Hormone blockade therapy for prostate cancer entails risks of diabetes and cardiovascular disease

Posted on October 31, 2010 by Dr. Jonathan

A recent FDA MedWatch announcement alerts doctors to the increased risk of diabetes, heart attacks and strokes for patients with prostate cancer undergoing hormone blockade therapy, specifically treatment with Gonadotropin-Releasing Hormone (GnRH) agonists such as Lupron.

“Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.”

The normal action of gonadotropin-releasing hormone is to stimulate the secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle stimulating hormone) from the pituitary. These hormones in turn stimulate the production of testosterone and sperm by the testes. The GnRH agonists flood the pituitary receptors causing an inhibition of gonadotropin secretion in the same way that over-stimulation of any hormone receptor suppresses the system (as occurs with topical hormone replacement, insulin resistance, etc.)

Incidentally the FDA also notes:

“The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established.“

I have personally seen how GnRH agonists exacerbate tendencies for metabolic syndrome and cardiovascular disease and appreciate the seriousness of their advice to practitioners:

“Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice.”

Most US doctors are still not paying proper attention to blood sugar

Posted on October 30, 2010 by Dr. Jonathan

It’s disturbing and worrisome to see how few doctors seem to be alert to the blood sugar dysregulation that precedes type 2 diabetes and many other chronic diseases in their patients as evidenced by a study just published in the journal Diabetes Care. The authors conducted their investigation to…

“…estimate the rates of prevalence, diagnosis, and treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).”

They examined a representative sample of the U.S. population that included 1,547 nondiabetic adults without a history of heart attack to determine the proportion who met the criteria for IFG/IGT, and the proportion of them who: 1) received a diagnosis from their physicians; 2) were prescribed lifestyle modification or medication for blood sugar; or 3) were currently on therapy. Their data painted a dismal picture:

“Of the 1,547 subjects, 34.6% had pre-diabetes; 19.4% had IFG only; 5.4% had IGT only, and 9.8% had both IFG and IGT. Only 4.8% of those with pre-diabetes reported having received a formal diagnosis from their physicians. No subjects with pre-diabetes received oral antihyperglycemics, and the rates of recommendation for exercise or diet were 31.7% and 33.5%, respectively.”

Yikes. It’s really up to the patient to be informed (one of the purposes of this blog) and seek proper care. Blood sugar dysregulation wrecks almost everything that clinicians practicing according to the functional model try to do to correct brain, hormone and immune dysregulation. It’s importance as a clinical focus is hard to over-emphasize. The authors’ disappointment is almost palpable in their conclusion:

“Three years after a major clinical trial demonstrated that interventions could greatly reduce progression from IFG/IGT to type 2 diabetes, the majority of the U.S. population with IFG/IGT was undiagnosed and untreated with interventions. Whether this is due to physicians being unaware of the evidence, unconvinced by the evidence, or clinical inertia is unclear.”

Perhaps this says something about why the scientists who authored another paper in the same issue of Diabetes Care saw fit to ask whether sugar-sweetened beverages would contribute to the risk of metabolic syndrome and type 2 diabetes (!):

“Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.”

Their meta-analysis included 310,819 participants from 11 acceptable studies. It’s troubling to allow that there may be physicians who might not anticipate the conclusion that their data defined:

“In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.”

It seems that even fewer physicians and their patients are aware of the role of glucose in ‘feeding’ cancer and the research being done to block the metabolism of sugar by tumor cells as described in a paper just published in the journal Oncogene. The authors state:

“Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials.”

While research investigates possible interventions to aggressively interrupt the glycolytic metabolism of tumor cells, doctors should assist their patients in controlling blood sugar and insulin (another tumor promoter) with the appropriate tools:

“Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels…Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death…”

Blood sugar dysregulation contributes to most chronic diseases including cardiovascular, autoimmune, neurodegenerative and malignant conditions. Supporting healthy blood sugar and insulin regulation is one of the most important things that practitioners and their patients can do together.

