Subclinical hypothyroidism worsens cardiometabolic profile

Subclinical hypothyroidism and cardiometabolic biomarkersSubclinical hypothyroidism (SCH), poor thyroid effect throughout the body in the presence of ‘normal’ thyroid serum tests, is a widespread yet under-appreciated clinical challenge. A recent study published in the Journal of the Endocrine Society documents adverse cardiometabolic biomarkers in the presence of subclinical hypothyroidism. Additionally, practitioners must bear in mind that more than adequate iodine intake can worsen the condition.

Clarifying the definition of normal thyroid function

The authors note that uncertainty around the definition of normal thyroid function can go beyond contention involving different opinions on laboratory reference ranges by examining the effect of suboptimal thyroid function on the entire organism.

“As thyroid function has multisystemic effects, its derangement could affect a broad range of cardiometabolic pathways potentially related to clinical manifestations. However, the definition of normal thyroid function has been intensely debated, with some experts advocating for lowering the upper limit of normal for thyroid stimulating hormone (TSH) and others for maintaining the current standard. In this regard, thyroid-related risk for incident type 2 diabetes (T2D) and cardiovascular disease (CVD) may impact the definition of TSH normality.”

They note some of the mechanisms by which SCH can adversely affect cardiovascular and metabolic function:

“The potential relationship of thyroid hypofunction with T2D and CVD may be mediated by abnormalities in lipids, lipoprotein subclasses, endothelial function, coagulation, inflammatory pathways, and insulin resistance.”

This hardly exhausts the list of adverse physiological effects since every part of the body, including the brain, requires the stimulus of thyroid hormone to produce energy and function. The public health implications are enormous.

“Detailed assessment of thyroid function effects on these mediators/markers may have high population health implications, especially along the milder hypofunction spectrum within euthyroidism and SCH. Understanding the role of thyroid function in cardiometabolic pathways may guide the clinically relevant definition of thyroid function and unveil potential targets for controlling related morbidity.”

Subclinical hypothyroidism increases cardiometabolic risk

Thus the authors set out to…

“…examine thyroid function across the spectrum of euthyroid to HT in relationship to cardiometabolic pathways represented by lipids, lipoproteins, inflammation, coagulation, glycemic, and insulin resistance biomarkers.”

They examined data for 28,024 apparently healthy middle-aged and older women, and indeed found that cardiometabolic health worsens on a gradient from normal thyroid (euthyroid) function, through subclinical hypothyroidism, to full-blown hypothyroid:

Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance: larger very-low-density lipoprotein size (nm); higher low-density lipoprotein (LDL) particle concentration (nmol/L), and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid to SCH and HT. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar.”

TSH, total and LDL cholesterol not so useful

They note that it was other biomarkers that revealed the actual progressive risk:

“In this population of apparently healthy middle-aged and older women, individuals with SCH and HT had differences in the lipid and lipoprotein subclass profile that indicated worsening insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol. Of the other biomarkers, only hs-CRP and HbA1c were associated with SCH and HT. For TSH quintiles mostly within the normal range, lipid and lipoprotein results for TSH quintiles were generally similar but null for other biomarkers. Hence, progressive thyroid hypofunction was associated with insulin-resistant and proatherogenic lipids and lipoproteins profile in a graded manner, with potential clinical consequences.”


Besides thyroid as a driver of metabolic activity, insulin resistance appears to play a key role. They point out that insulin resistance appears to affect lipoprotein metabolism before glucose metabolism, an observation important for clinicians to bear in mind.

Thyroid hormones act as modulators of cholesterol synthesis and degradation through key enzymes. One of the main mechanisms is the stimulus of thyroid hormones over sterol regulatory element–binding protein 2, which in turn induces LDL receptor gene expression. However, it was shown that the association of HT and higher LDL cholesterol levels is present only in insulin-resistant subjects. Indeed, the lack of LDL cholesterol differences could be explained by our insulin-sensitive study population (low HbA1c levels). HT has also been associated with lower catabolism of lipid-rich lipoproteins by lipoprotein lipase, hepatic lipase, and decreased activity of cholesterol ester transfer proteinthat mediates exchanges of cholesteryl esters of HDL particles with triglyceride-rich LDL and VLDL particles. These mechanisms might explain the relationship of thyroid hypofunction with atherogenic and insulin-resistant lipid and lipoprotein abnormalities. Finally, the milder differences noted in HbA1c compared with LPIR across thyroid categories may be explained by the earlier effects of insulin resistance on lipoprotein metabolism than on glucose metabolism.”

Practitioners should be attentive to the authors’ conclusion:

“In this large population of apparently healthy women, individuals with SCH had differences in their biomarker profile that indicated worsening lipoprotein insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol levels. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.

