Prediabetes, chronic inflammation and hemoglobin A1c

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

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

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

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

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

The authors conclude:

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

 Prediabetes and cardiovascular risk

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

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

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

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

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

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

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

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

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

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

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

 

Leaky gut: inflammation, chronic fatigue and depression

Neuroendocrinology Letters--leaky gut and chronic fatigueLeaky gut‘ is abnormal intestinal permeability that occurs when the epithelial tissues that comprise the gut barrier have been damaged. When intact the gut barrier prohibits antigenic contents of the intestines from access to the gut-associated lymphoid tissue (GALT) right on the other side of the intestinal wall. Gut barrier integrity (absence of leaky gut) is crucial to prevent loss of immune tolerance (autoimmunity) since the GALT comprises 60-80% of all immune tissue in the body.

Normalization of leaky gut improves chronic fatigue

LPS (lipopolysaccharide from bacterial cell walls) is so highly antigenic that it’s used as an adjuvant in vaccines. Translocation of LPS across a damaged gut barrier elicits systemic inflammation, accompanied by oxidative and nitrosative stress. A study published in Neuroendocrinology Letters demonstrates how normalization of the antibody responses to LPS not only ameliorates but can predict the clinical outcome in chronic fatigue syndrome (CFS). The authors state:

“There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).”

They investigated this by measuring serum concentrations of IgA and IgM to LPS of several gram-negative enterobacteria CFS patients, both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, while consuming a leaky gut diet during 10-14 months. They also measured corresponding result with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and after 10-14 months on the NAIOSs.

Good clinical response to lowered IgA and IgM

The improvement in CFS scores that they documented was very gratifying:

Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).”

The authors’ comments on their data can hardly be overemphasized for clinicians participating in case management of chronic fatigue and fibromyalgia:

“The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.”

High IgA response to normal gut bacteria fires up inflammation in CFS

Journal of Affective DisordersAn interesting study published in the Journal of Affective Disorders documents how LPS from commensal gut bacteria that translocates into the GALT provokes inflammation that drives CFS. The authors note:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin.”

These authors investigated the IgA/IgM responses to the LPS of 6 different enterobacteria by measuring serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). When they correlated with biomarkers for inflammation, CMI and the symptoms of ME/CFS the results were noteworthy:

“Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.”

This is extremely important in clinical practice due to the great functional significance of both systemic inflammation and autonomic nervous system regulation. The authors conclude:

“The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.”

Autoimmune attack on serotonin production

Another fascinating paper also published in the Journal of Affective Disorders reveals that bacterial translocation through the gut barrier into immune lymphoid tissue can provoke antibodies that attack 5-HT, the precursor of serotonin, contributing to chronic fatigue and depression. The authors state:

“Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.”

The examined 117 patients with ME/CFS for autoimmune activity against 5-HT, measuring plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria. This was correlated with the fibromyalgia and chronic fatigue syndrome rating scale. Their data show a strong association:

“The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.”

This is very significant for clinicians involved in case management of fatigue, depression, chronic pain and autonomic dysregulation. The authors sum it up:

“The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions…These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.”

Leaky gut, LPS and depression

Yet another study in the same journal investigated increased IgA and IgM antibodies aimed at gut commensal bacteria specifically in depression. The authors measured antibodies directed against Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in depressed patients and normal controls, and found a very significant correlation to symptoms of depression and fatigue:

“The prevalences and median values of serum IgM and IgA against LPS of these commensals were significantly higher in depressed patients than in controls. The IgM levels directed against the LPS of these commensal bacteria were significantly higher in patients with chronic depression than in those without. The immune responses directed against LPS were not associated with melancholia or recurrent depression. There was a significant correlation between the IgA response directed against LPS and gastro-intestinal symptoms.”

Clinical note

The treatment of chronic fatigue and depression demands a holistic, multidisciplinary approach. A core feature with a number of potential contributing causes that can vary in each case is up-regulation of immune pathways driving inflammation in the brain and against elements in neurotransmitter production. The authors highlight these considerations in their discussion:

“The results indicate that increased bacterial translocation with immune responses to the LPS of commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression…The findings suggest that “translocated” gut commensal bacteria activate immune cells to elicit IgA and IgM responses and that this phenomenon may play a role in the pathophysiology of (chronic) depression by causing progressive amplifications of immune pathways.”

