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.”

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.”

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.”

Moreover…

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.

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.”

Qigong benefits type 2 diabetes

Diabetes CareThis randomized controlled study recently published in the journal Diabetes Care (the journal of the American Diabetes Association) nicely validates the recommendation of qigong exercises as a treatment adjunct for type 2 diabetes. The investigators used fasting glucose, insulin, hemoglobin A1C and calculated insulin resistance as metrics to determine efficacy. Their conclusion: “Qigong therapy for 12 weeks resulted in significant reductions in fasting glucose levels in patients with type 2 diabetes and demonstrated trends toward improvement in insulin resistance and A1C. These results suggest that Qigong may be an effective complementary therapy for individuals with type 2 diabetes.”

Watch that hemoglobin A1C for blood vessel thickening

Diabetes Care 1009A recent paper published in Diabetes Care delivers a compelling message to be on the alert for elevations of hemoglobin A1C—even when glucose tolerance is normal. The authors set out to “identify which marker of glycemic control is most informative with respect to the variation of IMT in individuals with NGT.” (IMT = intima-media thickness (thickening of the blood vessel walls) and NGT = normal glucose tolerance.) They found that “Only A1C was associated with IMT…whereas 1-h glucose was not informative.” This is something of a wake-up call to respect that elevations in hemoglobin A1C (which we routinely test) are associated with degenerative vascular changes even when the glucose appears normal.

Best (and easiest) blood test for diabetes

Investigators in this study published recently in the journal Diabetes Care verified that measuring hemoglobin A1C is preferable to fasting glucose for the diagnosis of diabetes. Hemoglobin A1C (glycosylated hemoglobin) is formed when glucose combines with hemoglobin in red blood cells. While fasting glucose is the ‘snapshot’ of a single point in time, HgbA1C amounts to an average of the glucose level over 3-4 months. Unlike fasting blood sugar, hemoglobin A1C can be drawn any time regardless of proximity to meals.