Insulin resistance increases cardiovascular disease

Insulin resistance (IR), resistance of the insulin receptor due to overstimulation, elicits a rise of insulin levels to overcome the reduced receptor sensitivity. The resulting elevated insulin levels damage tissues throughout the body, and are a major contributing cause of cardiovascular disease. This is well known to many practitioners, so it was disturbing to read an article in the New York Times describing endocrinologists who are baffled by the fact that medications for type 2 diabetes that increase insulin levels worsen the risk for cardiovascular disease. The wealth of scientific evidence has been accumulating for a long time.

Insulin resistance and coronary artery disease

Insulin resistance and CADA study published in 1996 in the journal Diabetologia described the strong connection between CAD (coronary artery disease) and insulin resistance with its consequent hyperinsulinemia.

“The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance.”

Of particular interest is that all the study subjects, both those with CAD and controls, had a normal oral glucose tolerance test. HOWEVER…

Fasting plasma insulin concentration and area under the plasma insulin curve following glucose ingestion were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal. The magnitude of insulin resistance was positively correlated with the severity of CAD.”

It is hard to over emphasize the importance to clinicians of being vigilant in recognizing insulin resistance in the presence of normal glucose levels.

“In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or ’syndrome X’.

Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease

In 1991 a paper published in Diabetes Care described how insulin resistance promotes multiple factors that cause atherosclerosis.

“Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found.”


“…insulin resistance…correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells.”

It is also well-known that IR with its hyperinsulinemia cause elevated lipid levels.

Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic.”

And elevated insulin directly fosters atherosclerosis:

“Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.”


Controlling insulin resistance more important than glucose or LDLA more recent study in Diabetes Care presents striking data demonstrating the massive impact reduction in heart attacks that would occur by preventing insulin resistance. In setting out to determine what portion of coronary artery disease is caused by IR, the authors used data from the National Health and Nutrition Examination Survey 1998–2004 to simulate a population representative of young adults in the U.S. They applied the Archimedes model was to estimate the proportion of heart attacks that would be prevented by maintaining insulin resistance at healthy levels. Their data painted a dramatic picture:

“In young adults, preventing insulin resistance would prevent ∼42% of myocardial infarctions. The next most important determinant of CAD is systolic hypertension, prevention of which would reduce myocardial infarctions by ∼36%. Following systolic blood pressure, the most important determinants are HDL cholesterol (31%), BMI (21%), LDL cholesterol (16%), triglycerides (10%), fasting plasma glucose and smoking (both ∼9%), and family history (4%).”

Preventing insulin resistance beat the pants off controlling LDL cholesterol and smoking! Interestingly, they found that the effects were especially important for women:

“The effects of insulin resistance are also affected by sex. Today’s young men face a higher rate of myocardial infarctions than today’s young women: 55 vs. 32%. However, insulin resistance plays a larger relative role in women than in men, with normalization of insulin resistance reducing the myocardial infarction rate ∼57% for women (from 32 to 14%), compared with ∼29% (from 55 to 39%) for men.”

Preventing insulin resistance carries more weight than controlling glucose

In their conclusion the authors make points that are crucial for clinicians to bear in mind:

“Of the risk factors that we believe are sufficiently well studied to permit quantitative analysis, insulin resistance is the most important single risk factor for CAD. Our results indicate that insulin resistance is responsible for approximately 42% of myocardial infarctions. Its effect on CAD is indirect, mediated through its effects on other variables such as SBP, HDL cholesterol, triglycerides, glucose, and apoB.”

Effect of insulin resistance on myocardial infarction

In comparing their results with other research, the authors highlight the critical error made by depending on medications that increase insulin to control glucose:

“Our results are not directly comparable with those of clinical trials, where the effects of glucose lowering on CAD were either much smaller or null. The reason is that in the clinical trials, the focus was on lowering blood glucose—not preventing or curing insulin resistance. The drugs used in the trials either lowered glucose without affecting insulin resistance (e.g., sulfonylureas and insulin) or lowered insulin resistance to some extent but did not eliminate it (e.g., metformin and rosiglitazone). Furthermore, we normalized insulin resistance over the entire lifetimes of the subjects, whereas the treatments in the trials were given only after individuals had developed diabetes and were given only for the limited durations of the studies. Thus, the results of the trials do not represent the full eff

ect of normalizing insulin resistance and are actually consistent with our results.”