Compounds that modulate neuroinflammation induced by LPS

Neurochemistry InternationalA wide range of therapeutic resources are available to the functional practitioner to employ, depending on the individual case, that can ameliorate autoimmune inflammation triggered by reactions to the LPS of bacteria translocated through a leaky gut. By way of one example among many, a paper published in Neurochemistry International shows that anthocyanins (polyphenolic compounds imparting a blue color, found in vegetation such as blueberries) can ameliorate inflammation triggered by reactions to LPS.

“Several studies provide evidence that reactive oxygen species (ROS) are key mediators of various neurological disorders. Anthocyanins are polyphenolic compounds and are well known for their anti-oxidant and neuroprotective effects. In this study, we investigated the neuroprotective effects of anthocyanins (extracted from black soybean) against lipopolysaccharide (LPS)-induced ROS-mediated neuroinflammation and neurodegeneration in the adult mouse cortex.”

This benign intervention produced a gratifying result:

“The immunoblotting and morphological results showed that anthocyanins treatment significantly reduced LPS-induced-ROS-mediated neuroinflammation through inhibition of various inflammatory mediators, such as IL-1β, TNF-α and the transcription factor NF-kB…Anthocyanins also prevent overexpression of various apoptotic markers, i.e., Bax, cytosolic cytochrome C, cleaved caspase-3 and PARP-1. Immunohistochemical fluoro-jade B (FJB) and Nissl staining indicated that anthocyanins prevent LPS-induced neurodegeneration in the mouse cortex.”

Of particular note to the clinician:

“Our results suggest that dietary flavonoids, such as anthocyanins, have antioxidant and neuroprotective activities that could be beneficial to various neurological disorders.”

Calcium supplementation may increase risk for dementia

NeurologyCalcium supplementation continues to come under scrutiny as evidence accumulates that it can increase the risk of inflammatory disorders, most notably cerebrovascular disease, likely by opposing the anti-inflammatory effects of magnesium. A study just published in the journal Neurology offers evidence that supplementation can increase the risk for dementia in women with cardiovascular disease. The authors set out to…

“…determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.”

700 dementia-free women aged 70–92 years were examined at baseline and at follow-up 5 years later with comprehensive neuropsychiatric and physical examinations. 447 underwent CT scans at baseline. Dementia was diagnosed according to DSM-III-R criteria, and this was correlated with information on the use and dosage of calcium supplements.

Calcium supplementation dramatically increased the risk for dementia

Neurology 2The risk more was increased almost 7 times for the subset of women with a history of stroke, and tripled for those with white matter lesions, in comparison to similar subjects who did not supplement:

Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40) than women not given supplementation (n = 602)….supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77) or presence of white matter lesions (OR 2.99), but not in groups without these conditions.”

Correspondence with previous studies

This was a relatively small study, but the findings correspond to earlier evidence that supplementation can increase the burden of systemic inflammation (some have been written about here). It opposes the absorption and action of magnesium, a likely mechanism accounting for these observations. Recall that osteoporosis is not a calcium deficiency disorder, rather a failure to maintain the protein matrix of bone to which the minerals attach. Though it was only subjects with a history of cerebrovascular disease or white matter lesions for whom the risk of dementia was markedly increased, clinicians should consider very carefully before recommending supplementation. The authors conclude:

Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.”

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.”

Circadian rhythms of inflammation

Arthritis Research & TherapyCircadian variation of symptoms caused by inflammation is common to conditions including rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, asthma, depression and many more. The adrenal circadian rhythm is an important factor when serum cortisol is inadequate relative to inflammation. An excellent paper published in Arthritis Research & Therapy examines the dynamics and clinical significance of circadian variation in inflammation associated with glucocorticoid regulation, an important consideration for anti-inflammatory treatment.

Brain’s central circadian oscillator connects with immune system

The suprachiasmatic nucleus of the hypothalamus that generates the circadian rhythm connects profusely to other brain centers and to the immune system through the HPA axis.

“The circadian activity of this particular nucleus is transferred to the immune system via the hypothalamic hypothalamic-pituitary-adrenal (HPA) axis, leading to the typical undulation of clinical symptoms in chronic inflammatory diseases with a maximum in the early morning hours. In this review we will describe circadian rhythms in rheumatoid arthritis (RA) and other rheumatic and chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic and chronic inflammatory diseases, the problem of adrenal suppression by glucocorticoid (GC) therapy, and whether or not chronotherapy with prednisone is more effective and aggravates adrenal suppression.”

