

 

Saudi Medical JournalA valuable paper published in the Saudi Medical Journal offers evidence that low T3 is the strongest correlate of suboptimal thyroid function with metabolic syndrome and insulin resistance. The authors determined to…

“…determine the association between thyroid hormones, insulin resistance, and metabolic syndrome in euthyroid women.”

They examine forty-five women free of past medical conditions by estimating body fat and measuring fasting blood for total triiodothyronine (T3), total thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), lipids, insulin, and glucose. T3 turned out to be a much more significant indicator than T4:

“The mean age of the participants was 32.6 +/= 9.6 years with a body mass index (BMI) of 29.9 +/= 3.8 kg/m2. Evidence of homeostasis model assessment index for insulin resistance (HOMA-IR) more than 3 was seen in 34 (75%) and metabolic syndrome in 29 (64%) participants. Total T3 showed a positive correlation with triglycerides, low density lipoprotein- cholesterol (LDL-C), total cholesterol, insulin, HOMA-IR and negatively with body fat. Thyroid-stimulating hormone correlated positively with BMI, insulin, HOMA-IR, LDL-C and negatively with HDL-cholesterol (p<0.05). Free triiodothyronine correlated positively with waist circumference and T4 did not correlate with metabolic syndrome parameters.”

The authors conclude:

“Our preliminary data show an association between thyroid hormones and some components specific of the metabolic syndrome in euthyroid women. Total triiodothyronine and TSH correlated more with variables of metabolic syndrome than FT3 and T4.”

 

Endocrine JournalLow-grade systemic inflammation is a common denominator of aging and almost every chronic disease. It is, of course, a key factor in both type 2 diabetes and thyroid disorders. A study published recently in the Endocrine Journal (Japan Endocrine Society) demonstrates the association of type 2 diabetes with low T3 in the context of low-grade systemic inflammation:

“Previous reports highlight the role of systemic inflammation in the genesis of non-thyroidal illness syndrome and type 2 diabetes mellitus (T2DM). Our objective was to assess whether body mass index and the low-grade systemic inflammation would be associated with changes in thyroid hormone metabolism in patients with type 2 diabetes.”

They examined data for 104 subjects, half with type 2 diabetes and half comprised a control group who were paired by age, gender and body mass index. They measured total (T) and free (F) thyroxine (T4) and triiodothyronine (T3), reverse T3 (rT3), the ratios FT3/rT3, FT3/FT4 and FT4/rT3, and obtained additional data on diabetes duration and complications, body mass index, waist circumference, hypertension, HbA1c, and high sensitivity C-reactive protein. T3 stands out here as well:

“Patients with DM presented lower levels of TT4, TT3 and FT3 and higher of FT4, waist circumference and C-reactive protein. Body mass index was inversely correlated with FT4 and TT3. C-reactive protein was positively correlated with rT3 and inversely with FT4/rT3 and FT3/rT3. Body mass index was an independent predictor for FT4 and TT3 levels. Inflammation predicted the FT4/rT3 ratio. C-reactive protein and body mass index were independent predictors for rT3.”

Clinical note: this implies that thyroid assessment is incomplete if it doesn’t include at least free and total T3 and T4 (along with TSH). The authors conclude with a statement of great significance because it is so common to encounter in clinical practice:

“In conclusion, type 2 diabetes was associated with a low T3 state. Body mass index and the low-grade systemic inflammation are related to the non-thyroidal illness syndrome in these patients, possibly by altering the activity of peripheral deiodinases.”

I find low-grade systemic inflammation impairment of the activity of deiodinase enzymes to convert T4 into the metabolically active T3 regularly in my patient population.

 

Journal of Clinical Endocrinology & MetabolismMore complete assessment of seemingly euthyroid (‘normal’ thyroid) patients is often dismissed with the  test data limited meagerly to TSH and total T4 levels, a practical flaw that likely fails to uncover many diagnoses. In a study published in the Journal of Clinical Endocrinology & Metabolism, the authors demonstrate that ‘low normal’ free T4 correlated significantly with metabolic syndrome and cardiovascular risk factors. The authors state:

“Thyroid disease and the metabolic syndrome are both associated with cardiovascular disease…The aim of this study was to explore the hypothesis that thyroid function, in euthyroid subjects, is associated with components of the metabolic syndrome, including serum lipid concentrations and insulin resistance.”

They assessed data for 2703 euthyroid adult subjects that included homeostasis model assessment for insulin resistance (HOMA-IR and usual criteria for metabolic syndrome:

“After adjustment for age and sex, free T4 (FT4) was significantly associated with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Both FT4 and TSH were significantly associated with HOMA-IR. Median HOMA-IR increased from 1.42 in the highest tertile of FT4 to 1.66 in the lowest tertile of FT4. FT4 was significantly related to four of five components of the metabolic syndrome (abdominal obesity, triglycerides, high-density lipoprotein cholesterol, and blood pressure), independent of insulin resistance.”

Clinical note: so-called euthyroid = ‘normal’ thyroid or ‘subclinical hypothyroid’ must not be overlooked in case management of metabolic syndrome and cardiovascular risk. The authors conclude by asserting:

“We have demonstrated an association between FT4 levels within the normal reference range and lipids, in accordance with the earlier observed association between (sub)clinical hypothyroidism and hyperlipidemia. Moreover, low normal FT4 levels were significantly associated with increased insulin resistance. These findings are consistent with an increased cardiovascular risk in subjects with low normal thyroid function.”

 

Metabolic Syndrome and Related DisordersMore on T3 and metabolic syndrome was presented in a study published in the journal Metabolic Syndrome and Related Disorders (yes, there is a journal by that title) in which the authors examined date for 211 patients with a mean age of about 40 years who had a body mass index (BMI) >30 kg/m(2) without any other hormonal disorder related to obesity. Measurements included fasting blood glucose (FBG), insulin, insulin resistance (HOMA-IR),total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free T3 (FT3), and free T4 (FT4). They used TSH cutoff value of 2.5 mU/L. Sure enough T3 stood out:

Metabolic syndrome positive patients had significantly higher FBG, triglycerides, FT4, systolic (SBP) and diastolic blood pressure (DBP), and statistically lower HDL-C and FT3/FT4 ratio than metabolic syndrome negative patients. TSH decreased with age and was not related with any metabolic syndrome parameters. The FT3/FT4 ratio negatively correlated with FBG, triglycerides, SBP, and DBP; TT3 positively correlated with HOMA-IR, FBG, and waist circumference.”

In other words, as free T3 went down in relation to free T4 fasting blood glucose, triglycerides, and both systolic and diastolic blood pressure went up. And as total T3 went down insulin resistance, fasting blood glucose and waist circumference went up. The authors conclude:

“”Metabolic syndrome parameters (except HDL) correlated with TT3, FT4, and the FT3/FT4 ratio. FT4 levels were associated with obesity and metabolic syndrome independently of insulin resistance, whereas TT3 levels were associated with both insulin resistance and metabolic syndrome. This relationship can be explained by compensatory effects of TT3, and probably FT4, on energy expenditure and thermogenesis in obese people.”