Iodine supplementation reminder

More than adequate iodine increases autoimmune thyroiditisClinicians who may be tempted to reflexively offer iodine supplementation for thyroid disorders including subclinical hypothyroidism should remember the body of evidence showing this can fire up autoimmune thyroiditis. One example by way of a reminder is a study published in the European Journal of Endocrinology showing that more thanequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis. The authors describe their intent:

“With the introduction of iodized salt worldwide, more and more people are exposed to more than adequate iodine intake levels with median urinary iodine excretion (MUI 200–300 μg/l) or excessive iodine intake levels (MUI >300 μg/l). The objective of this study was to explore the associations between more than adequate iodine intake levels and the development of thyroid diseases (e.g. thyroid dysfunction, thyroid autoimmunity, and thyroid structure) in two Chinese populations.”

They examined thyroid hormones, thyroid autoantibodies in serum, iodine levels in urine were measured. and B-mode ultrasonography of the thyroid for 3813 individuals, in two areas with differing levels of iodine exposure. The levels of iodine intake were: Rongxing, MUI 261 μg/l; and Chengshan, MUI 145 μg/l. (MUI =median urinary iodine excretion.) They found a blatant difference in thyroid biomarkers:

“The prevalence of subclinical hypothyroidism was significantly higher for subjects who live in Rongxing than those who live in Chengshan. The prevalence of positive anti-thyroid peroxidase antibody (TPOAb) and positive anti-thyroglobulin antibody (TgAb) was significantly higher for subjects in Rongxing than those in Chengshan. The increase in thyroid antibodies was most pronounced in the high concentrations of TPOAb (TPOAb: ≥500 IU/ml) and low concentrations of TgAb (TgAb: 40–99 IU/ml) in Rongxing.”

Their results suggest there is a discrete window for thyroid intake:

“Compared with the adequate iodine intake level recommended by WHO/UNICEF/ICCIDD MUI (100–200 μg/l), our data indicated that MUI 200–300 μg/l might be related to potentially increased risk of developing subclinical hypothyroidism or autoimmune thyroiditis. This result differs from the WHO’s suggestion that MUI >300 μg/l may increase the risk of developing autoimmune thyroid diseases.”

Practitioners should be cautious with dosing of supplemental iodine in keeping with the authors’ conclusion:

“In conclusion, compared with the population with MUI 145 μg/l in Chengshan, the population with MUI 261 μg/l in Rongxing had a higher risk to develop autoimmune thyroiditis and subclinical hypothyroidism. Thus, more than adequate iodine intake might not be recommended for the general population in terms of keeping a normal function of thyroid.”

Readers may wish to also see the earlier post Hypothyroidism can be provoked by small amounts of supplemental iodine.

Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”


HgbA1c (hemoglobin A1c) predicts prediabetes better than glucose

HgbA1c predicts prediabetesHgbA1c (hemoglobin A1c) is hemoglobin that has been ruined by glycation (bonding with sugar). It has long been recognized as a biomarker for average glucose over an approximately three month time span as well as a metric for the degree of damaging glycation occurring throughout the body. Now further evidence for its superior value as a predictor for prediabetes is presented in a study just published in The Lancet Diabetes & Endocrinology.The authors…

“…compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions.”

HgbA1c compared to fasting and 2 hour glucose

They compared several prediabetes definitions in their ability to predict major long-term health problems. They analyzed data from over seven thousand subjects drawn from four communities across the USA who participated in the Atherosclerosis Risk in Communities (ARIC) study. HgbA1c was pitted against fasting and 2 hour postprandial glucose:

“Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6–6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1–6·9 mmol/L), HbA1c (ADA HbA1ccutoff 5·7–6·4% [39–46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0–6·4% [42–46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8–11·0 mmol/L).”

HgbA1c better identifies those at risk for diabetes and serious complications

Chronic kidney disease, cardiovascular disease and death were more accurately predicted by HgbA1c than by fasting glucose:

“After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories. The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions.”

Clinical Significance

HgbA1c study reviewed in Medscape Family Medicine

Medscape Family Medicine remarks:

“The researchers found that using an HbA1c-based definition, those identified as having prediabetes were 50% more likely to develop kidney disease, twice as likely to develop CVD, and 60% more likely to die from any cause compared with those with normal HbA1c.”

The authors, quoted in Medscape Family Medicine, comment on the practical significance of their findings:

“When someone is told they have prediabetes, we hope it will cause them to make changes to their habits in order to prevent the development of diabetes and its complications,” added the study’s senior author, Elizabeth Selvin, PhD, MPH, a professor in the Bloomberg School’s department of epidemiology.

“Being identified as having prediabetes can also make it easier to receive weight-loss and nutritional counseling as well as reimbursement for these services. Intensive lifestyle changes and weight loss can reduce the risk of diabetes, so it is critically important we identify those persons who are at high risk.

At the same time, we also don’t want to overdiagnose people. Using the hemoglobin A1c test allows us to more accurately identify those persons at highest risk,” she added.

This is important information for physicians and it is also important information for professional organizations. Coming to a global consensus on how to define and diagnose prediabetes would really help move the field forward — and help patients all over the world,” she concluded.”

The authors conclude:

“Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall.”

Autoimmune diabetes (type 1): half develops after age 30

EASD abstract on autoimmune diabetesAutoimmune diabetes (type 1), earlier thought to occur almost exclusively in the pediatric population, is dramatically increasing among adults. Data recently presented at the 2016 Annual Meeting of the European Association for the Study of Diabetes (EASD) and reported in Medscape confirms that it now occurs as frequently in adults over 30 as it does in children.

