Coffee polyphenols may suppress body fat accumulation

A research paper just published in the American Journal of Endocrinology and Metabolism adds to the list of potential benefits from coffee. The authors state:

“The prevalence of obesity is increasing globally, and obesity is a major risk factor for type 2 diabetes and cardiovascular disease. We investigated the effects of coffee polyphenols (CPP), which are abundant in coffee and consumed worldwide, on diet-induced body fat accumulation.”

They fed the animal subjects either a control diet, a high-fat diet, or a high-fat diet supplemented with 0.5% to 1.0% CPP for 2 to 15 weeks. What did the data show?

Supplementation with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, and infiltration of macrophages [inflammatory white blood cells] into adipose tissues. Energy expenditure evaluated by indirect calorimetry was significantly increased in CPP-fed mice.”

The authors delineated the details of the genetic expression and molecular signaling elicited by coffee polyphenols, concluding:

“These findings indicate that CPP enhances energy metabolism and reduces lipogenesis by downregulating SREBP-1c and related molecules, which leads to the suppression of body fat accumulation.”

Hypoglycemia as a cause of cardiovascular injury

While insulin resistance and pre-diabetic but elevated glucose levels are widely recognized as  contributors to cardiovascular disease, it is less well-known that hypoglycemia also damages the cardiovascular system. A study just published in the journal Diabetic Medicine reports on one of the mechanisms:

“Intensive glycaemic control increases the incidence of hypoglycaemia. We sought to define the effects of hypoglycaemia on aldosterone, a hormone involved in cardiovascular injury and baroreflex impairment.”

The authors examined the effects of hypoglycaemia and normal blood sugar (euglycemia) on aldosterone and plasma renin activity through the use of the hypoglycaemic hyperinsulinaemic clamp protocol in which the glucose is dropped in a controlled fashion with insulin. What did the data show?

“In Study 1, aldosterone increased approximately 2.5-fold during hypoglycaemic hyperinsulinaemia but did not rise with euglycaemic hyperinsulinaemia. In Study 2, aldosterone increased significantly at glucose levels of 2.8 mmol/l; this increase was amplified with glucose of 2.2 mmol/l. Aldosterone increases paralleled those of ACTH.”

Parallel increases of ACTH (adrenacorticotropic hormone) show that the aldosterone increase is part of the hypothalamus-pituitary-adrenal  axis reaction to hypoglycemia. Regarding the signficance for cardiovascular disease, the authors state in conclusion:

Hypoglycaemia increases aldosterone in a dose-dependent fashion…Because aldosterone activation of the mineralocorticoid receptor is implicated in the pathophysiology of cardiovascular injury, including vascular dysfunction, inflammation, baroreflex impairment and cardiac arrhythmias, these findings may be of relevance in individuals who experience hypoglycaemia.”

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

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

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

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 or more effective than trans-RSV in attenuating TNF-{alpha}–mediated inflammation and insulin resistance in primary human adipocytes.”

Magnesium, inflammation, insulin resistance and diabetes

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.

Why not skip breakfast?

Most readers here probably understand that the biological response to skipping breakfast does widespread damage to the body. It provokes a catabolic (‘tearing down’) sympathetic nervous system response as the brain forces the breakdown of muscle tissue with ‘fight or flight’ chemicals (catecholamine neurotransmitters) to satisfy its need for steady glucose (gluconeogenesis). Meanwhile, weight loss is defeated by the suppression of thyroid function as an adaptation to perceived ‘famine’. A study just published in the American Journal of Clinical Nutrition documents the long-term negative cardiovascular effects:

“The objective was to examine longitudinal associations of breakfast skipping in childhood and adulthood with cardiometabolic risk factors in adulthood.”

2184 Australian children were followed over a period of twenty years into young adulthood. Skipping breakfast was defined as not eating between 0600 and 0900. Differences in mean waist circumference and blood glucose, insulin, and lipid concentrations were calculated (after controlling for relevant confounding variables). What did the data show?

“…participants who skipped breakfast in both childhood and adulthood had a larger waist circumference and higher fasting insulin, total cholesterol, and LDL cholesterol concentrations than did those who ate breakfast…”

This certainly makes sense in consideration of the compensatory blood sugar and insulin reaction to the hypoglycemic state imposed by failing to ‘break’ the nighttime ‘fast’ in the morning.