Quercitin as effective as resveratrol for inflammation with diabetes and obesity

Posted on October 27, 2010 by Dr. Jonathan

There has been a lot of interesting science, some of it reported here, documenting the benefits of resveratrol for factors contributing to inflammation, insulin resistance, obesity, diabetes and longevity. A paper just published in the American Journal of Clinical Nutrition offers evidence that the valuable phenolic compound quercitin may be even more effective than resveratrol for reducing the inflammation associated with insulin resistance and diabetes. The authors state:

“Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes…The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes [fat cells] treated with tumor necrosis factor-{alpha} (TNF-{alpha})—an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.”

They stimulated fat cells with TNF-{alpha} to promote inflammation after pretreatment with quercetin and trans-RSV, then measured gene and protein markers of inflammation and insulin resistance. What did the data show?

Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-{alpha}–induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1… Quercetin, but not trans-RSV, decreased TNF-{alpha}–induced nuclear factor-{kappa}B transcriptional activity. Quercetin and trans-RSV attenuated the TNF-{alpha}–mediated suppression of peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}) and PPAR{gamma} target genes and of PPAR{gamma} protein concentrations and transcriptional activity….”

Quercitin is known to be helpful for gut inflammation associated with food allergies, and I have found it to be a surprisingly helpful palliative for airborne allergies. In light of this the authors’ conclusion is not a surprise:

“These data suggest that quercetin is equally ormore effective than trans-RSV in attenuating TNF- ${alpha}$ –mediatedinflammation and insulin resistance in primary human adipocytes.”

Magnesium, inflammation, insulin resistance and diabetes

Posted on October 26, 2010 by Dr. Jonathan

Magnesium is important for a multitude of functions and functional deficiencies of magnesium are extremely common. A study just published in the journal Diabetes Care illuminates the role of magnesium in the chronic inflammation associated with insulin resistance and diabetes. The authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

They examined 4,497 Americans, aged 18-30 years and without diabetes, for magnesium intake and the subsequent onset of diabetes; along with key inflammatory markers (high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen) and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“During 20-year follow-up, 330 incident diabetic cases were identified. Magnesium intake was inversely associated with incidence of diabetes [those with the lowest magnesium had 53% more chance of developing diabetes]…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

The association between magnesium and the inflammation markers hs-CRP, IL-6 and fibrinogen is significant for more than diabetes because chronic inflammation is a hallmark of most chronic diseases including cardiovascular disease and cancer. The same goes for insulin resistance as indicated by HOMA-IR. Serum magnesium is not a sensitive indicator of deficiency. Measuring magnesium concentration in the red blood cells is a more accurate representation. Urinary organic acids can also indicate when key metabolic pathways are impaired due to magnesium deficiency. Muscle cramps at rest are very often associated with magnesium deficiency and clear up when magnesium sufficiency has been restored.

Magnesium deficiency and death from cardiovascular disease

Posted on September 16, 2010 by Dr. Jonathan

Magnesium deficiency is so common that it’s hard to find individuals with optimal levels. A study just published in the American Heart Journal adds to the growing body if evidence for the great importance of magnesium in cardiovascular disease. The authors state:

“We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD).”

They assessed risk factors and levels of serum Mg in 14,232 45- to 64-year-old subjects and followed them for an average of 12 years. During that time there were 264 cases of SCD that they used to evaluate the association of serum Mg with risk of SCD. The data made a clear statement:

“Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD in quartile 4 versus 1 of serum Mg observed in the fully adjusted model.”

This is a potent result, summed by the authors’ conclusion:

“This study suggests that low levels of serum Mg may be an important predictor of SCD.”

A whole body of emerging research is illuminating the mechanisms by which suboptimal magnesium levels can have this effect. In a study just published in the journal Diabetes Care the authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

The authors followed 4,497 Americans aged 18-30 (who had no diabetes at the beginning) for 20 years. During that time they identified 330 cases of diabetes which they correlated with quintiles of magnesium intake. They also investigated the associations between magnesium intake and inflammatory markers including high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

As you know, these are powerful markers for cardiovascular disease risk. As the authors state in their conclusion:

“This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.”