Onset of type 1 diabetes is just as likely to occur in people older than 30 years of age as in those younger, new research shows.”

This is a manifestation of the giant increase in autoimmune and autoinflammatory conditions present but too often overlooked in clinical practice.

Autoimmune diabetes lurks in the general population

MedscapePractitioners active in case management of autoimmune conditions are already aware of this, but to many it may come as a surprise.

“Obtained using genetic data from the UK Biobank, the startling results refute the long-held belief that type 1 diabetes is primarily a “juvenile” condition…Clinically, the findings are particularly relevant for primary care, where people who develop autoimmune-mediated diabetes in adulthood are often misdiagnosed as having type 2 and prescribed metformin instead of insulin.”

Dr Nicholas JM Thomas, of the Institute of Biomedical and Clinical Science, University of Exeter Medical School, United Kingdom, who presented the data, is quoted in Medscape:

“I think it’s an eye-opener and obviously has implications for how we diagnose and manage people and also the education people receive. We very much focus on childhood and adolescence and perhaps people diagnosed later don’t get the same education.”

Autoimmune diabetes can be mixed with type 2 (metabolic)

2016-10-23_17-29-31Experienced clinicians will recognize that HgbA1c going up in a lean adult almost always implies an autoimmune component. Harder to recognize is a person for whom both are occurring: there is insulin resistance with compensatory elevated insulin forcing the storage of calories as fat resulting in overweight or obesity but combined with further carbohydrate intolerance due to an autoinflammatory attack on beta cells, insulin, the GAD enzyme, or other factors that further damage blood glucose regulation. It can develop rapidly or slowly as LADA (latent autoimmune diabetes of adults).  I am seeing this in practice and I’m sure others paying attention are too.

Medscape further quotes Dr. Thomas:

“He advised that clinicians should at least be aware that adults can develop autoimmune diabetes, as either classic type 1 or the slower-onset phenomenon known as “latent autoimmune diabetes of adulthood (LADA).”

“It’s knowing this does happen, and therefore just keeping an open mind when you spot someone who’s not behaving like type 1 or not responding as you would anticipate when you go through the usual treatment guidelines for type 2,” he said, citing the example of British Prime Minister Theresa May, who was diagnosed with type 1 diabetes at age 56 and who “progressed very rapidly.”

He reiterated that type 1 diabetes is evenly distributed within the first 6 decades of life, but after age 30, the increase in type 2 diabetes makes the type 1 cases harder to recognize and treat correctly.


Antibody measurements, particularly to the islet cells, insulin and glutamic acid decarboxylase 65 are a mainstay even though subject to the vulnerabilities of antibody expression. And there is a new approach:

“Dr Thomas and colleagues used a “robust, novel, genetic approach” using a risk score comprising 30 single nucleotide polymorphisms associated with type 1 diabetes (T1D-GRS).”

Firstly the clinician should be alert to impaired blood glucose control in adult patients who are not overweight or for whom the correct diet (LCHF) and targeted therapies are not yielding the result they should. This is a tipoff that the case has to be managed as autoimmune diabetes or LADA with the underlying causes for loss of immune tolerance investigated and targeted for therapy.

The session comoderator Catharine Owen, MD, associate professor of diabetes at the Oxford Center for Diabetes, Endocrinology, and Metabolism, United Kingdom, is also quoted in Medscape:

“I think it’s absolutely crucial for people to be aware that type 1 diabetes can present at any age. Physicians shouldn’t be complacent when people aren’t responding to oral agents, or they’re not bringing A1c down to target when they should.”

Breast cancer recurrence reduced by prolonged nightly fasting

JAMA Oncology breast cancer and prolonged nightly fastingBreast cancer risk and prognosis is affected by glucose and insulin regulation. The authors of a study recently published in JAMA Oncology demonstrate that fasting intermittently by extending the overnight fast between dinner the night before and eating the next day reduces the risk of cancer recurrence. They state:

“To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes.”

So they set out to…

“…investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A1c), chronic inflammation (C-reactive protein), obesity, and sleep.”

Breast cancer and HgbA1c reduced by prolonged nightly fasting; sleep improved

They analyzed data collected over 12 years for 2413 women with breast cancer but without diabetes aged 27 to 70 years at diagnosis who were participants in the Women’s Healthy Eating and Living study. Their main outcomes were recurrence, new primary tumors, mortality, assess concentrations of hemoglobin A1c and C-reactive protein. Happily their data show significant improvements in recurrence, HgbA1c and sleep duration:

“The cohort of 2413 women reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality or a statistically significant higher risk of all-cause mortality. In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A1c levels and a longer duration of nighttime sleep.”

Intermittent fasting

The two most main methods of intermittent fasting are 5:2 and 16:8. 5:2 is 5 days of normal eating alternating with two very low calorie days (500 cal for females and 600 cal for males). 16:8, which I prefer, delays eating and drinking anything other than water, coffee or tea (black) until 16 hours after dinner the night before. This has numerous metabolic and immune benefits, and should be a mainstay in the ‘oncology toolbox.’ The authors conclude:

Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis.”