 

Journal of Clinical InvestigationAt the crux of the matter is the manner in which low grade chronic inflammation impairs conversion of the relatively inactive T4 thyroid hormone to the active T3. The authors of a very valuable paper published in The Journal of Clinical Investigation shed light on an important mechanism by describing the role of the pro-inflammatory cytokine IL-6.

Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3′ triiodothyronine (T₃) that occurs in chronically ill patients; the degree of reduction in T₃ is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T₄ to active T₃, whereas the type III enzyme (D3) inactivates T₄ and T₃. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS.”

They investigated this by measuring the effect of IL-6 the different types deiodinase activities in human cell lines. (Recall that deiodinase enzyme activity is required to convert T4 to T3.) Their results reveal not only the role of pro-inflammatory IL-6, but implicate glutathione (GSH) as a likely key factor:

Active T₃ generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T₃ production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T₃.”

The authors’ conclusion contains comments of great clinical significance:

“In conclusion, our findings demonstrated that pathophysiologically relevant concentrations of IL-6 reduce D1 and D2 function and increase that of D3, providing a single mechanistic explanation for the decreased serum T3 and increased rT3 observed in the acute phase of NTIS. The decrease in D1 will both reduce plasma T3 production and impair rT3 deiodination, while the decrease in D2 will supplement this by impairing intracellular T4-to-T3 conversion. On the other hand, the increased D3 protein, which has its function preserved by its more ready access to GSH (or other extracellular reducing agents), will further decrease plasma T3 and increase the production of rT3 from T4. The general increase in the cellular deiodinase proteins is caused by a combination of IL-6–induced ROS (also found with H2O2) and specific activation of JAK/STAT pathways by this cytokine.”

In a larger context…

“Although other factors in sick patients may also contribute to NTIS, these observations and unifying hypothesis represent a major step forward in unraveling this longstanding enigma, leading to what we believe to be a previously unrecognized combinatorial pathway that may be viewed largely as a general response to oxidative stress. Our results therefore suggest that rather than a protective or a maladaptive process, the changes in plasma T4, T3, and rT3 are a consequence of cellular stress. Whether antioxidants, such as NAC, could be beneficial as an adjuvant therapy together with other therapeutic measures in critically ill patients remains to be evaluated.”

 

Nephrology Dialysis TransplantationFurther insight into the nature of the low T3 in thyroid dysregulation associated with chronic disease is offered in a study published in the journal Nephrology Dialysis Transplantation on chronic kidney diseae (CKD) and low T3. These authors observe:

“The evaluation of thyroid function in systemic illness remains complex because the changes occur at all levels of the hypothalamic-pituitary-thyroid axis. During illness, a decrease in triiodothyronine (T3) and pulsatile thyroid-stimulating hormone (TSH) release and increases in reverse T3 occur. This constellation of findings is termed the low T3 syndrome, the euthyroid sick syndrome or non-thyroid illness. Low T3 syndrome is the most common manifestation in non-thyroid illness and this phenomenon has been believed to be due to inhibition of 5′-deiodinase, which is a catalyzing enzyme for production of T3 from circulating T4. To date, a variety of alterations in thyroid hormone levels and metabolism have been reported in patients with chronic renal failure and low T3 has been consistently found to be the most common disturbance.”

Of widespread importance:

“Several lines of evidence suggested that low T3 was an independent predictor of survival in various illness states. Furthermore, the recent data proposed that biomarkers of inflammation were associated with low T3 levels in haemodialysis and peritoneal dialysis patients and thyroid dysfunction might be implicated in the pathogenetic pathway which link microinflammation to survival in dialysis patients.”

They determined to see if low T3 correlated to chronic kidney disease prior to the stage of dialysis:

“However, there are no data about the prevalence of low T3 in persons with chronic kidney disease (CKD) who do not require maintenance dialysis. We hypothesized that the prevalence of low T3 would be increased according to the increase of a CKD stage. This study was performed to explore the prevalence in each stage of CKD and relationship with eGFR.”

Their data on 2284 subjects with normal serum TSH and not taking thyroid hormones confirmed their hypothesis, leading to the conclusion:

“This study showed that low T3 syndrome was highly prevalent in CKD and was a remarkable finding in early CKD. Furthermore, serum T3 levels were associated with severity of CKD even in the normal TSH level.”

 

Iranian Journal of Kidney DiseasesAlong these lines a study showing that low T3 in various conditions including CKD is linked to systemic low grade inflammation reflected in altered cytokines was published in the Iranian Journal of Kidney Diseases. The authors evaluated the interleukins (IL) IL-6 and IL-10 and euthyroid sick syndrome (ESS) in patients with nonthyroidal illnesses (NTI) including chronic kidney disease (CKD), congestive heart failure (CHF), or acute myocardial infarction (MI) while measuring serum levels of IL-6 and IL-10, thyroid stimulating hormone (TSH), total T4, and T3:

“In the 60 patients with NTI, we detected a significantly lower T3 and T4 levels compared to controls, while TSH level was within the reference range. Also, IL-6 level was substantially higher than that in controls and correlated with T3 and T4. Similarly was IL-10 level that correlated with T3, but not with T4. The ILs correlated positively with each other. Only IL-6 was a predictor of low T3. The proportion of patients with subnormal T3, T4, and TSH levels was highest in those with MI along with greatest IL-6 and IL-10 levels compared to patients with CHF and CKD. Patients with CKD showed the least disturbance in IL-6 and IL-10 despite the lower levels of T3, T4, and TSH in a higher proportion of them compared to patients with CHF.”

Their discussion of these results contains some key points for clinicians:

“In the current study, we observed a considerably lower serum T3 and total T4 concentrations, signifying thyroid dysfunction, in patients with variable NTIs, while serum TSH showed a mean value that was not significantly different from that in the healthy controls…In this study, we detected a substantially high level of the pro-inflammatory cytokine, IL-6, in patients with NTI, supporting its possible role as an endocrine cytokine with a regulatory effect on many endocrine systems including the thyroid gland.”

Here is something readers who test cytokines may have seen too that illustrates a fundamental principal in case management and disease progression: suppression of receptors due to chronically high levels of signaling agents (in this case anti-inflammatory IL-10):

We also detected a considerably high level of the anti-inflammatory cytokine, IL-10 in the patients with NTI.Therefore, within the cytokine network, activation of pro-inflammatory mediators such as IL-6 is followed by increased production of endogenous inhibitory molecules including the antagonistic cytokine IL-10 in an attempt to suppress release of pro-inflammatory cytokines. This dimorphic response may be related to macrophages resistance to the suppressive effect of IL-10 as a result of down-regulation of the expression of soluble IL-10 receptors. The high IL-10 levels was hoped for to minimize the deleterious effect of the raised IL-6. Taniguchi and colleagues highlighted this potential protective effect of IL-10 in their 25 patients with systemic inflammatory states…In this study, the suppressed thyroid hormones were inversely associated with serum IL-6 elevations.”