An earlier paper published in the journal Magnesium Research documents how low magnesium in conjunction with high fructose consumption promotes inflammation associated with metabolic syndrome. The authors begin by observing:

“The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance.”

They present present experimental evidence showing that metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. The data they gathered showed that:

“…a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration.”

These findings remind of the recent research linking calcium supplementation to increased heart attacks. The authors conclude:

“Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.”

It goes without saying that these are primary inducers of cardiovascular disease. Another paper published last year in the same journal note the association of magnesium deficiency and C-reactive protein:

“Recent findings from epidemiologic studies support that magnesium intake is inversely associated with C-reactive protein concentration, an important marker of inflammation strongly associated with cardiovascular disease risk.”

A fascinating study published in the American Journal of the Medical Sciences investigates magnesium deficiency promotes inflammation and cardiovascular disease through neurogenic pathways:

“This review highlights some key observations that helped formulate the hypothesis that release of substance P (SP) [an inflammatory signalling molecule] during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses.”

The authors further state:

“…SP-mediated events may…facilitate development of in situ cardiac dysfunction, especially with prolonged dietary Mg restriction.”

Additional intriguing research published in the British Journal of Anaesthesia adds even more evidence to the assertion that magnesium helps reduce cardiovascular disease by opposing calcium. The authors begin by stating:

“Magnesium sulphate (MgSO4) has potent anti-inflammatory capacity. It is a natural calcium antagonist and a potent L-type calcium channel inhibitor. We sought to elucidate the possible role of calcium, the L-type calcium channels, or both in mediating the anti-inflammatory effects of MgSO4.”

And magnesium sulphate is not the most bioavailable form of magnesium supplementation. When the authors induced inflammation by exposure to lipopolysaccharide (LPS) as evidenced by macrophage inflammatory protein-2, tumour necrosis factor-α, interleukin (IL)-1β, IL-6, nitric oxide/inducible nitric oxide synthase, prostaglandin E2/cyclo-oxygenase-2, and NF-κB activation.

“MgSO4…significantly inhibited the LPS-induced inflammatory molecules production and NF-κB activation. Moreover, the effects of MgSO4 on inflammatory molecules and NF-κB were reversed by extra-cellular calcium supplement with CaCl2 and L-type calcium channel activator BAY-K8644.”

In other words, in addition to opposing inflammation, magnesium is nature’s calcium channel blocker. The authors conclude:

“MgSO4 significantly inhibited endotoxin-induced up-regulation of inflammatory molecules and NF-κB activation… The effects of MgSO4 on inflammatory molecules and NF-κB may involve antagonizing calcium, inhibiting the L-type calcium channels, or both.”

More evidence that metformin can cause vitamin B12 deficiency

Posted on July 4, 2010 by Dr. Jonathan

British Medical Journal Patients with advanced diabetes whose insulin receptors have sustained years of damaging insult sometimes require the medication metformin. Clinicians and patients alike need to bear in mind that metformin tends to cause a deficiency of the critical nutrient cofactor vitamin B12. Research just published in the British Medical Journal reminds us that this is not in question or a matter of opinion. The authors set out to…

“…study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin.”

Incidentally, this reference for vitamin B-12 is extremely low and far from optimal. After following 390 patients with type 2 diabetes who were treated with 850 mg metformin or placebo three times a day for 4.3 years, what did they conclude from their data?

“Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered.”

Do remember that serum B12 is not a reliable indicator. To ascertain that your genetic and circumstantial needs for this critical cofactor are actually being methylmalonic acid, measured in serum or urine, is much more reliable.