Insulin resistance indicated by neutrophil-lymphocyte ratio

BMC Endocrine DisordersInsulin resistance (IR) is central to type 2 diabetes and a contributing cause to cardiovascular and neurodegenerative disorders, chronic kidney disease (CKD), a number of cancers and more. A study recently published in BMC Endocrine Disorders the ratio between neutrophils and lymphocytes (neutrophil-lymphocyte ratio, NLR) is a valuable and inexpensive predictive marker for insulin resistance. The authors note:

“Insulin resistance (IR) is a reduction in reaction or sensitivity to insulin and is considered to be the common cause of impaired glucose tolerance, diabetes, obesity, dyslipidemia, and hypertensive diseases….several studies have confirmed the relationship between systemic inflammation and insulin resistance, in which an altered immune system plays a decisive role in the pathogenesis of DM. The immune response to various physiological challenges is characterized by increased neutrophil and decreased lymphocyte counts, and NLR is often recognized as an inflammatory marker to assess the severity of the disease.”


“Scholars have rarely investigated the relationship between IR and NLR. This study aims to evaluate the relationship between IR and NLR, and determine whether or not NLR is a reliable marker for IR.”

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

Mean neutrophil-lymphocyte ratio (NLR) values of the groups. Group 1 is diabetic w/o IR, Group 2 is diabetic with IR.

So they investigated the neutrophil-lymphocyte ratio in 413 patients with T2DM, 310 of whom had a HOMA-IR value (fasting plasma glucose (mmol/L) multiplied by fasting serum insulin (mIU/L) divided by 22.5) of > 2.0, indicating insulin resistance. They were compared to a control group of 130 healthy subjects and found a strong association:

“The NLR values of the diabetic patients were significantly higher than those of the healthy control, and the NLR values of the patients with a HOMA-IR value of > 2.0 are notably greater than those of the patients with a HOMA-IR value of ≤ 2.0. Pearson correlation analysis showed a significant positive correlation of NLR with HOMA-IR. Logistic regression analysis showed that the risk predictors of IR include NLR, TG and HbA1c. NLR levels correlated positively with IR. The IR odds ratio increased by a factor of 7.231 (95%) for every one unit increase in NLR.”

 Diabetes, cancer and cardiovascular diseases

In relation to their confirmation of NLR as a predictor for insulin resistance the authors observe…

“Many epidemiological studies have determined that DM is associated with chronic inflammation, which may contribute to the acceleration of diabetic microangiopathy and the development of macroangiopathy; IR is a characterized of T2DM, whereas the exact molecular action leading to IR is not yet understood, several studies have associated IR with inflammation, experimental studies have demonstrated a link between chronic inflammation and insulin resistance through mechanisms involving obesity and atherosclerosis. NLR has been recently defined as a novel potential inflammation marker in cancer and cardiovascular diseases. NLR can easily be calculated using the neutrophil-lymphocyte ratio in peripheral blood count. Calculating NLR is simpler and cheaper than measuring other inflammatory cytokines, such as IL-6, IL-1β, and TNF-α.”

Diabetes and chronic inflammation

These findings highlight the relationship between chronic inflammation, insulin resistance and type 2 diabetes.

“he pathological activation of innate immunity leads to inflammation of the islet cells, resulting in a decrease in pancreatic beta-cell mass and impaired insulin secretion. Patients with T2DM are in a state of low-degree chronic inflammation that induces hypersecretion of inflammatory factors, such as CRP, IL-6, TNF-α, and MCP-1, which results in a constantly elevated neutrophilic granulocyte count. One mechanism by which increased levels of neutrophils could mediate IR may be through augmented inflammation. The increase in NLR appears to underlie the elevated levels of pro-inflammation, as evident from the persistent neutrophil activation and enhanced release of neutrophil proteases with T2DM.”

 NLR tracks HgbA1c and triglycerides

Glycation of hemoglobin (HgbA1c) and triglycerides (TG) both go up as insulin resistance progresses along with the neutrophil-lymphocyte ratio.

“A logistic regression analysis of the following risk factors was conducted: NLR, TG and HbA1c. In our study, in conjunction with the rising of the level of HbAlc, the degree of IR increased significantly. HbA1c showed an association with early-phase insulin secretion assessed by insulinogenic index. Heianza et al. reported that elevated HbA1c levels of above 41 mmol/mol (>5.9%) were associated with a substantial reduction in insulin secretion and insulin sensitivity as well as an association with β-cell dysfunction in Japanese individuals without a history of treatment of diabetes. Increased accumulation of TG has been observed in human muscle tissue of obese and type 2 diabetic subjects, and associated with IR, which is in agreement with the present study. IR reduces the inhibition effect of lipolysis in adipose tissue, resulting in the increase of the free fatty acid (FFA) level in plasma.”

NLR is a superior biomarker

Although susceptible to modification by dehydration, elevated PSA or catecholamine release induced by exercise, the NLR is more sensitive than the neutrophil count alone or CRP levels.