This pertains to the classic aggravation of stiffness and pain in the morning as well as the oscillation of other symptoms caused by inflammation, including neuropsychiatric disorders.

Nocturnal inflammation, melatonin and cortisol

As melatonin goes up at night cortisol, which ‘keeps a lid on’ inflammation, goes down and inflammatory biomarkers are seen to increase.

“Classical symptoms of RA, such as morning stiffness and swelling, show a clear temporal relationship with nocturnally elevated levels of proinflammatory cytokines, as a consequence of a cascade of increased nocturnal inflammation. Several of these cytokines, such as tumor necrosis factor (TNF) alpha and interleukin (IL)-6, are highly increased in patients with active RA in the early hours of the day, but are found at very low levels after noon.”

This is characteristic of a healthy cortisol rhythm…

“Also, the cortisol rhythm – which is also present in healthy individuals, and therefore is primary, with low levels at night – may explain nocturnal inflammation. Since cortisol is the strongest endogenous anti-inflammatory substance, its downregulation during the evening and night is linked to an increase of inflammation during the early morning, and its upregulation in the early morning is most probably related to inhibition of inflammation during the day. The early morning inflammatory signs, typical for many inflammatory rheumatic conditions, can thus be explained.”

Polymyalgia rheumatica, ankylosing spondylitis and asthma

These conditions too have cyclic undulations that correspond to the circadian rhythm of immune activity, with implications for treatment.

“Furthermore, in polymyalgia rheumatica (PMR), symptoms of pain and stiffness typically are most prominent during the early morning, similar to RA…Of note, in ankylosing spondylitis – another inflammatory arthritic condition – pain and stiffness also seem to be most prominent during the early morning hours. Finally, it is now also evident that symptoms of diseases such as RA, which is T helper 1 dependent, but also asthma, which is T helper 2 dependent, are influenced by diurnal rhythms and natural regulatory T cells. In particular, secretion of IL-2, interferon gamma and IL-10 by naïve CD4+ T cells follows a diurnal rhythm.”

This ties together the nervous, immune and hormonal systems that interact in a rhythmic fashion:

“All of these processes are closely linked to regulatory interactions between the endocrine, nervous and immune systems, with distinct 24-hour daily rhythms (neuroendocrine immunology).”

HPA axis dysfunction in chronic inflammatory disorders

HPA axis function in inflammationNormally the adrenocortical response should track the circadian oscillator or inflammation. The authors describe a fascinating study in which the cortisol response to infusions of the pro-inflammatory cytokine IL-6 were delineated:

“In a fairly heroic study in 18 healthy young men, either saline or low or high doses of recombinant human IL-6 were infused into one femoral artery for 3 hours. Subjects experienced clinical symptoms such as shivering and discomfort during high-dose IL-6 administration, but were asymptomatic during low-dose IL-6 administration. Plasma cortisol concentrations did not change during infusion of saline but markedly increased during both high and low doses of IL-6. While concentrations of plasma cortisol declined after 2 hours of infusion in low doses of IL-6, they remained elevated in high doses of IL-6 at 3 hours of infusion…The increase of cortisol levels in reaction to IL-6 infusion is provoked by activation of the HPA axis. Remarkably, the relation between IL-6 levels and the adrenocorticotropic hormone (ACTH)/cortisol levels is linear. In a study of 15 healthy young men in which recombinant IL-6 was applied subcutaneously, plasma ACTH concentrations and plasma cortisol levels increased dose dependently, and the ratio of hormone to IL-6 serum levels was constant.”

By contrast however, in chronic inflammation levels of cortisol are insufficient to ‘put out the fire.’

In chronic inflammation, cortisol secretion appears to be inadequate in relation to inflammation. In a retrospective study with 34 patients with RA, 46 patients with reactive arthritis and 112 healthy subjects, the authors measured serum levels of IL-6, TNF and cortisol. The absolute levels of IL-6 were lower in healthy controls than in reactive arthritis and RA patients. However, the ratio of serum cortisol to serum cytokines was much higher in healthy controls than in reactive arthritis and RA patients, due to similar cortisol levels in all groups.”