Inflammation and insulin resistance genes are activated by surgery

Posted on June 28, 2010 by Dr. Jonathan

This interesting paper recently published in the Journal of Clinical Endocrinology & Metabolism describes one of the reasons why support when undergoing a surgical procedure is so important (and links to the risks for delirium and accelerated dementia after surgery in the elderly). The authors set out to investigate the…

“…mechanisms behind postoperative insulin resistanceand impaired glucose utilization…”

They shrewdly analyzed the expression of 21 target genes in abdominal adipose (fat) tissue from samples taken at the beginning and end of patients undergoing abdominal surgery. What did the data show?

“After surgery, both sc [subcutaneous] and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced. TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue.”

In other words, surgery elicits a shift in genetic expression that favors insulin resistance and inflammation. The authors conclude:

“The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery…This could be of importance for the metabolic aberrations associated to postsurgical complications…”

This helps to understand why patients who are lucky enough to receive adjunctive support for the insulin and inflammatory signaling pathways and receptors recover faster and with less complications.

Metabolic syndrome (pre-diabetes) is as bad as diabetes for heart attack risk

Posted on June 24, 2010 by Dr. Jonathan

A study recently published in the Journal of the American College of Cardiology is provides more evidence that the insulin resistance and other aspects of metabolic syndrome leading up to but before diabetes has been established can already do sufficient damage to precipitate a heart attack.

“This study examines the risk of acute myocardial infarction (MI) conferred by the metabolic syndrome (MS) and its individual factors in multiple ethnic populations.”

The authors evaluated data from 26,903 subjects in 52 countries according to the World Health Organization (WHO) and International Diabetes Federation (IDF) criteria for MS, and correlated them with the occurrence of heart attack to calculate the odds. Crunching the numbers produced these results:

“Using the WHO definition, the association with MI by the MS is similar to that of diabetes mellitus and hypertension and significantly stronger than that of the other component risk factors…The IDF definition showed similar results.”

The practical conclusion to be drawn from this evidence is that the evaluation and treatment of metabolic syndrome in general and insulin resistance in particular is mandatory for realistic heart attack risk assessment and prevention.

Cholesterol crystals are a trigger for local and systemic inflammation. What then?

Posted on June 6, 2010 by Dr. Jonathan

There is an evidence-based middle ground between the dogmas of those who assert that cholesterol is the main cause of cardiovascular disease and those who insist that its contribution is trivial. An interesting paper just published in the Journal of Clinical Lipidology illustrates an important mechanism by which cholesterol crystals trigger an inflammatory response.

“The response to arterial wall injury is an inflammatory process, which over time becomes integral to the development of atherosclerosis and subsequent plaque instability…In this review, a model of plaque rupture is hypothesized with two stages of inflammatory activity.”

In the first stage buildup of cholesterol crystals inside the “foam” cells that accumulate cholesterol induces their death (“apoptosis”); these dead cells elicit an inflammatory response that gathers more lipids into a vulnerable plaque. In stage two further expansion of crystals leads to intimal (blood vessel wall) injury…

“…which can manifest as a clinical syndrome with a systemic inflammation response…We recently demonstrated that when cholesterol crystallizes from a liquid to a solid state, it undergoes volume expansion, which can tear the plaque cap. This observation of cholesterol crystals perforating the cap and intimal surface was made in the plaques of patients who died with acute coronary syndrome.”

The authors refer to their previous work showing that alcohol, aspirin and statins can dissolve cholesterol crystals. Their conclusion:

“…we propose that cholesterol crystallization could help explain in part both local and systemic inflammation associated with atherosclerosis.”

American Journal of Cardiology Of course there are a number of other pathways to inflammation in cardiovascular disease (please see related posts) but this is one of the reasons why I prefer that patients who have both high cholesterol and evidence of inflammation have the benefit of the natural statin derived from red rice yeast with the necessary supportive and protective cofactors including coenzyme Q10. This paper published recently in the American Journal of Cardiology provides evidence that red rice yeast is as effective and better tolerated than the commonly prescribed drug pravastatin:

“The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia.”

The authors enrolled adults who had to discontinue statins due to muscle pain. Their findings are reassuring for those who prefer a natural alternative to pharma statins:

“The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.”