There was a particularly strong association with heart attacks (MI), consonant with the degree of thyroid dysfunction tracking the severity of non-thyroidal illness:

“We observed a highest level of IL-6 along with lowest measurements of both serum T3 and serum T4 in the patients with MI, while the least changes were noticed in patients with chronic illness exemplified by CHF. This is in accordance with the hypothesis that the magnitude of thyroid hormones’ alteration parallels the severity of the associated NTI.”

 

Clinical note: It is very important for practitioners to bear in mind that thyroid effect, in addition to thyroid hormone production and conversion, encompasses thyroid hormone transporters and receptors. The felt metabolic and brain effects of thyroid activation depends on all of these. Failing to take them into consideration is a common reason why ‘subclinical hypothyroidism’, NTIS (nonthyroidal illness syndrome) or ESS (euthyroid sick syndrome) is often overlooked.

Journal of Molecular EndocrinologyA paper published in the Journal of Molecular Endocrinology sheds light on the role of MCT8, MCT10, organic anion transporting polypeptides (OATP) transporters:

“Thyroid hormone is a pleiotropic hormone with widespread biological actions. The follicular cells of the thyroid gland produce predominantly thyroxine (T4), but it is mainly 3,3′,5-tri-iodothyronine (T3) that binds to the nuclear thyroid hormone receptor. The biological activity of T3 is therefore largely determined by the intracellular T3 concentration which is dependent on a) the circulating T3 concentration; b) the transport of thyroid hormone across the cell membrane; and c) the presence of iodothyronine deiodinases, which activate or inactivate thyroid hormone. To date, three deiodinases have been characterized as homologous selenoproteins. Both D1 and D2 converts T4 to T3, whereas D3 catalyzes the degradation of T4 to reverse T3 (rT3) and of T3 to 3,3′-T2.”

The enzymes that convert T4 to T3 have their active portions inside the cell, and transporters are required to get T4 through the cell membrane into the cytoplasm where the action happens:

“The deiodinases are membrane proteins with their active sites located in the cytoplasm. Therefore, transport across the cell membrane is essential for thyroid hormone action and metabolism. Based on the lipophilic structure of thyroid hormones, it is long thought that thyroid hormone enters the cell through passive diffusion. However, it has become increasingly clear that there are specific thyroid hormone transporters, and that the activity of these transporters in part determines the intracellular thyroid hormone concentration.”

Thyroid hormone transporters MCT8 and MCT10Transporters MCT8, MCT10 and OATP have been the most studied:

“To date, several transporters with high affinity for thyroid hormone, but with different tissue distributions and ligand affinities have been identified. This review will focus on the molecular aspects of the monocarboxylate transporter 8 (MCT8) and MCT10, and several members of the organic anion transporting polypeptide (OATP) family…both MCT8 and MCT10 increase the intracellular availability of iodothyronines, as evidenced by the marked increase in their intracellular deiodination by co-transfected deiodinases. However, both MCT8 and MCT10 facilitate not only the cellular uptake but also the efflux of iodothyronines.”

In other words, they get necessary thyroid stuff both into and out of the cell. These transporters are subject to genetic variation of course, and some mutations in the MCT8 gene can cause severe psychomotor retardation:

Mutations in the MCT8 gene cause a syndrome of severe psychomotor retardation and high serum T3 levels in affected male patients, known as the Allan–Herndon–Dudley syndrome. The neurological deficits are probably explained by an impeded uptake of T3 in MCT8-expressing central neurons and, hence, an impaired brain development. This has been reviewed in detail elsewhere. Since mutations in the MCT8 gene have such profound effects, the question arises whether small changes in the MCT8 gene may affect transport activity as well.”

Such as depression, etc. The implication is that much milder disruption of MCT8 transporter function can significantly diminish metabolism in the brain that impairs cognition and mood. The authors conclude their lengthy paper detailing the action of other transports with comments of great clinical significance:

“…it has become clear that thyroid hormone requires active transport across cell membrane to carry out its biological functions…It is surprising that few studies have been published investigating the association of polymorphisms in these transporters with serum thyroid parameters or thyroid hormone-related endpoints, especially since polymorphism studies have yielded new insights into the role of thyroid hormone in several processes in the human body. For instance, a genome-wide linkage scan identified the type 2 deiodinase as a susceptibility locus for osteoarthritis. In addition, genetic variation seems to play a role in psychological well-being…”

 

Thyroid ResearchThe authors of a paper published in the journal Thyroid Research chime in with an expansion of these observations:

Thyroid hormones are of crucial importance for the functioning of nearly every organ. Remarkably, disturbances of thyroid hormone synthesis and function are among the most common endocrine disorders affecting approximately one third of the working German population. Over the last ten years our understanding of biosynthesis and functioning of these hormones has increased tremendously. This includes the identification of proteins involved in thyroid hormone biosynthesis like Thox2 and Dehal where mutations in these genes are responsible for certain degrees of hypothyroidism. One of the most important findings was the identification of a specific transporter for triiodothyronine (T3), the monocarboxylate transporter 8 (MCT8) responsible for directed transport of T3 into target cells and for export of thyroid hormones out of thyroid epithelial cells.”

They remind of the role of thyroid dysregulation in depression and dementia:

“Disturbed TH action is linked with major health problems especially in critical life phases such as development, disease or ageing. Thus, lack of TH action in the adult brain causes impaired neuro-cognitive function and psychiatric states such as severe depression and dementia. Not only hypothyroidism but also hyperthyroidism affects the CNS and frequently results in agitation, increased irritability and dysregulation of body temperature.”

Cardiovascular disease can also have a thyroid component:

“There is ample epidemiological evidence that both, hyper- and hypothyroidism confer an increased risk for cardiovascular morbidity(e.g. arrhythmia, heart failure and stroke) and mortality.”

Interestingly in regard to obesity:

“Besides the classic hormones T4 and T3 new data demonstrate that the rare thyroid hormone metabolite 3,5-T2 is effective in the prevention of high fat diet-induced adiposity and prevents hepatic steatosis, however, without exerting the severe side effects on the cardiac system that have been observed with T3-based treatments. The vital importance of thyroid hormones for regulation of thermogenesis and for maintenance of the homeostasis of the mitochondrial energy metabolism has long been established. However, the functional interactions between the activities of uncoupling proteins (UCP) which are triggered by T3 and catecholamines affecting brown adipose tissue (BAT) as well as skeletal muscle of the adult, provide new possibilities for therapeutic intervention in obesity that have only recently become apparent.”

Old and new concepts of thyroid hormone actionThey summarize a ‘bird’s-eye’ view of hormone physiology:

“Thus in the present concept of thyroid hormone action, the cellular thyroid hormone status is defined by thyroid hormone transporters, thyroid hormone membrane receptors, thyroid hormone molecules and TAM mediated actions.

There is no question that aging increases the tendency to subclinical hypothyroid conditions:

“Epidemiology has shown unequivocally that with age the ratio of subclinical to clinically manifest thyroid disorders increases, thus thyroid disorders are a disease of the ageing population. In light of the demographic changes of our societies, improvements of human health care systems should not be limited to better management of only cardiovascular disorders, cancer, and neurodegenerative diseases. We believe that modern and future-oriented health politics and policy making institutions need to take an endocrine organ into account that has been known for decades, but is still not fully “revealed”, the thyroid gland.”