And in another RA study…

“…comparing the circadian course of ACTH and cortisol levels in patients with RA and in healthy subjects, despite 10 times higher serum levels of cytokines in patients with RA, serum level curves of ACTH and cortisol were identical. The ACTH/cortisol hormone secretion in patients with RA is thus inadequate in relation to inflammation.”

And giant cell arteritis…

“In a study comparing serum values of ACTH, cortisol and CRP in patients with PMR/giant cell arteritis and controls, ACTH and cortisol levels were not different in patients with PMR/giant cell arteritis and controls, whereas the ratios of serum ACTH/serum CRP and serum cortisol/serum CRP were significantly lower in PMR/giant cell arteritis patients than in healthy controls. Thus, in PMR/giant cell arteritis there also appears to be an inadequate cortisol secretion in relation to inflammation in terms of relative adrenal insufficiency.”

The liver-HPA-kidney axis in chronic inflammation

In important observations that call to mind principles of traditional Chinese medicine (TCM), the authors delineate the function of hepato-hypothalamic-pituitary-adrenal-renal axis:

“Recently, evidence has accumulated, been reviewed and presented as a concept that dysfunction of the HPA axis in chronic inflammation is not simply an adaptation to chronic stress, but may be due to increased negative feedback of active cortisol on the HPA axis. The HPA axis has been recognized to be extendable to a hepato-hypothalamic-pituitary-adrenal-renal axis by GC [glucocorticoid] metabolism.”

The liver in chronic inflammation

HPA axis dysfunction in inflammationThe kidney inactivates cortisol to protect its receptor from over-stimulation and subsequent suppression, and the liver turns it back on:

“Active cortisol is converted to inactive cortisone mainly by the kidney, via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, in order to protect the nonspecific mineralocorticoid receptor from activation by cortisol. On the other hand, the major organ for converting inactive cortisone to active cortisol is the liver, via 11β-HSD1.”

Pro-inflammatory cytokines over-activate the liver 11β-HSD1 enzyme:

Expression of 11β-HSD1 is markedly enhanced by TNF and proinflammatory cytokines. The liver therefore becomes an important player in systemic inflammation, even if the conversion also occurs in multiple other tissues including the brain, adipocytes, vascular cells, osteoblasts and fibroblasts. Given the role of the 11β-HSD1 in GC metabolism, its effect on the HPA axis and its interaction with inflammatory cytokines, it is hypothesized that in chronic inflammatory diseases, cytokine-induced increased expression of 11β-HSD1 induces a change in the HPA axis. Increased negative feedback of active cortisol on the HPA axis induced during inflammation may thus be the mechanism of dysfunction of the HPA axis in chronic inflammation.”

Tertiary adrenal insufficiency

Synthetic glucocorticoids such as prednisone suppress adrenal function through the same negative feedback mechanism:

“During the physiological regulation of the HPA axis, cortisol release is terminated by negative feedback regulation of cortisol on the hypothalamus and anterior pituitary. Also, synthetic GCs – as applied in GC therapy – can cause negative feedback regulation, leading to adrenal suppression in terms of tertiary adrenal insufficiency.”

Besides the clinical presentation, this can be confirmed by low cortisol and ACTH levels and lack of increase in plasma cortisol with the corticotropin-releasing hormone (CRH) or ACTH stimulation test. The magnitude of the dose matters:

“The frequency of adrenal suppression increases with increasing GC dosages. In arthritis and asthma patients treated with prednisone equivalent doses ranging from 5 to 20 mg, cortisol response in the ACTH test was normal (that is, cortisol rise ≥7 μg/dl) in all of the patients taking a single morning dose of 5 to 7.5 mg prednisone, was blunted (that is, cortisol rise <7 μg/dl) in 33% and 47% of the patients taking 10 to 12.5 mg and 15 mg prednisone, respectively, and was suppressed (no rise) in 44% of the patients taking 20 mg prednisone.”

Duration also takes its toll:

After 12 weeks of 7.5 mg prednisolone, the mean values for the 60-minute response to ACTH were reduced by 35%. Following treatment, 46% of patients taking 7.5 mg prednisolone failed to reach the normal maximum cortisol response to ACTH, even if the HPA axis response generally remained within the normal range.”

Chronotherapy with prednisone

Primary concerns are maximizing effectiveness while minimizing adrenal suppression through negative feedback regulation. Several daily divided doses worsen the tendency to suppression:

“In the 1960s several studies confirmed that splitting the daily dose into several divided doses strongly increases the risk of adrenal suppression. For example, whereas endogenous cortisol secretion was not altered with a single dose of 8 mg triamcinolone given at 8:00 a.m., application of four divided 2 mg doses resulted in marked suppression of cortisol levels.”