“NLR represents a combination of two markers where neutrophils represent the active nonspecific inflammatory mediator initiating the first line of defense, whereas lymphocytes represent the regulatory or protective component of inflammation. NLR is superior to other leukocyte parameters (e.g., neutrophil, lymphocyte, and total leukocyte counts) because of its better stability compared with the other parameters that can be altered by various physiological, pathological, and physical factors. Thus, as a simple clinical indicator of IR, NLR is more sensitive compared with the neutrophilic granulocyte count and CRP levels, which are widely used as markers of IR.”

Clinical bottom line

Practitioners should not fail to make use of this significant, inexpensive biomarker that is under our noses every day. The authors sum it up:

“…in the present study, NLR serves an important function in predicting the risk of IR. IR in diabetic patients is related to chronic inflammation, and NLR may be helpful in assessing the prognoses of these patients…We recommend that the NLR values of diabetic patients be calculated as NLR is a cheap, predictive, and prognostic marker for IR. High NLR values were independently related to IR.”

Insulin resistance damages brain white matter even with normal glucose

Neurology 82 (18)Insulin resistance (IR) exposes the brain along with the rest of the body to elevated insulin levels produced to overcome receptor resistance. Following earlier studies noted here including Dementia risk increased by higher blood sugar before diabetes, a new study just published in the journal Neurology offers yet more evidence that the higher levels of insulin damage brain white matter well before glucose and HgbA1c levels become elevated.

To investigate the relationship between insulin resistance and brain white matter (WM, myelinated axonal tissue) damage the authors correlated diffusion tensor imaging of the brains of 127 subjects age 41–86 years with insulin resistance as determined by the homeostasis model assessment of IR (HOMA-IR). There was indeed a significant association:

“Participants were divided into 2 groups based on HOMA-IR values: “high HOMA-IR” (≥2.5, n = 27) and “low HOMA-IR” (<2.5, n = 100)…The high HOMA-IR group demonstrated decreased axial diffusivity broadly throughout the cerebral WM in areas such as the corpus callosum, corona radiata, cerebral peduncle, posterior thalamic radiation, and right superior longitudinal fasciculus, and WM underlying the frontal, parietal, and temporal lobes, as well as decreased fractional anisotropy in the body and genu of corpus callosum and parts of the superior and anterior corona radiata, compared with the low HOMA-IR group, independent of age, WM signal abnormality volume, and antihypertensive medication status. These regions additionally demonstrated linear associations between diffusion measures and HOMA-IR across all subjects, with higher HOMA-IR values being correlated with lower axial diffusivity.”

In other words, regardless of age, higher insulin resistance predicted more abnormalities in the brain white matter. The authors conclude:

“In generally healthy adults, greater IR is associated with alterations in WM tissue integrity. These cross-sectional findings suggest that IR contributes to WM microstructural alterations in middle-aged and older adults. “

Clinical note: It is imperative for practitioners to assess for insulin resistance well before HgbA1c and glucose become elevated.

Cognitive decline: major overlooked causes

Cognitive decline, the insidious thief of quality of life in its milder forms and appalling despoiler of human qualities in more advanced dementia and Alzheimer’s disease, is fueled by NEJM Journal Watchbiological causes that have not received adequate attention as noted in an editorial in NEJM Journal Watch under the title What Most Causes Cognitive Decline Is Not What We’ve Been Looking For. Stating…

“The most common factors are not the common degenerative diseases.”

Annals of Neurology…the editor is commenting on a study just published in Annals of Neurology in which the authors examined whether the commonly assumed causes were largely to blame:

“The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline.”

They correlated measures of Alzheimer pathology (amyloid load and tangle density), cardiovascular disease (macroscopic and microscopic infarcts) and Lewy bodies with global cognitive decline in the brains of 856 deceased subjects. While important, these measures failed to accounted for the bulk of it:

“In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline.”

In other words, there’s a lot more contributing to cognitive decline than the Alzheimer’s form of dementia and strokes. The authors conclude:

“The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.”


Neurology Vol 81 Num 20Of particular importance because this risk factor is relatively easy to modify is another study,  just published this time in Neurology, showing that glucose levels when only mildly elevated contribute to cognitive decline. The authors determined to see if there is a correlation between HgbA1c (hemoglobin A1c), memory and brain atrophy (specifically in the hippocampus, the ‘center’ for short-term memory) at mildly elevated, non-diabetic levels of glucose:

“For this cross-sectional study, we aimed to elucidate whether higher glycosylated hemoglobin (HbA1c) and glucose levels exert a negative impact on memory performance and hippocampal volume and microstructure in a cohort of healthy, older, nondiabetic individuals without dementia.”

They tested memory, fasting HbA1c, glucose, and insulin and did MRI scans for hippocampal volume and microstructure in 141 subjects:

Lower HbA1c and glucose levels were significantly associated with better scores in delayed recall, learning ability, and memory consolidation. In multiple regression models, HbA1c remained strongly associated with memory performance. Moreover, mediation analyses indicated that beneficial effects of lower HbA1c on memory are in part mediated by hippocampal volume and microstructure.”