 

Journal of EndocrinologyAppreciation of the weighty influence of the MCT8 transporter is enhanced by recognition of its role in the global neurological impairment of intrauterine growth restriction (IUGR) as described in a study published in the Journal of Endocrinology:

Intrauterine growth restriction (IUGR) describes the failure of a fetus to attain its genetically determined growth potential, with the most common underlying etiology being uteroplacental failure associated with abnormal placental development. IUGR is often characterized by continued head and brain growth at the expense of other less vital organs resulting in an elevated brain:liver weight ratio postnatally. IUGR complicates 5–10% of pregnancies and is associated with increased perinatal mortality. Survivors demonstrate an increased prevalence of cognitive impairment compared with babies born appropriately grown for gestational age.”

They measured changes in cortical MCT8 expression with IUGR by immunohistochemistry performed on brain sections obtained from appropriately grown for gestational age (AGA) human fetuses and MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses which was compared with that in the occipital cortex of gestationally matched AGA fetuses:

“When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses… Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development…This study is the first to demonstrate significantly reduced cortical MCT8 expression within the developing CNS of human fetuses stillborn with severe IUGR. Our results suggest that altered TH transporter activity in cerebral neurons could be a contributory factor to the pathophysiology of neurodevelopmental impairment associated with IUGR.”

 

Molecular and Cellular EndocrinologyAs described in an earlier post (Depression, aging and brain inflammation: indications for sustainable treatment) there is evidence that the global driving factor of biological aging is inflammation in the hypothalamus, practitioners doing case management of thyroid conditions should know the importance of thyroid hormone feedback in the hypothalamus and pituitary as described in a paper published in Molecular and Cellular Endocrinology:

“A major change in thyroid setpoint regulation occurs in various clinical conditions such as critical illness and psychiatric disorders. As a first step towards identifying determinants of these setpoint changes, we have studied the distribution and expression of thyroid hormone receptor (TR) isoforms, type 2 and type 3 deiodinase (D2 and D3), and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the human hypothalamus and anterior pituitary.”

Their examination of these agents through immunoreactivity and immunostaining revealed important activity of hypothalamic glial cells:

“These findings suggest that the prohormone thyroxine (T4) is taken up in hypothalamic glial cells that convert T4 into the biologically active triiodothyronine (T3) via the enzyme D2, and that T3 is subsequently transported to TRH producing neurons in the PVN. In these neurons, T3 may either bind to TRs or be metabolized into inactive iodothyronines by D3. By inference, local changes in thyroid hormone metabolism resulting from altered hypothalamic deiodinase or MCT8 expression may underlie the decrease in TRH mRNA reported earlier in the PVN of patients with critical illness and depression.”

The pituitary, of course, also comes into play:

“In the anterior pituitary, D2 and MCT8 immunoreactivity occurred exclusively in folliculostellate (FS) cells. Both TR and D3 immunoreactivity was observed in gonadotropes and to a lesser extent in thyrotropes and other hormone producing cell types.”

The authors summarize their results:

“Based upon these neuroanatomical findings, we propose a novel model for central thyroid hormone feedback in humans, with a pivotal role for hypothalamic glial cells and pituitary FS cells in processing and activation of T4. Production and action of T3 appear to occur in separate cell types of the human hypothalamus and anterior pituitary.”

 

Pediatric Endocrinology ReviewsHormone receptors are a critical link in the signaling chain for thyroid as for other hormones and neurotransmitters. Receptor function can be impaired by elevated hormone levels, genetic mutation and chronic inflammation. A paper published in Pediatric Endocrinology Reviews serves as a reminder to consider thyroid hormone receptor function in case management:

The important physiological actions of the thyroid hormones are mediated by binding to nuclear thyroid hormone receptors (TRs), encoded by two genes TRalpha and TRbeta. These receptors act as hormone-dependent transcription factors by binding to DNA motifs located in the regulatory regions of target genes…”

Receptor resistance to thyroid hormones can cause a hypothyroid state in the presence of normal TSH and thyroid hormone levels:

“TRbeta gene mutations cause resistance to thyroid hormones (RTH), characterized by inappropriately high thyroid-stimulating hormone (TSH) levels due to lack of feedback inhibition of thyroid hormones on the hypothalamus and pituitary gland, and to reduced sensitivity of other TRbeta target tissues to thyroid hormones. Very recently, patients heterozygous for TRalpha mutations have been identified. These patients exhibit clinical symptoms of hypothyroidism in TRalpha target tissues such as intestine or heart and near normal circulating TSH and thyroid hormone levels.”

 

Nephrology Dialysis TransplantationChronic low-grade inflammation, also termed micro-inflammation, is an almost universal ‘fact of life’ in chronic disorders and aging. Its link to peripheral thyroid resistance and low T3 is seen in high magnification in Nephrology Dialysis Transplantation in which the authors observe its role in continuous ambulatory peritoneal dialysis (CAPD) patients with end-stage renal disease (ESRD):

Low T3 is a frequent alteration in patients with ESRD. This derangement has been recently linked to inflammation in haemodialysis patients. Whether this association holds true in peritoneal dialysis patients has not been studied…We investigated the relationship between low-grade inflammation [IL-6, C-reactive protein (CRP) and serum albumin levels] and free tri-iodothyronine (fT3) in a cohort of 41 CAPD patients without heart failure and inter-current illnesses.”

 

They found multiple correlations, including low free T3 as a predictor of mortality:

“CAPD patients had lower fT3 levels than healthy subjects of similar age. Free T3 levels were directly related to those of serum albumin and inversely to IL-6 and CRP. Age, haemoglobin levels and diastolic blood pressure were also related to fT3. In multiple regression models adjusting for all variables related to fT3, CRP and albumin were retained as independent correlates of fT3…Plasma fT3 levels were lower in patients who died compared with survivors. In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors.”

 

The association of micro-inflammation and low free T3 noted by the authors likely applies to numerous other conditions:

“The relationship between fT3, CRP and serum albumin suggests that inflammation–malnutrition might be involved in the low T3 syndrome in CAPD patients. Thyroid dysfunction might be implicated in the pathogenic pathway which links micro-inflammation to survival in PD patients.”

 

Journal of Endocrinological InvestigationClinicians should also keep in mind that low T3 can be the only thyroid abnormality contributing to psychiatric depression. A paper published in the Journal of Endocrinological Investigation focuses on the link between low T3 syndrome and depression.

“In euthyroid sick syndrome [non-thyroidal illness (NTI)], a number of investigators have described TSH and serum thyroid hormone abnormalities, low T3, low T3 and T4, increased T4, low TSH, etc. Those cases of NTI where there is only T3 decrease [and normal serum T4, free T4 (FT4), and TSH levels] are specifically referred to as low T3 syndrome. However, the information in regard to low T3 syndrome in psychiatric subjects who are clinically euthyroid and do not have any other systemic illness is scanty. In our facility, since thyroid function is routinely assessed in psychiatric patients at admission, this provided the opportunity to study low T3 syndrome in a large group of psychiatric patients.”