Note the implication that cardiovascular damage by IR occurs long before losing glucose control and crossing the border into diabetes territory.

Insulin resistance without diabetes causes cardiovascular disease

Investigators publishing in PLoS One make the same point about cardiovascular damage caused by IR well before diabetes sets in.

“To enable a comparison between cardiovascular disease risks for glucose, insulin and HOMA-IR, we calculated pooled relative risks per increase of one standard deviation…We included 65 studies (involving 516,325 participants) in this meta-analysis. In a random-effect meta-analysis the pooled relative risk of CHD (95% CI; I2) comparing high to low concentrations was 1.52 (1.31, 1.76; 62.4%) for glucose, 1.12 (0.92, 1.37; 41.0%) for insulin and 1.64 (1.35, 2.00; 0%) for HOMA-IR. The pooled relative risk of CHD per one standard deviation increase was 1.21 (1.13, 1.30; 64.9%) for glucose, 1.04 (0.96, 1.12; 43.0%) for insulin and 1.46 (1.26, 1.69; 0.0%) for HOMA-IR.”

They concluded that insulin resistance (HOMA-IR) was the leading culprit:

“The relative risk of cardiovascular disease was higher for an increase of one standard deviation in HOMA-IR compared to an increase of one standard deviation in fasting glucose or fasting insulin concentration.”

The authors also demonstrate that IR is a much better biomarker than fasting insulin:

 “The present meta-analyses showed that fasting glucose, fasting insulin and HOMA-IR were all associated with incident cardiovascular disease in individuals without diabetes. In a standardized meta-analysis we found that coronary heart disease risk increased with 46% for an increase of one standard deviation in HOMA-IR concentration compared to an increase of 21% for fasting glucose concentration and an increase of 4% for fasting insulin concentration.”

Insulin resistance causes fat expansion and vascular endothelial damage

An excellent paper published in Arteriosclerosis, Thrombosis, and Vascular Biology details how IR causes cardiovascular disease beyond abnormal glucose, lipids, hypertension, and its proinflammatory effects.

“…insulin’s action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications.”

The authors describe how IR causes vascular inflammation and atherosclerosis:

“Insulin action directly on vascular endothelial cells affects endothelial function beyond regulating blood flow or capillary recruitment. Conditional knockout of the insulin receptor in endothelial cells causes a 2- to 3-fold increase in the atherosclerotic lesion size in apolipoprotein E–null mice…the increased atherogenesis in this model can be attributed to insulin action directly on endothelial cells rather than effects mediated through systemic parameters. The accelerated atherosclerosis in mice with endothelial cell insulin receptor knockout is preceded by a dramatic increase in leukocyte rolling and adhesion to endothelium and an increase in expression of vascular cell adhesion molecule-1…insulin signaling independent of NO is responsible for this effect.”

They state that IR promotes the necrotic core at the heart of vulnerable plaque:

Insulin resistance in macrophages, however, promotes formation of a necrotic core in atherosclerotic plaques by enhancing macrophage apoptosis. This is an important event in advanced atherosclerosis because exposure of the necrotic core to circulating blood in the event of plaque rupture can precipitate thrombosis, leading to unstable angina pectoris, transitory cerebral ischemia, stroke, or myocardial infarction.”

Regarding cardiomyocyte function…

“…it is likely that the changes in metabolic substrate inflexibility and increased mitochondrial production of oxidants caused by cardiomyocyte insulin resistance can contribute to development of heart failure in the metabolic syndrome.”

The authors conclude with important clinical points:

“Research on insulin receptor signaling using tissue–specific gene manipulation in mice as well as other methods has provided important insights into insulin action and revealed insulin effects in tissues that a decade or 2 ago were considered nonresponsive to insulin….insulin sensitizers would theoretically have better profiles of action if they improved insulin resistance in tissues regulating glucose and lipid metabolism, as well as in the endothelium and other vascular tissues where impaired insulin signaling is proatherosclerotic independent of metabolic effects. Second, insulin analogues should be carefully evaluated for deleterious effects on insulin signaling pathways which are not affected by insulin resistance, such as those pathways which promote dyslipidemia or increase vascular expression of endothelin-1.”