There is really no excuse for clinicians to not make glucose and insulin regulation a top priority in case management for healthy aging and prevention of cognitive decline. The authors conclude:

“Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials.”


Biological PharmacologyThe authors of a paper published in Biological Pharmacology associate insulin with the crucial issue of neuroinflammation.

“The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer’s disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill-equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of α-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients’ cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer’s disease, and the treatment approaches they provide.”

Altered cytokine-insulin axis in neurodegenerative diseaseThey underline a connection between inflammatory cytokines, insulin resistance in the brain and neurodegeneration:

“A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier.”


Neuroscience ResearchCommenting on the importance of neuroinflammation, the authors of a paper published in Neuroscience Research state:

Neuroinflammation is central to the common pathology of several acute and chronic brain diseases. This review examines the consequences of excessive and prolonged neuroinflammation, particularly its damaging effects on cellular and/or brain function, as well as its relevance to disease progression and possible interventions. The evidence gathered here indicates that neuroinflammation causes and accelerates long-term neurodegenerative disease, playing a central role in the very early development of chronic conditions including dementia. The wide scope and numerous complexities of neuroinflammation suggest that combinations of different preventative and therapeutic approaches may be efficacious.”

They articulate these critical highlights:

  • Neuroinflammation is central to the common pathology of diseases/disorders.
  • Neuroinflammation causes acute brain cell death.
  • Neuroinflammation causes and accelerates long-term neurodegenerative disease.
  • Preventative and therapeutic approaches are needed to dampen-down neuroinflammation.


Frontiers In Integrative NeuroscienceA paper recently published in Frontiers In Integrative Neuroscience expands of the role of neuroinflammation in Alzheimer’s disease:

“Although there are different genetic and environmental causes, all patients have a similar clinical behavior and develop identical brain lesions: NFTs (neurofibrillary tangles) consisting of Tau (τ) protein and NPs (neuritic plaques) consisting of amyloid-β (Aβ) peptides. These alterations are the final result of post-translational modifications and involve different genes and render AD as a complex multigenic neurodegenerative disorder.”

The identify the activation of inflammation by amyloid-β as a pivotal step:

“In addition to this multi-genic complexity in AD, now we know that Aβ promotes an inflammatory response mediated by microglia and astrocytes, thus activating signaling pathways that could lead to neurodegeneration…Although it was previously thought that the central nervous system (CNS) was an immune-privileged site, now is well known that certain features of inflammatory processes occur normally in response to an injury, infection or disease. The resident CNS cells generate inflammatory mediators, such as pro-inflammatory cytokines, prostaglandins (PGs), free radicals, complement factors, and simultaneously induce the production of adhesion molecules and chemokines, which could recruit peripheral immune cells. This review describes the cellular and molecular mediators involved in the inflammatory process associated with AD and several possible therapeutic approaches describe recently.”

Inflammation in Alzheimer's diseaseThey summarize their extensive review of this topic:

“…inflammation induced by Aβ has an important role in the neurodegenerative process. The inflammatory process itself is driven by microglial and astrocytic activation through the induction of pro-inflammatory molecules and related signaling pathways, thus leading to synaptic damage, neuronal loss, and the activation of other inflammatory participants… Although, the role of amyloid as a potential initiator of inflammation is not obvious, its accumulation exerts an indirect effect by activating caspases and transcription factors, such as NF-κ B and AP-1, which produce numerous inflammation amplifiers (IL-1β, TNF-α, and IL-6). Pro-inflammatory cytokines, such as TNF-α and IL-1β and IL-6, could act directly on the neuron and induce apoptosis. Similarly, TNF-α and IL-1β can activate astrocytes, which could release factors that have the capacity to activate microglia… Furthermore, APP, BACE1, and PSEN expression is governed by factors such as NF-κ B. The genes encoding these proteins have sites in their promoter regions, which are recognized by NF-κ B; in turn, the expression of these factors is upregulated by the presence of pro-inflammatory cytokines.”

Neuronal damage and Aβ deposition trigger inflammationMoreover…

Inflammatory mediators acting on neurons contribute to an increase in amyloid production and activate microglia-mediated inflammation. The microglia-neuron communication amplifies the production of factors that contribute to AD-type pathology.”

IL-1β plays a key role:

“This cascade is primarily mediated by the pro-inflammatory cytokine IL-1β, which is expressed by microglia cells. IL-1β may cause neuronal death via various pathways, which activate microglia and consequently increase the release of IL-1β, thus generating a self-sustaining mechanism that is amplified by itself. This slow but steady inflammation state, generated for long periods in the brain eventually can destroy neurons and contribute to the clinical symptoms observed in the disease.”


Journal of Alzheimer's DiseaseAutoimmunity in cognitive decline and dementia is a major topic on its own and will be featured in forthcoming posts. For now, an interesting study just published in the Journal of Alzheimer’s Disease describes how early changes in cognitive function due to autoimmune inflammation precede amyloid-β or tau pathologies. The authors set out to discriminate whether autoimmunity is causal or consquential:

“Immune system activation is frequently reported in patients with Alzheimer’s disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration… The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology.”