The authors found low T3 syndrome in a substantial percentage of depressed patients:

Out of 250 subjects with major psychiatric depression, 6.4% exhibited low T3 syndrome (mean serum T3 concentration 0.94 nmol/l vs normal mean serum concentration of 1.77 nmol/l). The low T3 levels could not be ascribed to malnutrition or any other illness and the metabolic parameters were all normal…The depression might constitute an illness having the same relation to low T3 as found in the low T3 syndrome previously described in euthyroid sick subjects. The present findings, besides describing low T3 syndrome in psychiatric patients without systemic illnesses, suggest the possibility of subgrouping in clinical psychiatric depression which may have a broader clinical significance.”

 

Minerva EndocrinologicaA point of premiere clinical importance is that supplemental T3 can be the treatment of choice in depression with hypothyroid as asserted by the authors of an excellent paper published in Minerva Endocrinologica:

Hypothyroidism has been linked to depression as there is irrefutable evidence that it triggers affective disease and psychic disorders. Depressive patients have a higher frequency of hypothyroidism and patients with hypothyroidism have a higher occurrence of depressive syndrome. Hypothyroidism exhibits considerable alterations in blood flow and glucose metabolism in the brain. Furthermore, patients with major depression may have structural abnormalities of the hippocampus that can affect memory performance. Thyroid peroxidase antibodies have, moreover, been positively associated with trait markers of depression.”

Remember that more than 90% of hypothyroid in developed countries is autoimmune thyroiditis (Hashimoto’s disease) with the presence of thyroid peroxidase antibodies, a frequent finding on laboratory tests that can be very significant even at ‘predictive’ (low) levels. Furthermore…

Depressive symptomatology is variable and is influenced by susceptibility and the degree, though not always, of thyroid failure. In addition, glucose homeostasis and rapid weight loss have been associated to thyroid hormones and increased depressive symptoms. Thyroxine treatment in patients older than 65 years does not improve cognition. In contrast, T3 administration is the therapy of choice in patients with resistance to antidepressive drugs, and especially to SSIR. Genetic variants of thyroid hormone transporters or of deiodinases I and II may predispose to depression and, therefore, a personalized approach should be implemented.”

 

BMC CancerAlso of great interest is the finding that treatment of subclinical hypothyroid/non-thyroidal illness syndrome (NTIS) with T3 can improve the response to chemotherapy in breast cancer as reported in a study published in BMC Cancer:

Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the response to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence during chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy.”

The authors examined thyroid hormone levels and NTIS prevalence at initial diagnosis of breast cancer and during chemotherapy in 685 patients (369 with breast cancer, 316 with breast benign lesions). They also measured the influence of thyroid hormones on chemotherapeutic efficacy by the chemosensitization test and compared chemotherapeutic efficacy between breast cancer cells with chemotherapeutics plus triiodothyronine (T3) versus chemotherapeutics only. A distinct benefit from treatment by T3 emerged from their data:

“In breast cancer, NTIS prevalence at the initial diagnosis was higher and increased during chemotherapy, but declined before the next chemotherapeutic course. Thyroid hormones decreased significantly during chemotherapy. T3 can enhance the chemosensitivity of MCF-7 to 5-Fu and taxol, with progression from G0-G1 phase to S phase. The similar chemosensitization role of T3 were found in MDA-MB-231. We compared chemotherapeutic efficacy among groups with different usage modes of T3, finding pretreatment with lower dose of T3, using higher dose of T3 together with 5-Fu or during chemotherapy with 5-Fu were all available to achieve chemosensitization, but pretreatment with lower dose of T3 until the end of chemotherapy may be a safer and more efficient therapy.”

Their conclusions are highly important for breast cancer management:

“Taken together, thyroid hormones decreasing during chemotherapy was found in lots of breast cancer patients. On the other hand, thyroid hormones can enhance the chemotherapeutic efficacy through gathering tumor cells in actively proliferating stage, which may provide a new adjuvant therapy for breast cancer in future, especially for those have hypothyroidism during chemotherapy.”

 

Clinical Endocrinology & MetabolismThyroid function tests may be often oversimplified to the detriment of the patient. As studies shown above and many more have shown, low T3 can be a complicating factor in a wide range of disorders. Dysregulation of thyroid function has multiple forms and causes. In a paper entitled Pitfalls in the measurement and interpretation of thyroid function tests published in Clinical Endocrinology & Metabolism the authors review conditions in which measuring TSH alone can be be particularly misleading:

When measuring TSH alone may misleadAnd they offer a diagram of different patterns of thyroid function tests and their causes:

Microsoft PowerPoint - ybeem_930_Koulouri et al - FIGURES - FINA

 

Nature Reviews EndocrinologyFinally, a paper recently published in Nature Reviews Endocrinology articulates an eloquent case for adding T3 to T4 and the need to recognize the patients who may need it:

Impaired psychological well-being, depression or anxiety are observed in 5–10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T4 and decreased free T3 serum concentrations, which result in the abnormally low free T4:free T3 ratios observed in 30% of patients on levothyroxine.”

Furthermore…

“Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone.”

No wonder then that more are resorting to the combination of T4 (levothyroxine) and T3 (liothyronine):

Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T4:free T3 ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T3 available for binding to T3 receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered.”

 

‘Executive Summary’

This post is merely a ‘sampling’ of the vast subject of thyroid hormone regulation and case management. Forthcoming posts will examine other aspects. Here are key points contained in this limited presentation:

  • Thyroid activity is vitally important for all systems throughout the body. Thyroid dysfunction can play a role in common cardiovascular, metabolic, renal and brain disorders.
  • Low T3 syndrome, also known as subclinical hypothyroidism, ‘euthyroid sick syndrome’ and ‘non-thyroidal illness syndrome’ occurs frequently and contributes to morbidity and mortality in numerous ways, adding to the burden of cardiovascular disease, metabolic syndrome (insulin resistance), type 2 diabetes, kidney disease, overweight, depression and dementia.
  • Low T3 is often overlooked due to insufficient testing in clinical practice when TSH and T4 are appear normal.
  • Chronic low grade inflammation is ubiquitous contributing cause to low T3.
  • Disturbances of enzymes that convert T4 to T3, transporters that usher thyroid agents into and out of cells, and peripheral receptor resistance are common and also contribute to Impaired thyroid function.
  • T3 can enhance to response to chemotherapy in the treatment of breast cancer.
  • Treatment of a hypothyroid component in depression can require T3.

Magnesium: insulin, brain, heart and inflammation

PLOS ONEMagnesium may be the critical nutrient most commonly drained by modern environmental stress to suboptimal levels. It seems to be commonly overlooked in clinical practice, even for muscle cramps and spasms for which it is often effective (if given at an adequate dose), and is a prime parasympathetic nervous system support. Recent studies add evidence to its indication for insulin resistance, diabetes, cognitive impairment, atrial fibrillation, cardiovascular disease, and neurogenic inflammation. A recent study published in PLOS One (Public Library of Science) confirms an association of lower levels of magnesium with diabetes and diabetic complications:

“The effect of magnesium (Mg) deficiency on the prevalence of diabetes and diabetic complications has received a great attention. The present study investigated the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications.”