Timing of the single dose also matters:

“The time point of application of the single daily dose also plays a role for adrenal suppression. This can be explained easily: circadian GC secretion exhibits two peaks, one large peak in the morning around 8:00 a.m. and a smaller peak in the afternoon around 2:00 p.m. Of note, cortisol levels are high during the first peak in the morning, causing downregulation of ACTH levels via negative feedback regulation. In consequence, cortisol secretion is also downregulated. At a certain point, reduced cortisol levels cause upregulation of ACTH again, leading in turn also to upregulation of cortisol secretion during the second peak in the afternoon. If exogenous GCs were applied in the evening, the so-called quiet period for the adrenal gland, this would cause a negative signal on ACTH and therefore also cortisol secretion in the morning.”

Note: With a healthy cortisol rhythm the afternoon “bump” in cortisol may be barely discernible. A single daily dose is easier to manage but many patients require two to control inflammation.

Several studies evaluating nocturnal doses at 2:00 a.m. yielded better results for morning stiffness than conventional morning doses. But the impracticality of dosing at 2:00 am plus questions about HPA suppression led to the development of a modified-release (MR) prednisone tablet that releases the dose four hours after ingestion (2 a.m. if taken at 10 p.m.).

MR prednisone produced a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone…These results lead to the question of whether chronotherapy with MR prednisone affects adrenal suppression. The influence of long-term, low-dose chronotherapy with MR prednisone on the HPA axis was investigated by CRH tests in a subgroup of 28 patients in the CAPRA-1 study…There were no measurable differences in mean cortisol changes after CRH injection between baseline and the end of the study. Furthermore, there was no indication that changing treatments from immediate-release prednisone to MR prednisone increased the risk of HPA axis insufficiency, or resulted in deterioration of preexisting suppression.There was thus no difference between immediate-release prednisone and MR prednisone in numbers of normal/suppressed/no response reactions. In addition, no adverse events that could be attributed to HPA axis insufficiency were observed during treatment with low-dose MR prednisone for the entire treatment period of 12 months.”

Dosing at 2:00 a.m. (by modified release) may even benefit HPA axis activity:

“A recent study showed an increase of endogenous cortisol after 2 weeks of MR prednisone therapy in patients with active RA who had received no GCs by any route in the preceding 3 months. MR prednisone released at 2:00 a.m. suppressed the pathological early morning rise in plasma IL-6 in RA. The nocturnal rise in plasma cortisol was not suppressed but was enhanced with a peak value increase from 14.1 to 19.3 μg/dl, consistent with a changing relationship between HPA axis and immune system activation. This observation may be an indication that the HPA axis is preserved and is activated even more during MR prednisone treatment compared with pre-MR prednisone treatment.”

Clinical Note

Nutrition JournalMinimizing adrenal suppression while enhancing anti-inflammatory effectiveness by circadian dosing of prednisone also implies that effect of other anti-inflammatory agents can be enhanced by chronotherapeutic timing. Curcumin is one of the most extensively researched natural anti-inflammatory agents. A study published in the Nutrition Journal on the comparative absorption of curcumin formulations demonstrates that a newer preparation markedly extends the plasma concentrations of bioactive components including the key metabolite tetrahydrocurcumin.

“The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard.”

A curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) were compared to a standardized curcumin mixture (CS). There was a dramatic result in favor of the CHC preparation.

“Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001).”

Plasma concentrations time-curves for curcumin productsTetrahydrocurcumin is particularly valuable…

“Tetrahydrocurcumin plays an important role in the antioxidant mechanism of curcumin and has been shown to be the most potent antioxidant of the curcuminoids measured in this study. In addition, tetrahydrocurcumin has been reported to have health promoting benefits. It has been shown to have greater anti-inflammatory potency than curcumin in carrageenan-induced paw edema.”

The data shows that the CHC preparation yields high levels of curcuminoids that would sustain through the night into the morning if taken at bedtime to cover the critical inflammatory period when cortisol levels are naturally low. Adrenal suppression is, of course, not a concern with curcumin. This is advantageous not just for rheumatological disorders but all conditions involving chronic inflammation.