They assessed behavioral performance and autoimmune/inflammatory markers in a group of study animals genetically predisposed to Alzheimer’s disease and a control group, and found an association between cognitive impairment that predated the onset of AD and autoimmune inflammation:

“Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first six months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology.”

In other words, they found that Alzheimer’s disease is a smoldering process that coincides with systemic inflammation and takes years to evolve:

The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior.”


Journal of NeuroinflammationA fascinating paper recently published in the Journal of Neuroinflammation demonstrates how Down syndrome (DS) and Alzheimer’s disease share similar cytokine-driven neuroinflammatory gial activity:

“In the brain, neuritic amyloid-β (Aβ) plaques – a characteristic neuropathological feature of Alzheimer’s disease (AD) – are a virtually certain finding in adults with DS and have been noted in some children with DS. For instance, among 12 children with DS, two (ages 8 and 9 years) had Aβ plaques, and among those between the ages of 35 and 45 years, all had neuritic Aβ plaques and other AD pathologies, such as neurofibrillary tangles and glial activation… the prediction of AD neuropathological changes at middle age is reported to be a virtual certainty in those with DS.”

The process starts right away in Down syndrome:

“Three such early events have been reported in DS fetuses and each is related to the others as they induce, and are induced by each other and by cytokines subsequent to neuroinflammatory changes. In particular, these include overexpression of two chromosome 21 gene products – APP and S100B – and the resultant overexpression of the pluripotent neuroinflammatory cytokine IL-1, which is encoded by chromosome 2 genes IL-1A and IL-1B. Complex interactions between APP, glial activation, S100B, and IL-1 include upregulation of the expression of IL-1α and β by both APP and S100B, and induction of both APP and S100B by IL-1β. Such interactions have been shown to be elicited by multiple neural insults, each of which is characterized by gliosis-related neuroinflammation and risk for development of the characteristic neuropathological changes of AD… Such glial activation and cytokine overexpression occurs years before the virtually certain appearance at middle age of the Aβ plaques in DS.”

They note that this process is not confined to DS and AD, but associated with cognitive decline in other conditions:

“By analogy, without regard to the diversity of the source of neuronal stress, for example, traumatic brain injury, epilepsy, aging, or AIDS, the downstream consequence is increased risk for development of the neuropathological changes of AD marked by increased expression of neuronal APP, activation of glia, and neuroinflammatory cytokine expression.”

Inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21And a particularly evil aspect of this process is that it is self-propagating, that is it feeds on itself:

“The danger of chronic induction of neuroinflammation with its manifestation of glial activation and cytokine overexpression is related to the capacity of proinflammatory cytokines such as IL-1β to self-propagate as they, themselves, activate microglia and astrocytes and further excess expression of IL-1β. In addition to IL-1β induction of the precursors of the principal neuropathological changes in AD, viz., APP for Aβ plaques, S100B for non-sensical growth of dystrophic neurites in plaques, synthesis and activation of MAPK-p38 for hyperphosphorylation of tau, favors formation of neurofibrillary tangles. In addition to favoring formation of these anomalies, IL-1β induces the synthesis and the activity of acetylcholinesterase, thus favoring the breakdown of acetylcholine, an important neurotransmitter in learning and memory, which is known to be decreased in AD. Similarly devastating, excess IL-1β, as observed in DS and AD, is associated in vitro and in vivo with decreases in the expression of synaptophysin, which is a hallmark of the synaptic loss in AD. Such neuropathophysiological changes would be expected to further stress neurons, promote more neuroinflammation, and in this way create a self-propagating cycle of ever increasing neuronal stress, dysfunction, and loss.”

This is one important reason why once ‘the train leaves the station and gets up to full speed’ it’s so hard to treat.


Food and Chemical ToxicologyA paper recently published in Food and Chemical Toxicology directs attention to the contribution of oxidative stress and glycation along with inflammation. In measuring markers of oxidative stress and endothelial dysfunction in the blood of 21 AD patients under standard treatment for AD compared with 10 controls, they saw significant differences in the ability to manage oxidative damage with glutathione and in levels of glycation end-products due to poor blood glucose regulation:

“Results indicate that IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients. Protein carbonyls levels were higher in AD group, while glutathione reductase and total antioxidant capacity were lower, depicting decreased defense ability against reactive oxygen species. Besides, a higher level of advanced glycation end-products was observed in AD patients. Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed: in Rivastigmine-treated group, IL6 levels were 47% lower than the average value of the remaining AD patients; homocysteine and glutathione reductase were statistically unchanged in the Rivastigmine and Donepezil–Memantine, respectively Donepezil group.”

They highlighted these conclusions:

  • IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients compared to controls.
  • Protein carbonyls levels were increased in AD patients.
  • GSH (glutathione) level and TAC (total antioxidant capacity) were lower in AD patients, suggesting an impaired self-defense ability against oxidative stress.
  • Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed.