The authors examined data for patients with type 1 diabetes (T1D), type 2 diabetes (T2D), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), along with the incidence of nephropathy, retinopathy or peripheral neuropathy in associateion with serum and urinary magnesium (Mg) levels…

Serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control.”

Importantly, they revealed evidence that statins can contribute to magnesium deficiency:

“There was an early study that showed a reduction trend of serum Mg in the T2D patients treated with 4-month simvastatin treatment compared to T2D patients treated with placebo. In the present study, we found no reduction of serum Mg, but significant reduction of urinary Mg in the T2D patients treated with simvastatin…The above findings suggest that there was a risk for reducing either serum Mg or urinary Mg. Since we have appreciated, based on the above discussion, that Mg appears to play a vital function in the prevention of insulin resistance, diabetes and diabetic complications; In addition, Mg has been also reported to have anti-inflammatory and statin-like effect as well as the stimulating effect of Mg at physiological level on the statin passive diffusion into hepatocytes and their pharmacological actions on cholesterol biosynthesis. Therefore, combination of statin administration with supplementation of certain amount of Mg may be required to avoid the reduction of the Mg level either in the blood or urine caused by supplementation with statin alone. In fact, the combination of Mg with a statin has been recently suggested as a potential and seemingly-promising avenue to reduce cholesterol, C-reactive protein, and cardiovascular disorders.”

The authors sonclude:

“By directly measuring serum and urinary Mg here we demonstrated the significantly low serum Mg level not only in T2D, but also in IFG, IGT, and T1D…In the present study, we demonstrated for the first time that T1D patients also exhibited a significant low of serum Mg level compared to control…We also demonstrated the increase secretion of Mg in urine for both T1D and T2D patients…Therefore, the potential impact of Mg in metabolic syndrome, diabetes and diabetes-related or no-related cardiovascular disorders needs to be received special attention.”

 

NutrientsThese findings were echoed in another study recently published in the journal Nutrients showing that dietary magnesium improves insulin resistance in subjects with metabolic syndrome, and the need for adequate magnesium may not be met through diet. The authors state:

“Many cross-sectional studies show an inverse association between dietary magnesium and insulin resistance, but few longitudinal studies examine the ability to meet the Recommended Dietary Allowance (RDA) for magnesium intake through food and its effect on insulin resistance among participants with metabolic syndrome (MetS). The dietary intervention study examined this question in 234 individuals with MetS.”

They assessed magnesium intake, along with fasting glucose, insulin and insulin resistance estimated by the standard homeostasis model assessment (HOMA-IR) for 234 individuals with MetS at baseline, 6, and 12 months. Clinicians really need to bear in mind what their data reveals:

“Baseline magnesium intake was 287 ± 93 mg/day, and HOMA-IR, fasting glucose and fasting insulin were 3.7 ± 3.5, 99 ± 13 mg/dL, and 15 ± 13 μU/mL, respectively. At baseline, 6-, and 12-months, 23.5%, 30.4%, and 27.7% met the RDA for magnesium. After multivariate adjustment, magnesium intake was inversely associated with metabolic biomarkers of insulin resistance. Further, the likelihood of elevated HOMA-IR (>3.6) over time was 71% lower in participants in the highest quartile of magnesium intake than those in the lowest quartile. For individuals meeting the RDA for magnesium, the multivariate-adjusted OR for high HOMA-IR over time was 0.37.”

In other words, magnesium from diet alone just doesn’t cut it for most people in regard to insulin resistance. The authors conclude:

“These findings indicate that dietary magnesium intake is inadequate among non-diabetic individuals with MetS and suggest that increasing dietary magnesium to meet the RDA has a protective effect on insulin resistance…Since this population has a higher risk of cardiovascular disease and type 2 diabetes, dietary behaviors that have the ability to impact insulin resistance can have far-reaching clinical implications.”

 

The Journal of Neuroscience 33(19)Of premiere importance is the role that magnesium plays in neuroplasticity and protects against loss of cognitive function. A study published recently in The Journal of Neuroscience provides evidence for the benefit of magnesium in Alzheimer’s disease:

“Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits…”

They examined the effect of magnesium levels on AD-like pathologies in the brains of their study subjects (a a transgenic (Tg) mouse model of Alzheimer’s disease), including Aβ (amyloid beta) plaque formation, molecules necessary for neuronal energy metabolism, and influence on signaling pathways involved in synaptic plasticity and density. Their data showed a remarkable correlation:

MgT treatment reduced Aβ plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression… In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and β-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPβ and β-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices.”

Reduction of amyloid plaque by magnesiumIn other words, the magnesium treatment profoundly ameliorated neuronal damage and memory loss. The authors note some fascinating observations:

“Our studies demonstrate that an increase in magnesium intake enhances memory in young rats, reverses memory decline in aged rats (Slutsky et al., 2010), and prevents memory deterioration a mouse model of AD (the present study). However, it is intriguing that after long-term magnesium supplementation, the Mg2+ concentration in the CSF only increased by 15% (Slutsky et al., 2010) and the total magnesium in brain increased by 30%. Can small increases in [Mg2+]CSF have major impact on synapse density? In a separate study, we found that increasing extracellular Mg2+ by 15% led to an ∼50% increase in synapse density in cultured hippocampal synapses (unpublished observations). These data suggest that hippocampal synapse density might be very sensitive to small changes in extracellular Mg2+ concentrations. Under normal physiological conditions, whole-body magnesium is tightly regulated by kidney function. Daily fluctuation of plasma magnesium associated with food intake is <0.1 mm above a baseline of 0.7 mm (Witkowski et al., 2011). Brain magnesium is supposed to be more stable because the blood–brain barrier isolates the brain from daily fluctuations in blood magnesium. Therefore, despite the high sensitivity of the synapses to Mg2+ concentration, synapse density is likely to be stable under physiological conditions. Conversely, if brain magnesium is reduced under pathological conditions, this might have a profound impact on synapse density and memory function. Interestingly, in the hippocampus of AD patients, the total magnesium level is reduced by 18% (Andrási et al., 2005).”

They conclude:

“Therefore, restoration/elevation of brain magnesium in AD patients might be beneficial for ameliorating the cognitive deficits of AD. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.”

 

The Journal of NutritionOf course there is an abundance of evidence for the importance of magnesium in cardiovascular disease. A paper just published in The Journal of Nutrition links magnesium intake with death from all causes in people at high cardiovascular risk. The authors state:

“The relation between dietary magnesium intake and cardiovascular disease (CVD) or mortality was evaluated in several prospective studies, but few of them have assessed the risk of all-cause mortality, which has never been evaluated in Mediterranean adults at high cardiovascular risk. The aim of this study was to assess the association between magnesium intake and CVD and mortality risk in a Mediterranean population at high cardiovascular risk with high average magnesium intake.”