This is a serious issue. Statin-associated myalgia or the diagnosis rhabdomyolysis does not do justice to the devastating side effects I recently observed in a patient who had a bad reaction to lovastatin.

Atherosclerosis But how do we know when to intervene since high cholesterol alone is not a reliable risk factor and CRP (c-reactive protein) may not be elevated if the inflammation it is supposed to report is also preventing the liver from making it? One very helpful test for discriminating whether high cholesterol is contributing to vascular disease is the lipoprotein-associated phospholipase A2 (Lp-PLA2, PLAC) test, described here in an earlier post, that is associated specifically with inflammation in plaques. Another relies on the fact that it is cholesterol that has been damaged by oxidation that participates in the vascular lesion. To gauge this we can measure lipid peroxides. As this paper published in the journal Atherosclerosis documents, atherosclerosis is strongly associated with the presence of oxidized LDL:

“We investigated the relation between serum lipids including oxidized LDL and the severity of coronary atherosclerosis. Serum lipids and oxidized LDL was measured in 62 men (33–66 years), who underwent diagnostic coronary angiography and sonography to measure the carotid intima-media thickness…Regression analysis indicated that the carotid intima-media thickness and…the ox-LDL:LDL ratio…were the only factors associated independently with the severity of coronary atherosclerosis.”

We have also a fascinating study just published in the German medical journal Seminars in Thrombosis & Hemostasis that shows how oxidized LDL taken up by platelets induces inflammation in the blood vessel:

“Platelets are involved in the initiation of atherosclerosis by adherence to inflamed endothelium…In this study we investigated the functional consequences of oxidized low-density lipoprotein (oxLDL) uptake on platelet function and interaction with the endothelium.”

The authors were actually able to visualize the intracellular vesicles (microscopic sacs) containing the oxidized LDL using immunoflorescence microscopy. They made a fascinating observation: the platelets containing oxLDL provoked more cellular stickiness than regular LDL, oxLDL in the bloodstream or platelets without oxLDL.

“Furthermore, oxLDL-laden platelets induced foam cell development from CD34+ progenitor cells. On endothelial regeneration, oxLDL-laden platelets had the opposite effect: The number of CD34+ progenitor cells (colony-forming units) able to transform into endothelial cells was significantly reduced in the presence of oxLDL-platelets, whereas native LDL had no effect.”

This is a striking insight: it was only the oxidized LDL that prevented the endothelial cells (lining the blood vessel wall) from repairing, not the ‘native’ LDL.

Doctors and patients alike need to bear in mind the summary of their findings:

“Our results demonstrate that activated platelets internalize oxLDL and that oxLDL-laden platelets activate endothelium, inhibit endothelial regeneration, and promote foam cell development. Platelet oxLDL contributes significantly to vascular inflammation and is able to promote atherosclerosis.”

Lipids But, you may ask, since diabetes and pre-diabetes (metabolic syndrome) are so strongly associated with cardiovascular disease shouldn’t there be some kind of connection here? This study published in the journal Lipids shows the evidence that there is.

“Oxidized low-density lipoprotein (ox-LDL) plays a key role in the progression of atherosclerosis and diabetes complications. The aim of this study was first, to evaluate the association between ox-LDL and diabetes duration, and second, to examine serum level of ox-LDL in patients with prolonged diabetes and a desirable LDL-cholesterol level.”

It’s important to appreciate that the study group had ‘regular’ LDL in the desirable range, so a typical blood test would appear to be fine. Their very interesting observation is that the longer the person had diabetes (= the longer the risk factor for cardiovascular disease was building up) the more oxLDL they had in proportion to regular LDL:

“The ox-LDL-to-LDL ratio was dramatically higher in patients with diabetes duration >5 years in comparison to newly diagnosed patients and healthy participants. Ox-LDL was significantly associated with diabetes duration.”