Insulin resistance promotes advanced plaque progression

A paper published in Cell Metabolism details additional mechanisms by which IR promotes atherosclerosis. The authors note that…

“…the pathophysiological processes involved in the initiation and progression of early lesions are quite different from those that cause the formation of clinically dangerous plaques,…advanced plaque progression is influenced primarily by processes that promote plaque necrosis and thinning of a collagenous “scar” overlying the lesion called the fibrous cap… and distinguishing the effects of insulin resistance and hyperglycemia on these processes is critically important.”

They echo other investigators who point out the crucial fact that insulin resistance does damage before glucose control is lost:

“There is ample clinical evidence that insulin resistance increases the risk for coronary artery disease (CAD) even in the absence of hyperglycemia. Insulin resistance syndromes can promote both atherogenesis and advanced plaque progression, and the mechanisms likely involve both systemic factors that promote these processes, particularly dyslipidemia but also hypertension and a proinflammatory state, as well as the effect of perturbed insulin signaling at the level of the intimal cells that participate in atherosclerosis, including endothelial cells, vascular smooth muscle cells, and macrophages.”

They highlight the critical clinical implication that insulin resistance also entails overstimulation of various tissues by insulin elevated in compensation for receptor resistance or by insulin-elevating medications:

“…“insulin resistance” can mean either defective insulin receptor signaling or, ironically, overstimulation of insulin receptor pathways caused by hyperinsulinemia.”

They also note the difference between ‘ordinary’ atherosclerosis and the lesions, vulnerable plaque, that actually cause heart attacks and ischemic strokes.

“Most importantly, the primary objective of this study was to address an entirely different question, namely, the effect of myeloid IR deficiency on advanced lesional macrophage apoptosis and plaque necrosis. Recall that most atherosclerotic lesions in humans do not cause acute coronary artery disease, because they undergo outward remodeling of the arterial wall, which preserves lumen patency, and do not undergo plaque rupture or erosion and thus do not trigger acute lumenal thrombosis. The small percentage of lesions that do cause acute vascular disease are distinguished by the presence of large areas of necrosis and thin fibrous caps, which promote plaque disruption, acute lumenal thrombosis, and tissue infarction. This concept is particularly important for the topic of this review, because advanced atherosclerotic lesions in diabetic subjects are characterized by large necrotic cores when compared with similarly sized lesions from nondiabetic individuals”

In their conclusion the authors state the role of insulin resistance over hyperglycemia:

“These studies have provided evidence that insulin resistance in macrophages and endothelial cells may play important roles in both atherogenesis and clinically relevant advanced plaque progression. Hyperglycemia, on the other hand, appears to primarily promote early stages of lesion formation…”

Insulin resistance inhibits nitric oxide synthase

An interesting paper published in the Italian journal Panminerva Medica further elucidates key mechanisms, including the damage by IR to nitric oxide regulation done by increasing asymmetric dimethylarginine, which inhibits nitric oxide synthase. The author includes this under the rubric ‘insulin resistance syndrome’.

“…the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration….Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome.”

Specifically in regard to cardiovascular disease…

“…in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension.”


“The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects.”


A paper published in Diabetes Metabolism Research and Reviews draws this point further.

“In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism.”

And a vicious cycle ensues…

“Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction.”

In their conclusion the authors state:

“…endothelial dysfunction and insulin resistance commonly occur together and can be detected early in the pathogenesis of atherosclerosis. Insulin resistance can be inferred by the presence of a cluster of metabolic and cardiovascular abnormalities known collectively as the metabolic syndrome or by direct measurement of impaired insulin-stimulated glucose and lipid metabolism . Endothelial dysfunction can be documented by the demonstration of inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries. Lack of endothelial-derived NO may provide the link between insulin resistance and endothelial dysfunction.”

Plea to clinicians

Many resources are available for practitioners to apply a functional medicine model of objectively targeted treatment to resuscitate insulin receptor function and address lifestyle issues, especially diet, for the management of type 2 diabetes that minimizes the use of agents that lower glucose by increasing insulin, and therefore insulin resistance. It is my sincere wish that not only endocrinologists, but all clinicians, recall the mechanisms by which medications that promote insulin resistance increase cardiovascular disease, and act accordingly to protect their patients.

Insulin resistance is a huge topic, and there are numerous posts here pertaining to IR an conditions as diverse as Alzheimer’s disease and breast cancer that can be viewed by using the search box. They include the earlier post on the correlation of IR with blood vessel damage leading to heart attack and stroke.