They examined data for 7216 men and women assigned to one of two Mediterranean diets (supplemented with nuts or olive oil) or advice on a low-fat control diet and, in particular, assessed the associations between yearly repeated measurements of magnesium intake and mortality…

“After a median follow-up of 4.8 y, 323 total deaths, 81 cardiovascular deaths, 130 cancer deaths, and 277 cardiovascular events occurred. Energy-adjusted baseline magnesium intake was inversely associated with cardiovascular, cancer, and all-cause mortality. Compared with lower consumers, individuals in the highest tertile of magnesium intake had a 34% reduction in mortality risk. Dietary magnesium intake was inversely associated with mortality risk in Mediterranean individuals at high risk of CVD.”

 

PACEAs expected when considering the critical role of magnesium in neuromuscular excitability, magnesium should be considered in case management of cardiac arrhythmias. The authors of a paper published on magnesium and atrial fibrillation in the journal PACE (Pacing And Electrical Physiology) state:

“Magnesium (Mg) is an important intracellular ion with cardiac metabolism and electrophysiologic properties. A large percentage of patients with arrhythmias have an intracellular Mg deficiency, which is out of line with serum Mg concentrations, and this may explain the rationale for Mg’s benefits as an atrial antiarrhythmic agent.”

They further note:

“A current limitation of antiarrhythmic therapy is that the potential for cardiac risk offsets some of the benefits of therapy. Mg enhances the balance of benefits to harms by enhancing atrial antiarrhythmic efficacy and reducing antiarrhythmic proarrhythmia potential as well as providing direct antiarrhythmic efficacy when used as monotherapy in patients undergoing cardiothoracic surgery.”

 

American Journal of Clinical NutritionIschemic heart disease (IHD) is also influenced by magnesium sufficiency as documented in a study published in the American Journal of Clinical Nutrition. The authors set out to…

“…investigate whether urinary magnesium excretion and plasma magnesium are associated with IHD risk.”

To do so they examined 7664 subjects without for urinary magnesium excretion as measured in 2 baseline 24-h urine collections and found that…

“Mean ± SD urinary magnesium excretion was 4.24 ± 1.65 mmol/24 h for men and 3.54 ± 1.40 mmol/24 h for women. During a median follow-up of 10.5 y, 462 fatal and nonfatal IHD events occurred. After multivariable adjustment, urinary magnesium excretion had a nonlinear relation with IHD risk. The lowest sex-specific quintile (men: <2.93 mmol/24 h; women: <2.45 mmol/24 h) had an increased risk of fatal and nonfatal IHD (multivariable HR: 1.60) compared with the upper 4 quintiles of urinary magnesium excretion. A similar increase in risk of the lowest quintile was observed for mortality related to IHD (HR: 1.70). No associations were observed between circulating magnesium and risk of IHD.”

This interesting study demonstrates two clinically significant points: (1) magnesium status is indeed associated with the risk of ischemic heart disease, and (2) serum magnesium is a very poor indicator of magnesium status (a fact that all experienced clinicians should be aware of). The authors conclude:

Low urinary magnesium excretion was independently associated with a higher risk of IHD incidence. An increased dietary intake of magnesium, particularly in those with the lowest urinary magnesium, could reduce the risk of IHD.”

 

Heart Failure ReviewsPerhaps of premiere importance is the fact that suboptimal magnesium promotes neurogenic inflammation that can contribute to not only cardiovascular disease but any inflammatory disease, and be a contributing factor in the progression of intestinal permeability. This is presented in a paper published in Heart Failure Reviews:

“Magnesium is a micronutrient essential for the normal functioning of the cardiovascular system, and Mg deficiency (MgD) is frequently associated in the clinical setting with chronic pathologies such as CHF, diabetes, hypertension, and other pathologies. Animal models of MgD have demonstrated a systemic pro-inflammatory/pro-oxidant state, involving multiple tissues/organs including neuronal, hematopoietic, cardiovascular, and gastrointestinal systems; during later stages of MgD, a cardiomyopathy develops which may result from a cascade of inflammatory events. In rodent models of dietary MgD, a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide among others, was observed within days (1–7) of initiating the Mg-restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early “neurogenic inflammation” phase may be mediated in part, by the Mg-gated N-methyl-D-aspartate (NMDA) receptor/channel complex.”

Of the greatest importance for clinical case management…

“Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory-motor C-fibers to promote the subsequent pro-inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE2 levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants.”

Recall that sensory-motor C-fibers are also involved in chronic pain. And of great interest to practitioners managing autoimmunity and gastrointestinal infection:

“Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1–3 weeks MgD) inflammatory/pro-oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co-existing with other pathologies, may enhance the risk of developing chronic heart failure.”

 

Clinical note: Suboptimal magnesium levels are so common, and involved in so many pathophysiological processes (only a fraction of which have been described here)—that so often go unrecognized in clinical practice—I urge practitioners to keep this in mind.

Insulin resistance is a risk factor for breast cancer even with normal fasting glucose and insulin

Journal of Experimental & Clinical Cancer ResearchWell before fasting glucose and insulin rise out of the normal range, background surges of insulin associated with decreased insulin receptor sensitivity do harm throughout the body and, as confirmed by a study just published in the Journal of Experimental & Clinical Cancer Research shows, promote breast cancer. The authors observe:

“Metabolic Syndrome (MS) has been correlated to breast carcinogenesis [development of breast cancer]. MS is common in the general population (34%) and increases with age and body mass index. Although the link between obesity, MS and hormone related cancers incidence is now widely recognized, the molecular mechanisms at the basis of such increase are still poorly characterized. Crucial role is supposed to be played by the altered insulin signalling, occurring in obese patients, which fuels cancer cell growth, proliferation and survival. Therefore we focused specifically on insulin resistance to investigate clinically the potential role of insulin in breast carcinogenesis.”

They investigated the role of insulin resistance in the development of breast cancer by examining data for 975 women, specifically measuring insulin resistance with the Homeostasis Model Assessment score (HOMA-IR) in 975 women. Using the cut off value HOMA-IR >= 2.50 to define insulin resistance there was a clear connection:

“Higher prevalence of MS [metabolic syndrome] (35%) was found among postmenopausal women with breast cancer compared to postmenopausal healthy women (19%). A broad range of BMI spanning 19–48 Kg/m2 was calculated. Both cases and controls were characterized by BMI >= 25 Kg/m2 (58% of cases compared to 61% of controls). Waist circumference >88 cm was measured in 53% of cases and in 46% of controls. Hyperinsulinemia was detected in 7% of cases and only in 3% of controls. HOMA-IR score was elevated in 49% of cases compared to 34% of controls. That means insulin resistance can nearly double the risk of breast cancer development. Interestingly 61% of women operated for breast cancer (cases) with HOMA-IR >= 2.5 presented subclinical insulin resistance with fasting plasma glucose levels and fasting plasma insulin levels in the normal range. Both android fat distribution and insulin resistance correlated to MS in the subgroup of postmenopausal women affected by breast cancer.”

Practitioners should savor the significance of this: (1) insulin resistance nearly doubles the risk of breast cancer; (2) breast cancer-promoting insulin resistance can be subclinical, that is with normal fasting glucose and insulin. The authors elaborate:

Insulin resistance can often be defined as a subclinical condition. Consistently, most of our patients (68%) had levels of fasting plasma glucose in the normal range, and, interestingly, only through the use of HOMA score we classified them as insulin resistant. Similarly, fasting plasma insulin levels were diagnosed as normal in 88% of cases. These patients were identified as insulin resistant only by means of the HOMA score. HOMA-IR is widely-used in epidemiologic studies as a measure of insulin resistance, and has been shown to reflect euglycemic clamp insulin resistance more accurately than fasting insulin levels alone.”