The authors of the first study conclude:

“From a GC perspective, circadian rhythms of the HPA axis and connected subsystems, including the immune system, appear to be essential for understanding of pathophysiology and treatment in rheumatology. The circadian rhythm of the HPA axis in chronic inflammatory diseases may be defective in terms of not bringing the body into a position to overcome the signs and symptoms of the disease. GC therapy serves as a necessary aid to overcome the disease and perhaps restore the deranged circadian rhythm. In a number of patients (around 50%), GC therapy causes adrenal suppression, probably mainly due to as yet undefined individual factors (apart from dose, substance and duration of therapy). In order not to aggravate adrenal suppression, GC therapy should be applied in accordance with the circadian rhythm, to achieve greatest efficacy along with highest safety. It has been suggested that when the single morning dose is not effective enough to achieve sufficient disease control, especially in patients with strong night symptoms and morning stiffness, split doses in the morning and afternoon, or chronotherapy with MR prednisone, can to some extent avoid aggravation of adrenal suppression.”

Depression, inflammation and light therapy

JAMA PsychiatryDepression has much more going on under the surface than neurotransmitter deficiencies. A constellation of papers published recently illustrate the fascinating links between depression, inflammation and exposure to light (not just during the winter). The implies an exciting potential for relief from depression by combining management of chronic inflammation with bright light and chronotherapy to correct circadian dysregulation.

Depression and inflammation

Brain inflammation is recognized as a core contributing cause in numerous neuropsychiatric disorders (search ‘neuroinflammation‘ in this blog). A study just published in JAMA Psychiatry illustrates the association between depression and a variety of symptoms arising from systemic inflammation. The authors used C-reactive protein (CRP) as an inflammatory biomarker:

Elevated levels of inflammatory markers, such as C-reactive protein, are well-documented in people with depression. Raison and Miller suggested that this association may, in fact, be symptom-specific. Higher levels of inflammation are particularly likely to underlie depression symptoms that characterize sickness behavior, including fatigue, reduced appetite, withdrawal, and inhibited motivation…Here, we tested the hypothesis that the association between C-reactive protein and depression is symptom-specific.”

They examined the relationship between CRP and depression for specific symptoms using data on about 15,000 men and women in three US National Health and Nutrition Surveys. Inflammation was associated with cognitive and emotional symptoms including anhedonia, depressed mood, feelings of low self-worth, poor concentration, and thoughts of suicide though they were not independent of the other depression symptoms. Three symptoms particularly stood out:

Inflammation was associated with a range of depression symptoms, particularly with tiredness, lack of energy, sleep problems, and changes in appetite.”

Medscape Medical News quotes comments by Golam Khandaker, MBBS, MPhil, MRCPsych, PhD, clinical lecturer, Department of Psychiatry, University of Cambridge, United Kingdom (not an author of the study):

“While the association between inflammatory markers such as CRP and depression is well known, studies such as this looking at particular symptoms provide important clues for mechanism of illness pathogenesis…This work points to a potentially important role for inflammation in the pathogenesis of the so-called somatic symptoms of depression, such as sleep problems, anergia, and loss of appetite, which are, of course, an integral part of the syndrome of depression.”

The author of this coverage in also notes:

“As previously reported by Medscape Medical News, a recent meta-analysis of 14 relevant randomized, placebo-controlled studies found that nonsteroidal anti-inflammatory drugs (NSAIDs) may help ease depressive symptoms…Results showed that the adjunctive use of NSAIDs was associated with improved antidepressant treatment response without an increased risk for adverse effects.”

Of course safer antiinflammatory agents are readily available.

Circadian misalignment increases inflammation

Brain, Behavior, and ImmunityChronic inflammation can be caused by a disrupted circadian rhythm. In a study published in Brain, Behavior, and Immunity the authors investigated the effects of chronic circadian misalignment on cortisol levels and TNF-α, CRP and IL-10.

“How chronic circadian misalignment influences cortisol and inflammatory proteins, however, is largely unknown and this was the focus of the current study. Specifically, we examined the influence of weeks of chronic circadian misalignment on cortisol, stress ratings, and pro- and anti-inflammatory proteins in humans.”