Magnesium mediates insulin resistance, diabetes risk

Magnesium, insulin resistance and diabetesMagnesium is required for hundreds crucial functions, not least of which are its calming, parasympathetic nervous system supporting and anti-inflammatory effects. Patients in our practice are also informed that a good magnesium level is necessary for insulin receptor function, further evidence for which has just been published in the journal Diabetologia. The results of this study demonstrate a causal role for low magnesium in diabetes and prediabetes, especially through insulin receptor resistance.

Magnesium and diabetes

An association with diabetes has long been observed, but questions have remained regarding whether this is a cause or an effect. For this reason the authors investigated its role in prediabetes.

“Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk.”

 Prediabetes and insulin resistance

They examined data from 8555 subjects for an association with prediabetes/diabetes, and further sought to determine if genes influence diabetes risk through serum magnesium levels. They also aimed to determine how much of the effect is mediated through insulin resistance  by HOMA-IR). Their data show a robust role in regulating insulin receptor function and effect on diabetes risk.

A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation…significantly influenced diabetes risk and for CNNM2, FXYD2, SLC41A2 and TRPM6 this risk was completely mediated by serum magnesium levels.”

Condensing these results they state:

“In this large population-based cohort, we found that over a median follow-up of almost 6 years, low serum magnesium levels are associated with an increased risk of prediabetes, with comparable risk estimates to that of diabetes. Furthermore, we found that common genetic variants in magnesium-regulating genes influence diabetes risk and that this risk is mediated through serum magnesium levels.”

In the clinic

Practitioners are aware of two well-known facts: serum magnesium is a poor, insensitive biomarker for sufficiency; and clinical insufficiency is extremely common. (Even RBC membrane levels are not as dependable as the EXA test—see under ‘Useful Links’.) Thus when serum magnesium is suboptimal it should be diligently attended to by the clinician.

The authors conclude:

“…we found that low serum magnesium levels are associated with an increased risk of prediabetes, with similar effect estimates as compared with diabetes. The effect of serum magnesium on prediabetes and diabetes risk is partly mediated through insulin resistance. Furthermore, common genetic variation in magnesium regulating genes TRPM6, CLDN19, SLC41A2, CNNM2 and FXYD2 significantly modify the risk of diabetes through serum magnesium levels. Both findings support a potential causal role of magnesium in the development of diabetes...”

Insulin in the brain affects cognition, appetite and weight

Nature Reviews EndocrinologyInsulin has long been known as crucial for muscle, liver and adipose tissue metabolism. It’s effect in the brain on cognition, behavior and physiology is a more recent focus described in an excellent paper published recently in Nature Reviews Endocrinology.

The brain is sensitive to insulin

Since glucose uptake into the brain occurs independently it took a while to recognize the function of the receptors that are found there. The first clue came with the brain-specific knockout mouse model of the insulin receptor.

“Such knockout mice became obese due to increased food intake and developed whole-body insulin resistance with increased plasma levels of insulin and dyslipidaemia.”

Insulin-sensitive brain areasThen investigations comparing infusion of insulin versus saline on human brain activity has widespread effects.

“…these studies provided strong evidence that systemic insulin administration modulates cortical brain activity in humans…not only homeostatic areas (as shown in animal studies) but also higher functional areas involved in sensory and cognitive processes.”

And intranasal administration was shown to affect basal and evoked brain activity. How does it naturally get there?

Whole body insulin resistance affects the brain

“…various studies in animals clearly demonstrated that insulin was transported across the blood–brain barrier by a saturable transport system…”

And it humans it gets from the CSF (cerebrospinal fluid) through the BBB (blood brain barrier).

“Concentrations of insulin in the CSF increase when the hormone is administered into the bloodstream, again indicating transport across the blood–CSF barrier.”

Importantly, insulin resistance in the rest of the body affects the brain, and this has been associated with Alzheimer’s disease.

Insulin transport into CSF is attenuated in individuals with reduced whole-body insulin sensitivity, which suggests that insulin resistance at the blood–CSF barrier could impair transport of the hormone into the brain. Accordingly, insulin concentrations in CSF are lower in individuals with obesity, who are generally more insulin resistant, than in people without obesity. Furthermore, insulin concentrations within brain tissue and CSF are reduced in older individuals…In Alzheimer disease, a condition often associated with insulin resistance, insulin levels in the CSF have been reported to be reduced.”