Journal of Alzheimer's Disease & Other DementiasReaders of earlier posts on histamine intolerance will be particularly interested in a paper published this summer in the American Journal of Alzheimer’s Diseaes & Other Dementias in which the authors describe the role of histamine regulation in AD:

“Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H1 receptor (H4R). The histaminergic system has a role in the treatment of brain disorders by the development of histamine receptor agonists, antagonists. The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy. In this review, we focus on the role of histamine and its receptors in the treatment of AD, and we hope that histamine could be an effective therapeutic factor in the treatment of AD.”


Ageing Research ReviewsPrevention and treatment of cognitive decline is a huge topic that invites forthcoming posts. A nod in that direction considers the use of polyphenols such as resveratrol and curcumin that are shown to help quench neuroinflammation, as recognized in a paper just published in Ageing Research Reviews:

“Alzheimer’s disease (AD) is characterised by extracellular amyloid deposits, neurofibrillary tangles, synaptic loss, inflammation and extensive oxidative stress. Polyphenols, which include resveratrol, epigallocatechin gallate and curcumin, have gained considerable interest for their ability to reduce these hallmarks of disease and their potential to slow down cognitive decline. Although their antioxidant and free radical scavenging properties are well established, more recently polyphenols have been shown to produce other important effects including anti-amyloidogenic activity, cell signalling modulation, effects on telomere length and modulation of the sirtuin proteins.”


Brain accessible polyphenols with multiple effects on pathways involved in neurodegeneration and ageing may therefore prove efficacious in the treatment of age-related diseases such as AD, although the evidence for this so far is limited. This review aims to explore the known effects of polyphenols from various natural and synthetic sources on brain ageing and neurodegeneration, and to examine their multiple mechanisms of action, with an emphasis on the role that the sirtuin pathway may play and the implications this may have for the treatment of AD.”

They draw these highlights from their findings:

  • Polyphenols have been shown to act on many of the pathways involved in the pathogenesis of Alzheimer’s disease.
  • Polyphenols activate members of the sirtuin family of proteins which play an important role in cell survival and longevity.
  • Polyphenols positively influence oxidative stress, amyloid aggregation, inflammation, mitochondrial function and telomere maintenance.
  • Utilising synergistic combinations of polyphenols may prove beneficial in developing treatment strategies for Alzheimer’s disease.


The FASEB Journal Vol 27 Num 9Concerns for cognitive decline certainly come to the fore on the occasion of hospitalization for major surgery or illness. The authors of a study published in The FASEB Journal describe how a compound derived from aspirin can play a therapeutic role:

Hospitalization for major surgery or critical illness often associates with cognitive decline. Inflammation and dysregulation of the innate immune system can exert broad effects in the periphery and central nervous system (CNS)… Endogenous regulation of acute inflammation is providing novel approaches to treat several disease states including sepsis, pain, obesity and diabetes.”

The draw attention to the activity of resolvins:

Resolvins are potent endogenous lipid mediators biosynthesized during the resolution phase of acute inflammation that display immunoresolvent actions. Here, using a mouse model of surgery-induced cognitive decline we report that orthopedic surgery affects hippocampal neuronal-glial function, including synaptic transmission and plasticity. Systemic prophylaxis with aspirin-triggered resolvin D1 (AT-RvD1: 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, as little as 100 ng dose per mouse) improved memory decline following surgery and abolished signs of synaptic dysfunction. Moreover, delayed administration 24 h after surgery also attenuated signs of neuronal dysfunction postoperatively. AT-RvD1 also limited peripheral damage by modulating the release of systemic interleukin (IL)-6 and improved other clinical markers of tissue injury.”

The authors conclude:

“Collectively, these results demonstrate a novel role of AT-RvD1 in modulating the proinflammatory milieu after aseptic injury and protecting the brain from neuroinflammation, synaptic dysfunction and cognitive decline. These findings provide novel and safer approaches to treat postoperative cognitive decline and potentially other forms of memory dysfunctions.”


Note: Prevention and treatment of cognitive decline in its various manifestations is a complex and demanding clinical challenge emerging as one of the key responsibilities of any clinician. It requires a working familiarity with every facet of clinical systems biology. Forthcoming posts will highlight the emerging science in this critical area.

Dementia risk increased by higher blood sugar before diabetes

New England Journal of MedicineDementia and its association with insulin dysregulation and diabetes has been described by a number of investigators but this bears repeating on the occasion of a paper just published in The New England Journal of Medicine. The authors determined to see if blood sugar elevated to a lesser degree than in diabetes is linked to dementia:

“Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes.”

They examined glucose and glycated hemoglobin (HgbA1c) levels in 2067 subjects without dementia and followed them for an average of 6.8 years (adjusting for a number of variables that could also contribute to dementia) and found a clear association:

“During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia; with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18.

With diabetes, of course, it was worse:

“Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia; with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40.”

But insulin resistance and rising blood glucose levels do not have to evolve as far as type 2 diabetes to add to the risk for dementia as the authors conclude:

“Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes.”

Sugar turns LDL cholesterol “ultra-bad”

That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to…

“…study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.”

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn’t do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person’s blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall…A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.”

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the “ultra-bad cholesterol“. It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.”