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.”

Skipping breakfast worsens blood glucose and insulin later

Diabetes CareBreakfast is a cornerstone of healthy metabolism. A study just published in the journal Diabetes Care now shows that skipping breakfast damages the blood glucose and insulin response to meals later in the day. The authors note:

Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner. “

They compared postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) for subjects randomly assigned to one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Their data show that skipping the morning meal messed up metabolism for the rest of the day:

“Compared with YesB, lunch area under the curves for 0–180 min (AUC0–180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day. “

In other words, it worsened hyperglycemia and insulin resistance after both lunch and dinner. The authors conclude:

“Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.”

It’s also clearly important for prevention of type 2 diabetes and all the depredations of insulin resistance and dysregulated blood sugar.

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.”


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.”

Magnesium supplementation improves insulin resistance

Diabetes, Obesity and MetabolismInsulin resistance is benefited by magnesium supplementation according to mounting evidence. A study published in the journal Diabetes, Obesity and Metabolism documents significant improvements in insulin resistance by supplementation even when the subjects’ magnesium levels appeared normal (normomagnesemic). The authors state:

The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects.”

After collecting data on insulin sensitivity, plasma glucose, serum insulin, blood pressure and lipid profiles subjects were randomized to receive either a magnesium supplement or placebo for 6 months.The results offered strong evidence for the ability of magnesium supplementation to improve insulin resistance:

“Mg supplementation resulted in a significant improvement of fasting plasma glucose and some insulin sensitivity indices (ISIs) compared to placebo. Blood pressure and lipid profile did not show significant changes. The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimization of Mg status to prevent insulin resistance and subsequently type 2 diabetes.”

Magnesium, insulin resistance and cardiovascular risk reduction

Medical Science MonitorIn another study published in Medical Science Monitor that included subjects with  hypertension, magnesium supplementation improved both insulin resistance and blood fats:

“Epidemiological studies have associated low dietary Mg2+ intake with insulin resistance (IR) and increased risk for metabolic syndrome…This study aimed to investigate the effects of oral Mg2+ supplementation on insulin sensitivity (IS) and serum lipids.”

Forty-eight patients were divided into a magnesium supplementation with lifestyle recommendations and a lifestyle only group, with measurements of fasting glucose and insulin levels, serum lipids and other standard laboratory tests, as well as an oral glucose tolerance test (OGTT) for insulin sensitivity were made at the beginning and after 12 weeks. Data for the magnesium supplementation group showed numerous improvements not present in the controls:

In the Mg2+ supplementation group the OGTT-derived IS indices of Stumvoll, Matsuda and Cedercholm in were increased between baseline baseline and study-end. In contrast, none of these parameters were changed in the control group. Reductions in total cholesterol, LDL-cholesterol and triglyceride levels, along with a parallel increase in HDL-cholesterol levels, were evident at study-end in the intervention group, but not in the control group.”

Clinical note: Magnesium supplementation should be a routine consideration to lower cardiovascular risk in patients with hypertension, especially with insulin resistance. The authors conclude:

“This study suggests that oral Mg2+ supplementation improves IS and lipid profile in mildly hypertensive patients. These potential beneficial effects of Mg2+ on associated metabolic factors could be helpful for patients with hypertension in terms of overall cardiovascular risk reduction.

Magnesium improves metabolism with normal weight but insulin resistance

Archives of Medical ResearchAnd a study recently published in Archives of Medical Research showed similar improvements in insulin resistance and metabolism with magnesium supplementation in a randomized placebo-controlled trial with metabolically obese, normal-weight (MONW) individuals.

“A total of 47 MONW individuals with hypomagnesemia were enrolled in clinical a randomized double-blind placebo-controlled trial. Individuals in the intervention group received 30 mL of MgCl2 5% solution (equivalent to 382 mg of magnesium) and individuals in the control group 30 mL of placebo solution, once daily during 4 months. In the absence of obesity or overweight, the presence of fasting glucose levels ≥100 mg/dL, HOMA-IR index ≥3, triglyceride levels ≥150 mg/dL and/or systolic and diastolic blood pressure ≥140 and 90 mmHg defined the presence of the MONW phenotype. Hypomagnesemia was defined by serum magnesium concentration ≤1.8 mg/dL.”

Clinical note: Even with a cut-off point of 2.0 mg/dL serum magnesium is a ‘blunt’ indicator that misses many if not most cases needing supplementation. Practitioners should be alert to clinical manifestations of suboptimal magnesium levels. Objective verification when necessary can be reliably obtained with the Exa Test.