Skipping breakfast worsens blood glucose and insulin later

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

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

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

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

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

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

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

Prostate cancer metastasis, insulin and IL-17

The ProstateProstate cancer risk factors include high levels of insulin and chronic inflammation. An insightful study just published in the journal Prostate reveals an additional mechanism by which they promote prostate cancer metastasis. The authors state:

Extravasation is a critical step in cancer metastasis, in which adhesion of intravascular cancer cells to the vascular endothelial cells is controlled by cell surface adhesion molecules. The role of interleukin-17 (IL-17), insulin, and insulin-like growth factor 1 (IGF1) in adhesion of prostate cancer cells to the vascular endothelial cells is unknown, which is the subject of the present study.”

They analyzed human umbilical vein endothelial cells (HUVECs) and human prostate cancer cell lines (PC-3, DU-145, LNCaP, and C4–2B) for expression of vascular cell adhesion molecule 1 (VCAM-1), integrins, and cluster of differentiation 44 (CD44) to observe the effects of IL-17, insulin, and IGF1 on VCAM-1 expression and adhesion of prostate cancer cells to HUVECs.

IL-17 and autoimmunity

Practitioners should bear in mind that IL-17 is a key player in autoimmune inflammation, and that diffuse inflammatory phenomena that appear long before evolving into a well-differentiated diagnosis of specific autoimmune disease. This phenomenon appears to now be clinically ubiquitous and a factor in most complex chronic disorders. Insulin, of course, is in excess a well-known tumor promoter.

IL-17 and insulin together significantly promote prostate cancer metastasis

The authors’ data reveals that IL-17 and insulin help prostate cancer cells stick the lining of blood vessels, an important step in metastasis:

Insulin and IGF1 acted with IL-17 to increase VCAM-1 expression in HUVECs…When HUVECs were treated with IL-17, insulin or IGF1, particularly with a combination of IL-17 and insulin (or IGF1), adhesion of PC-3 and DU-145 cells to HUVECs was significantly increased. In contrast, adhesion of LNCaP and C4–2B cells to HUVECs was not affected by treatment of HUVECs with IL-17 and/or insulin/IGF1.”

This revelation reminds clinicians to be attentive to the hazardous combination of chronic IL-17 mediated low grade inflammation due to loss of immune tolerance plus insulin resistance. The authors conclude:

“CD44-VCAM-1 interaction mediates the adhesion between prostate cancer cells and HUVECs. IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through increasing VCAM-1 expression in the vascular endothelial cells. These findings suggest that IL-17 may act with insulin/IGF1 to promote prostate cancer metastasis.”

Prediabetes increases cancer risk

DiabetologiaPrediabetes, elevated levels of blood sugar that are still ‘within’ the normal range, increases cancer risk among its mob of other afflictions as further validated by a meta-analysis just published in Diabetologia. The authors state:

Prediabetes is a general term that refers to an intermediate stage between normoglycaemia and overt diabetes mellitus. It includes individuals with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or a combination of the two. In 2003, the ADA redefined the range of fasting plasma glucose (FPG) concentration for diagnosing IFG from 6.1– 6.9 mmol/l to 5.6–6.9 mmol/l [101-124 mg/dL] in order to better identify individuals at risk of developing diabetes.”

Because this lower range has been disputed with inconsistencies in previous studies, the authors set out to…

“…to evaluate the putative association between different definitions of prediabetes and risk of cancer.”

Their data adds yet more weight to the vital clinical importance of regulating blood sugar and insulin:

“In this meta-analysis of 16 prospective cohort studies comprising more than 890,000 individuals, we found that the presence of prediabetes at baseline was significantly associated with increased risks of cancer in the general population, particularly for liver cancer and stomach or colorectal cancer. The risks were increased when a lower FPG value of 5.6– 6.9 mmol/l [101-124 mg/dL] was used, according to the current ADA definition of IFG, as well as in participants with IGT. The results were consistent across cancer endpoints, age, study characteristics, follow-up duration and ethnicity.”

Much has been written here about the importance of glucose and insulin regulation for a wide range of conditions. The authors echo these themes in comments about likely mechanisms:

Hyperglycemia, advanced glycation end-products and oxidative damage

“First, chronic hyperglycaemia and its related conditions, such as chronic oxidative stress and the accumulation of advanced glycation end-products, may act as carcinogenic factors. It has been reported that diabetes is associated with an increased production of reactive oxygen species and greater oxidative damage to DNA. Recently, it has also been reported that the overall frequency of DNA damage and cytotoxicity correlates with the level of HbA1c in people with prediabetes.”