Their final comments must be borne in mind by anyone caring for patients with both diabetes and a significant burden of insulin resistance:

“In conclusion, this study showed that the serum ox-LDL level increases with the length of diabetes, even though the patients’ LDL-cholesterol level is maintained at a desirable level. Our findings highlight that possibly more attention should be focused on markers of oxidative stress in the management of lipids in diabetic patients.”

Can we reliably measure oxidized LDL as implied by the lab test mentioned above? This study published in the journal Blood Pressure assure us that we can:

“Cardiovascular diseases are accompanied by the presence of active oxygen species and organic free radical generation. The aim of this study was to examine the possibility of using malondialdehyde (MDA)-modified low-density lipoprotein (LDL) analyses as a diagnostic and prognostic biomarker.”

MDA-modified LDL is the same as oxLDL. What conclusion did they draw from their data?

“MDA-modified LDL estimation has a diagnostic accuracy and may be used as an independent biochemical marker for atherosclerosis.”

Truthfully, the functional approach to cardiovascular disease encompasses a number of other important aspects, but I’m wondering if you’ve gotten this far. As a reward for your diligence I’ll conclude this limited post with a few interesting items of satisfying practical significance. First we have a paper just published in The Journal of Steroid Biochemistry & Molecular Biology that reassures us of the benefit of vitamin D in the prevention and treatment of cardiovascular disease.

“Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). In type 2 diabetics, the prevalence of vitamin D deficiency is 20% higher than in non-diabetics, and low vitamin D levels nearly double the relative risk of developing CVD compared to diabetic patients with normal vitamin D levels.”

The authors endeavored to uncover the mechanism behind vitamin D’s benefit:

“We found that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] suppressed foam cell formation by reducing acetylated low density lipoprotein (AcLDL) and oxidized low density lipoprotein (oxLDL) cholesterol uptake in diabetics only. …In addition, 1,25(OH)2D3…improved insulin signaling, downregulated SR-A1 expression, and prevented oxLDL- and AcLDL-derived cholesterol uptake.”

You can remember their conclusion when getting your vitamin D level checked:

“The results of this research reveal novel insights into the mechanisms linking vitamin D signaling to foam cell formation in diabetics and suggest a potential new therapeutic target to reduce cardiovascular risk in this population.”

Throw some nuts in there too. A nice original study was published not long ago in The Anatolian Journal of Cardiology evaluated the benefit of hazelnuts (filberts) on atherosclerosis. The authors observed a number of interesting effects:

“Lag time for oxidation and α-tocopherol content of LDL were found to be increased while ox-LDL levels decreased during the study period. Total cholesterol, LDL-cholesterol, apolipoprotein (apo) B and apo B/apo AI ratio were found to be significantly lower while apo AI was higher. In respect to LDL subfraction, ratio of large/small LDL was significantly increased at the end of the study.”

They summed up their ‘take home’ message on hazelnuts (which earlier posts suggest applies to most if not all nuts) accordingly:

“Hazelnut-enriched diet may play important role in decrease in atherogenic tendency of LDL by lowering the susceptibility of LDL to oxidation and plasma ox-LDL levels, and increasing the ratio of large/small LDL beyond its beneficial effect on lipid and lipoprotein levels.”

Digestive Diseases and Sciences Helicobacter pylori infection is, as you likely know, extremely common—according to WHO the most common infection in the world. It is a causative agent in almost all gastric ulcers. We see it here all the time. Finding out if you have it and getting it treated is another important therapeutic point for cardiovascular disease as this paper just published in the journal Digestive Diseases and Sciences reminds us. The authors investigated the impact of H. pylori infection on coronary atherosclerosis by examining the effects of infection on levels of serum lipid, high-sensitivity C-reactive protein (hsCRP) and oxidized low-density protein (oxLDL). What did their data show?

“The levels of total cholesterol, LDL, apolipoprotein B, serum hsCRP, oxLDL were significantly elevated and the severity of coronary atherosclerosis was significantly increased in H. pylori…group.”