After 3 weeks of maintaining regular sleep–wake schedules at home and six laboratory baseline days and nights, then a 40 hour constant routine (CR, total sleep deprivation) their subjects endured a 25-day laboratory entrainment protocol with eight of them selected for circadian disruption. Their data showed a shift in inflammatory biomarkers in the subjects induced for circadian misalignment:

Circadian misalignment significantly increased plasma tumor necrosis factor-alpha (TNF-α), interleukin 10 (IL-10) and C-reactive protein (CRP). Little change was observed for the TNF-α/IL-10 ratio during circadian misalignment, whereas the TNF-α/IL-10 ratio and CRP levels decreased in the synchronized control group across weeks of circadian entrainment.”

In other words, as the normally circadian synchronized subjects adapted to the lab conditions their TNF-α/IL-10 (pro/anti-inflammatory) ratio decreased, which was not the case in those subject to circadian misalignment. Interestingly, they also found a difference in cortisol levels between acute sleep deprivation which is used as a therapeutic intervention and chronic circadian misalignment:

“Acute total sleep deprivation significantly increased cortisol levels, whereas chronic circadian misalignment significantly reduced cortisol levels.”

Bottom line here is that circadian misalignment promotes a proinflammatory state.

Bright Light Therapy—Not Just For Seasonal Affective Disorder

Harvard Review of PsychiatryCommenting on the scope of bright light therapy in a paper published recently in the Harvard Review of Psychiatry entitled The Psychiatry of Light, the authors state:

“Bright light therapy and the broader realm of chronotherapy remain underappreciated and underutilized, despite their empirical support. Efficacy extends beyond seasonal affective disorder and includes nonseasonal depression and sleep disorders, with emerging evidence for a role in treating attention-deficit/hyperactivity disorder, delirium, and dementia. A practical overview is offered, including key aspects of underlying biology, indications for treatment, parameters of treatment, adverse effects, and transformation of our relationship to light and darkness in contemporary life.”

JAMA PsychiatryMore evidence supporting the use of this “underappreciated and underutilized” therapy was just added in a study published in JAMA Psychiatry in which bright light therapy outperformed fluoxetine (Prozac®) in the treatment of nonseasonal major depressive disorder (MDD). The authors set out to:

…determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD.

In an eight week randomized, double-blind, placebo- and sham-controlled trial in adults with MDD of at least moderate severity were assigned to one of four interventions: (1) light monotherapy (active 10 000-lux fluorescent white light box for 30 minutes per day in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 minutes per day plus fluoxetine 20 mg/day); (3) combination light and antidepressant; or (4) total placebo (inactive negative ion generator plus a placebo pill). The efficacy of bright light therapy shone clearly in this trial:

A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination and light monotherapy were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%).”

In other words, bright light therapy by itself was very effective. It was slightly more effective when combined with fluoxetine, but the fluoxetine (Prozac®) by itself did no better than placebo. The authors state in their conclusion:

Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD.”

Medscape Medical News quotes comments on the study by Michael Terman, PhD, professor of psychiatry, Columbia University, and director of the Comprehensive Chronotherapy Group, New York City:

“The major surprise was the failure of a standard therapeutic dose of fluoxetine to beat the placebo rate, while light therapy showed a large effect size within 4 weeks…If light had proved ineffective or only weakly effective in comparison with fluoxetine, it would have consigned light therapy to the dustbin, but the dramatic, opposite result turns the tables on the choice of somatic treatment for major depression ― 10,000 lux light therapy upon awakening or, by implication, a walk outdoors if the sun is up ― now can be recommended to patients with recurrent depression, many of whom will respond without recourse to drugs.”

Medscape Medical News also quotes the original study in regard to circadian phase-shifting:

“Nonseasonal major depressive disorder may also be associated with disturbances in circadian rhythms,” they write. “And bright light has predictable circadian phase-shifting effectiveness in humans.”

Circadian rhythms and inflammation in rheumatoid arthritis

Nature Reviews RheumatologyClosing the biological circle connecting depression, inflammation, bright light therapy and circadian rhythm it’s edifying to consider a paper published in Nature Reviews Rheumatology in which the authors discuss inflammation, depression and chronobiology in the context of rheumatoid arthritis:

“Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning.”

Effect of RA Chronotherapy on associated depressionThis suggests significant potential for the treatment of depression:

Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the ‘circadian concept’ in rheumatology from bench to bedside.”