Consonant with other studies magnesium supplementation showed a distinct benefit:

“At basal conditions there were no significant differences between groups. At the end of follow-up, changes in the mean of systolic (–2.1 vs. 3.9% mmHg, p <0.05) and diastolic (–3.8 vs. 7.5% mmHg, p <0.05) blood pressures, HOMA-IR index (–46.5 vs. –5.4%, p <0.0001), fasting glucose (–12.3 vs. –1.8% mg/dL, p <0.05) and triglyceride levels (–47.4% vs. 10.1% mg/dL, p <0.0001) were significantly lower in the subjects who received MgCl2 compared with individuals in the control group.”

The authors’ conclusion supports the practice of starting early (while weight is normal) with magnesium supplementation to address adverse metabolic changes:

“Oral magnesium supplementation improves the metabolic profile and blood pressure of MONW individuals.”

Clinical note: Magnesium may be the element most commonly insufficient universally. Critical to hundreds of metabolic pathways, it is ‘nature’s calming, antiinflammatory mineral’ and supports parasympathetic nervous system function. Deficiency should be highly suspect in the presence of muscle cramps.

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.

Depression, dementia and brain glucose

Psychiatry Research- NeuroimagingDepression and dementia, including Alzheimer’s disease, are strongly affected by brain glucose and insulin regulation. A study just published in the journal Psychiatry Research: Neuroimaging presents evidence that brain glucose dysregulation is a modifiable risk factor for both depression and dementia/Alzheimer’s disease in later life. The authors state:

“Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer’s disease (AD)…Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD.”


“Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD.”

So they correlated fasting serum glucose (FSG) levels in non-diabetic young (YC) and elderly controls (EC) and late-life depression patients with PET scans of cerebral glucose metabolism. There was indeed an association of brain dysglycemia with depression and dementia:

“The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions.”

In other words, increased serum glucose with cerebral insulin resistance (hence decreased brain glucose metabolism) correlated with both depression and cognitive deficits. The authors conclude:

“Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk.”

See earlier posts on insulin resistance, dysglycemia (glucose dysregulation), HgbA1c and brain health.

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.”

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.

Brain atrophy is associated with blood sugar on the higher end of normal

Brain atrophy, or the loss of brain mass due to accelerated neurodegeneration, is the gross anatomical aspect of cognitive impairment and dementia. There is abundant evidence that blood sugar and insulin dysregulation are harmful to the brain. A paper just published in the journal Neurology shows that even plasma glucose (‘blood sugar’) in the higher end of the ‘normal’ range is associated with brain atrophy. The authors state:

“Substantial evidence showing an association between type 2 diabetes (T2D) and cerebral atrophy, cognitive impairment, and dementia is accumulating. However, relatively little is known about the subclinical effects of high plasma glucose levels within the normal range. The aim of this study was to investigate the association between plasma glucose levels and hippocampal and amygdalar atrophy in a sample of 266 cognitively healthy individuals free of T2D, aged 60–64 years, taking part in a longitudinal study of aging.”

The hippocampus is the brain’s ‘center’ for short-term memory and adrenocortical regulation, and the amygdala modulates memory and emotional learning. The authors correlated fasting plasma glucose levels with the volumes of the hippocampus and amygdala determined by MRI at the beginning of the study and 4 years later. There was a strong association of plasma glucose and brain atrophy:

Plasma glucose levels were found to be significantly associated with hippocampal and amygdalar atrophy and accounted for 6%–10% in volume change after controlling for age, sex, body mass index, hypertension, alcohol, and smoking.”

This finding has great practical significance for the prevention and treatment of brain-based disorders. The health effects of brain atrophy are global and impair health and quality of life in a multitude of ways because the brain is the regulator of systemic physiology as well as the organ of cognition. The subjects in this study were not diabetic, their fasting plasma glucose was higher but still in the normal ranges. Astute clinicians know, however, that well before the onset of type 2 diabetes rising insulin levels do insidious damage throughout the body. Moreover, the factors contributing to this, including increased inflammation, can harm the brain and other tissues on their own. The authors conclude:

High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes.”

Insulin resistance and hypoglycemia both contribute to chronic inflammation. Clinicians should offer education for lifestyle factors and interventions based on the objective tests to determine strategies for healthy insulin and plasma glucose tuned to the individual.

Note: 6.1 mmol/L of glucose converts to 109.91 mg/dL.