Their conclusions are of the first importance for the prevention of breast cancer:

“Our results further support the hypothesis that MS, in particular insulin resistance and abdominal fat, can be considered as risk factors for developing breast cancer after menopause. We suggest that HOMA-IR, rather than fasting plasma glucose and fasting plasma insulin levels alone, could be a valuable tool to identify patients with subclinical insulin resistance, which could be relevant for primary prevention and for high risk patients screening…In conclusion, our experience suggests that insulin resistance and abdominal fat (more than BMI alone) represent the most important criteria of MS on which primary prevention should be concentrated. Interestingly, Homeostasis Model Assessment of insulin resistance promises to be a valuable tool for primary prevention, particularly for patients with subclinical insulin resistance, presenting fasting plasma glucose levels and fasting plasma insulin levels in the normal range. Our findings suggest that HOMA-IR could be useful in screening patients at higher risk of developing breast cancer.

Clinicians wishing to calculate model-derived estimates of insulin sensitivity and beta cell function derived from fasting plasma glucose and insulin can use the HOMA2 Calculator made available by the University of Oxford Centre for Diabetes, Endocrinology and Metabolism.

Sugar calories are worse for diabetes and obesity than others

PLOS ONEAttentive clinicians who have been exhorting their patients for years to avoid excessively stimulating insulin production with sugar are heartily welcoming the superb research just published in PLoS One (Public Library of Science) that drives a stake through the heart of the mistaken notions that calories from sugar have the same effect as others, and that obesity causes diabetes. The authors observe:

“Global diabetes prevalence has more than doubled over the last three decades, with prevalence rates far exceeding modeled projections, even after allowing for improved surveillance…Most of the worldwide rise is thought to be type 2 diabetes linked to the “metabolic syndrome” – the cluster of metabolic perturbations that includes dyslipidemia, hypertension, and insulin resistance. Obesity associated with economic development — particularly from lack of exercise and increased consumption of calories — is thought to be the strongest risk factor for metabolic syndrome and type 2 diabetes…”

But as the data from a number of studies shows…

“…several countries with high diabetes prevalence rates have low obesity rates, and vice versa. High diabetes yet low obesity prevalence are observed in countries with different ethnic compositions…Trends in diabetes and obesity are also dyssynchronous within some nations…”

Moreover…

“This population-level puzzle is accompanied by individual-level data. About 20% of obese individuals appear to have normal insulin regulation and normal metabolic indices (no indication of diabetes) and normal longevity, while up to 40% of normal weight people in some populations manifest aspects of the “metabolic syndrome”.

It’s been known for some time that sugars do a lot more damage than just contribute to obesity:

One controversial hypothesis is that excessive sugar intake may be a primary and independent driver of rising diabetes rates. Sugars added to processed food, in particular the monosaccharide fructose, can contribute to obesity, but also appear to have properties that increase diabetes risk independently from obesity. For example, liver fructose metabolism in the fed state generates lipogenic substrates in an unregulated fashion, which drives hepatic de novo lipogenesis and reduced fatty acid oxidation, forming excessive liver fat and inflammation that inactivates the insulin signaling pathway, leading to hepatic insulin resistance. Sugary foods have been significantly associated with the development of insulin resistance in laboratory-based studies. Reactive oxygen species are produced by the Maillard reaction, damaging pancreatic beta cells, and leading to a subcellular stress response (the “unfolded protein response” in the endoplasmic reticulum) that drives insulin inadequacy. In concert, insulin resistance and reduced insulin secretion lead to overt diabetes.”

To determine whether added sugars or obesity are the primary driver of the world-wide diabetes pandemic, the authors…

“…conducted a statistical assessment of panel data (repeated multi-variate data from multiple countries over a time period) to empirically evaluate whether changes in sugar availability, irrespective of changes in other foodstuffs, can in part account for the divergence in diabetes prevalence rates worldwide.”

To do so they used repeated cross-sectional data on diabetes and nutritional components of food from 175 countries over ten years, correlating with the prevalence overweight and obesity and the incidence of diabetes. Their exhaustive and detailed data accumulation and rigorous, multifaceted statistical analyses are the very model of superlative research. Their data provides the evidence to fuel important changes in public health policy:

“…we found that every 150 kcal/person/day increase in sugar availability (about one can of soda/day) was associated with increased diabetes prevalence by 1.1% (p <0.001) after testing for potential selection biases and controlling for other food types (including fibers, meats, fruits, oils, cereals), total calories, overweight and obesity, period-effects, and several socioeconomic variables such as aging, urbanization and income. No other food types yielded significant individual associations with diabetes prevalence after controlling for obesity and other confounders. The impact of sugar on diabetes was independent of sedentary behavior and alcohol use, and the effect was modified but not confounded by obesity or overweight. Duration and degree of sugar exposure correlated significantly with diabetes prevalence in a dose-dependent manner, while declines in sugar exposure correlated with significant subsequent declines in diabetes rates independently of other socioeconomic, dietary and obesity prevalence changes. Differences in sugar availability statistically explain variations in diabetes prevalence rates at a population level that are not explained by physical activity, overweight or obesity.”

There are, of course, mutiple factors that can contribute to diabetes and metabolic syndrome. The rising tide of autoimmunity (as readers here are likely aware) and inflammation supported by other causes including adipokines generated in visceral fat are notable. But the importance of this study is to reverse the mistaken notion that obesity is the primary cause of insulin resistance diabetes; it is, for the most part, the other way around, with the excessive rise in insulin compensatory for receptor resistance that forces the storage of calories as fat.

“The worldwide secular trend of increased diabetes prevalence likely has multiple etiologies, which may act through multiple mechanisms. Our results show that sugar availability is a significant statistical determinant of diabetes prevalence rates worldwide. By statistically studying variation in diabetes rates, food availability data and associated socioeconomic and demographic variables across countries and time, we identified that sugar availability appears to be uniquely correlated to diabetes prevalence independent of overweight and obesity prevalence rates, unlike other food types and total consumption, and independent of other changes in economic and social change such as urbanization, aging, changes to household income, sedentary lifestyles and tobacco or alcohol use. We found that obesity appeared to exacerbate, but not confound, the impact of sugar availability on diabetes prevalence, strengthening the argument for targeted public health approaches to excessive sugar consumption. We also noted that longer exposure to high sugar was associated with accentuated diabetes prevalence, while reduced sugar exposure was associated with decline in diabetes prevalence, and that the sugar-diabetes relationship appeared to meet criteria for temporal causality without being the result of selection biases or the effect of secular trends that may be artifacts of economic development or changes in surveillance…In summary, population-level variations in diabetes prevalence that are unexplained by other common variables appear to be statistically explained by sugar.”

Considering the massive dimensions of the diabetes pandemic and its grievous depredations, reducing sugar consumption is one of the leading public health issues of our time.