Chronotherapy with bright light beats exercise for depression

Acta Psychiatrica ScandinavicaExercise has been well-established as a remedy for depression, yet in a fascinating study recently published in Acta Psychiatrica Scandinavica chronotherapeutics with bright light therapy was significantly more effective. To investigate the long-term antidepressant effect of a chronotherapy they randomized 75 patients with major depression to fixed duloxetine and either a chronotherapeutic intervention (wake group) with three initial wake therapies, daily bright light therapy, and sleep time stabilization for 29 weeks. Chronotherapy was the clear winner for remission of major depression:

Patients in the wake group had a statistically significant higher remission rate of 61.9% vs. 37.9% in the exercise group at week 29. This indicated continued improvement compared with the 9 weeks of treatment response (44.8% vs. 23.4%) with maintenance of the large difference between groups. HAM-D17 endpoint scores were statistically lower in the wake group.”

Clinical note: All of the above argues in favor of a trial of chronotherapy with bright light plus exercise (free of fluoxetine or duloxetine) in case management of depression.

The authors of the this study conclude:

In this clinical study patients continued to improve in the follow-up phase and obtained very high remission rates. This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission.”

Bottom Line

  • Bright light therapy can be effective for major depression even when nonseasonal.
  • Brain inflammation is a core contributing biological cause of neuropsychiatric disorders including depression.
  • Correcting a misaligned circadian rhythm using early waking with bright light to phase shift is also anti-inflammatory.
  • These effective interventions combined can be enhanced by further optimizing brain metabolism and circulation based on appropriate tests.

Silicone breast implants and risk of lymphoma

Journal of AutoimmunitySilicone and possibly other substances used in the manufacture of breast implants can stimulate a chronic inflammatory reaction by the immune system. A paper just published in the Journal of Autoimmunity reviews evidence that the immune reaction to silicone in breast implants can promote the development of lymphoma. The authors note:

“The risk of hematological malignancies is mainly determined by genetic background, age, sex, race and ethnicity, geographic location, exposure to certain chemicals and radiation; along with the more recently proposed immune factors such as chronic inflammation, immunodeficiencies, autoimmunity, and infections. Paradigmatic examples include the development of lymphoma in Sjögren’s syndrome and Hashimoto thyroiditis, gastric MALT lymphoma in Helicobacter pylori infection, or lymphomas associated with infections by Epstein–Barr virus, human herpes virus 8 (HHV 8) and leukemia/lymphoma virus 1 (HTLV-1).”

Silicone implants stimulate an immune reaction

“A growing number of reports indicates an increased risk of lymphoma, particularly of the anaplastic large cell (ALCL) type. The implants, specifically those used in the past, elicit chronic stimulation of the immune system against the prosthetic material. This is particularly the case in genetically susceptible hosts. We suggest that polyclonal activation may result in monoclonality in those at risk hosts, ultimately leading to lymphoma.”

These key points emerge:

  • Chronic infection and inflammation have been implicated as the causative mechanisms in the development of lymphomas.
  • The connection between ALCL and breast implants has been hypothesized for several years. Since the earliest report in 1997, numerous cases were described, with 173 cases of breast-implant associated ALCL being recently reported.
  • An immune reaction to silicone or other substances used in manufacturing process of breast implants, might cause T cell infiltration with later clonal expansion of T lymphocytes. The T-cell response may be as well reaction to biofilms.
  • Skin injuries and Sjögren’s syndrome are two conceptual models providing intriguing insight to the connection between silicone implants and ALCL.

Patients with silicone breast implants should be monitored

Practitioners should keep in mind the authors’ conclusion and evaluate patients with silicone implants for chronic inflammation:

“We suggest that patients with an inflammatory response against silicone implants be monitored carefully.”

Insulin resistance indicated by neutrophil-lymphocyte ratio

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

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

Furthermore…

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

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

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

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

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

 Diabetes, cancer and cardiovascular diseases

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

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

Diabetes and chronic inflammation

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

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

 NLR tracks HgbA1c and triglycerides

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

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

NLR is a superior biomarker

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

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

Clinical bottom line

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

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

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

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

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

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

The authors’ data showed that…

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

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

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

Prevention: Metabolic syndrome and chronic kidney disease

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

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

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

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

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

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

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

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

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

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

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

Insulin resistance, of course, spurs chronic inflammation:

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

Sugar versus salt in hypertension and chronic kidney disease

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

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

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

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

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

This includes fructose:

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

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

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

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

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

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

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

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

Bottom line for chronic kidney disease

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