The authors conclude by stating:

Skipping breakfast over a long period may have detrimental effects on cardiometabolic health. Promoting the benefits of eating breakfast could be a simple and important public health message.”

Metabolic syndrome accelerates prostate cancer

An important study just published in the Annals of Oncology adds more evidence of the exceptional importance of  metabolic syndrome for prostate cancer. The authors state:

Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer.”

They proceeded to examine the impact of metabolic syndrome on prostate cancer patients treated with androgen deprivation therapy (ADT, blocking the production or signaling of male hormones). Comparing the data between patients with and without metabolic syndrome for the average time to PSA progression and overall survival (OS) yielded a stark contrast:

Median time to PSA progression for patients with MS was 16 versus 36 months without MS. The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS.”

The authors sum up their evidence in the usual understated fashion:

“This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.”

It’s troubling to see how often clinicians fail to emphasize the great importance of blood sugar and insulin control when managing prostate cancer. Patients need to be aware that the lifestyle factors that address this are among the most important things they can do.

Alzheimer’s disease and insulin resistance

Evidence continues to accumulate for the role of insulin resistance and type 2 diabetes in Alzheimer’s disease. Research just published in Archives of Neurology add more certainty to the association. The authors observe:

Insulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu)…in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset.”

They structured their investigation by setting out to…

“…examine whether greater homeostasis model assessment insulin resistance (HOMA-IR) is associated with reduced resting CMRglu in areas vulnerable in AD in cognitively normal adults with newly diagnosed PD or T2D (PD/T2D), and to determine whether adults with PD/T2D have abnormal patterns of CMRglu during a memory encoding task.”

They correlated data on adults with glycemic criteria for pre-diabetes or T2DM (and normal controls) with PET imaging of brain glucose metabolism and memory tests. They also examined the cerebral metabolic glucose rate (CMRglu) during the memory task. What did the data show?

Greater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-hour OGTT glucose concentration, or apolipoprotein E {varepsilon}4 allele carriage…Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.”

Their conclusion suggests both the role of insulin resistance in the development of AD as well as its use as an early indicator of risk:

Insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of mild cognitive impairment.

Interestingly, these findings were published along with another study in the same journal that reports on the accuracy of a constellation of blood test indicators for early diagnosis of AD. The authors set out…

“To develop an algorithm that separates patients with Alzheimer disease (AD) from controls.”

They analyzed serum protein–based biomarker data from 197 patients diagnosed with AD and compared it them 203 normal controls. The statistical analyses they used to create a biomarker risk score included a number of analytes that can be linked to insulin resistance and inflammation, including fibrinogen, interleukin-10, and C-reactive protein. When the numbers were crunched their biomarker risk score was highly accurate:

“The biomarker risk score had a sensitivity and specificity of 0.80 and 0.91, respectively, and an area under the curve of 0.91 in detecting AD [identified 80% with AD, excluded 91% without]. When age, sex, education, and APOE status were added to the algorithm, the sensitivity, specificity, and area under the curve were 0.94 [94%}, 0.84 [84%], and 0.95, respectively.”

This is very valuable because other proposed tests involve lumbar puncture for cerebrospinal fluid or expensive neuorimaging, both with obvious drawbacks. The authors’ conclusion also highlights the importance of inflammation (vascular and otherwise, associated with insulin resistance) in the development of AD:

“These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD. A disproportionate number of inflammatory and vascular markers were weighted most heavily in the analyses…suggesting the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients.”

Carbohydrates and death from inflammatory disease

As the authors of research just published in the American Journal of Clinical Nutrition state:

“Several studies suggest that carbohydrate nutrition is related to oxidative stress and inflammatory markers.”

The proceeded to examine whether dietary glycemic index (GI), dietary fiber, and carbohydrate-containing food groups were associated with death due to non-cardiovascular, non-cancer inflammatory disease in 1490 postmenopausal women and 1245 men. What did their data show?

“Over a 13-y period, 84 women and 86 men died of inflammatory diseases. Women in the highest GI tertile had a 2.9-fold increased risk of inflammatory death…Increasing intakes of foods high in refined sugars or refined starches and decreasing intakes of bread and cereals or vegetables other than potatoes also independently predicted a greater risk. In men, only an increased consumption of fruit fiber and fruit conferred an independent decrease in risk of inflammatory death.”

In other words, for postmenopausal women the high glycemic index diet almost tripled the risk of death from inflammatory disease.