Their conclusion echoes the findings of other investigators:

“More serious coronary atherosclerosis was observed in CHD patients with H. pylori…infection. H. pylori…infection might be involved in coronary atherosclerosis by modifying serum lipids, enhancing LDL oxidation, and activating the inflammatory responses.”

Remember, the most reliable ways to diagnose H. pylori infection are by stool antigens, a provoked breath test, or PCR (DNA amplification). H. pylori antibodies are not dependable.

Although it’s a major topic that deserves more space, mention at least much be made of the autoimmune aspect of cardiovascular disease as described in this recent paper published in the journal Angiology:

“Atherosclerosis is now recognized as a chronic inflammatory disease and is characterized by features of inflammation at all stages of its development. It also appears to display elements of autoimmunity, and several autoantibodies including those directed against oxidized low-density lipoprotein (ox-LDL) and heat shock proteins (Hsps) have been identified in atherosclerosis.”

The authors then describe their investigation of immune complexes, antibodies and receptor signaling in this process. Certain cases demand a thorough evaluation of the autoimmune component of their CVD.

It would also not be appropriate to close without at least alluding to the influence of hormones on cardiovascular disease, a topic that has many aspects treated in other posts. This paper recently published in the journal Endocrinology makes a very important but little known point for men (for whom most everyone knows that too little testosterone or excess conversion to estrogen is a big risk factor for CVD). Testosterone is normally converted into its dihydrotestosterone form (DHT) which does a lot of the heavy lifting because it’s ten times stronger than the original. Men with prostate disease are commonly prescribed medications (including saw palmetto) that block the conversion of testosterone to DHT, but without first measuring the levels of the bioactive forms of these hormones. These medications don’t always help because not everyone with a prostate condition has too much DHT. Moreover, DHT is important for protection against cardiovascular disease. The authors…

“…investigated the effect of…dihydrotestosterone (DHT) on the rabbit atherogenesis in relation to…oxidized-low-density lipoprotein receptor-1 (LOX-1) and its downstream molecules.”

What did they find?

“…DHT significantly reduced HCD-induced [high cholesterol diet-induced] foam cell formation…DHT inhibited the formation of foam cells induced by oxidized low-density lipoprotein. Moreover, the expression of LOX-1 and inflammatory cytokines in the cultured macrophages was significantly suppressed by DHT.”

Inappropriately blocking the conversion of testosterone to DHT can thus open a door to cardiovascular disease. So remember, both gentlemen and ladies: no hormone interventions without measuring the free-fraction bioactive levels before and after!

Do nuts really help with diabetes and cardiovascular disease?

Posted on May 8, 2010 by Dr. Jonathan

The authors of this paper published in the British Journal of Nutrition begin by observing…

“The ability of nuts to improve the blood lipid profile and reduce the risk of CHD (coronary heart disease) is now well established. The interest that health effects of nuts have gained recently has brought the possible benefits of consuming nuts, such as improvement in the conditions of the metabolic syndrome, and their potential to prevent and control diabetes into focus.”

They report an important observation:

“Acute feeding studies indicate that nuts have minimal effects on rising postprandial blood glucose levels when eaten alone, and diminish the postprandial glycaemic response when consumed with high-glycaemic index carbohydrate foods in both normoglycaemic and type 2 diabetic individuals.”

This means that whether your blood sugar is still OK or has already gone too high, if you consume nuts with a meal or snack—even if it is, at least to a degree, more glycemic than desirable—the nuts will prevent your blood sugar from spiking too high and overstimulating the release of insulin. And eating nuts alone has a trivial effect on raising blood sugar.

The authors further note…

“Nuts have a healthy nutritional profile, high in MUFA (monounsaturated fatty acids) and PUFA (polyunsaturated fatty acids), are a good source of vegetable protein and are rich in fibre, vitamins and minerals….early data indicate that the inclusion of nuts in the diets of individuals with diabetes and the metabolic syndrome is warranted, in view of their potential to reduce CHD risk.”

However, don’t forget that tree nuts are among the more common food allergens.