Insulin resistance

“Second, insulin resistance is a core defect responsible for the development of diabetes, and is established in individuals with prediabetes. The compensatory hyperinsulinaemia and increased level of bioavailable IGF 1 related to insulin resistance may promote the proliferation of cancer cells and may also relate to worsened cancer outcomes.”


Third, genetic ‘interferences’ may also play an important role in the development of cancer in prediabetic individuals. A recent study has suggested that nuclear receptor coactivator 5 is a haploinsufficient tumour suppressor, and that a deficiency of nuclear receptor coactivator 5 increases susceptibility to both glucose intolerance and hepatocellular carcinoma, partially by increasing IL-6 expression.”

The public health implications of their results are enormous:

“These findings have important clinical and public health implications. In the US population aged ≥18 years, the age- adjusted prevalence of prediabetes increased from 29.2% in 1999–2002 to 36.2% in 2007–2010. Considering the high prevalence of prediabetes, as well as the robust and significant association between prediabetes and cancer dem- onstrated in our study, successful intervention in this large population could have a major public health impact. The ADA suggest that lifestyle intervention is the mainstay of treatment for prediabetes in the general population, and metformin is recommended for delaying progression to overt diabetes if individuals present with other related risk factors, such as a BMI ≥35 kg/m2, dyslipidaemia, hypertension, a family history of diabetes or an HbA1c >6% (42 mmol/mol)]. It should be noted that metformin is now considered as having some ‘protective’ anticancer properties. Notably, metformin mediates an approximately 30% reduction in the lifetime risk of cancer in diabetic patients. However, whether this is true in prediabetic individuals is not yet known. Long-term, large- scale studies of high-risk individuals, especially those with IGT or a combination of IGT and IFG, are urgently needed…”

Of course, functional practitioners have a number of resources besides metformin to help recover insulin sensitivity and restore healthier blood glucose regulation. The authors conclude:

“Overall, prediabetes was associated with an increased risk of cancer, especially liver, endometrial and stomach/colorectal cancer.’

Inflammation and diabetes

Diabetes Research and Clinical PracticeConsidering that chronic inflammation is a key common denominator in diabetes, prediabetes (metabolic syndrome) and cancer, it’s edifying to reflect on a paper published recently in Diabetes Research and Clinical Practice:

“It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes.”

Cognitive decline: major overlooked causes

Cognitive decline, the insidious thief of quality of life in its milder forms and appalling despoiler of human qualities in more advanced dementia and Alzheimer’s disease, is fueled by NEJM Journal Watchbiological causes that have not received adequate attention as noted in an editorial in NEJM Journal Watch under the title What Most Causes Cognitive Decline Is Not What We’ve Been Looking For. Stating…

“The most common factors are not the common degenerative diseases.”

Annals of Neurology…the editor is commenting on a study just published in Annals of Neurology in which the authors examined whether the commonly assumed causes were largely to blame:

“The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline.”

They correlated measures of Alzheimer pathology (amyloid load and tangle density), cardiovascular disease (macroscopic and microscopic infarcts) and Lewy bodies with global cognitive decline in the brains of 856 deceased subjects. While important, these measures failed to accounted for the bulk of it:

“In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline.”

In other words, there’s a lot more contributing to cognitive decline than the Alzheimer’s form of dementia and strokes. The authors conclude:

“The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.”


Neurology Vol 81 Num 20Of particular importance because this risk factor is relatively easy to modify is another study,  just published this time in Neurology, showing that glucose levels when only mildly elevated contribute to cognitive decline. The authors determined to see if there is a correlation between HgbA1c (hemoglobin A1c), memory and brain atrophy (specifically in the hippocampus, the ‘center’ for short-term memory) at mildly elevated, non-diabetic levels of glucose:

“For this cross-sectional study, we aimed to elucidate whether higher glycosylated hemoglobin (HbA1c) and glucose levels exert a negative impact on memory performance and hippocampal volume and microstructure in a cohort of healthy, older, nondiabetic individuals without dementia.”

They tested memory, fasting HbA1c, glucose, and insulin and did MRI scans for hippocampal volume and microstructure in 141 subjects:

Lower HbA1c and glucose levels were significantly associated with better scores in delayed recall, learning ability, and memory consolidation. In multiple regression models, HbA1c remained strongly associated with memory performance. Moreover, mediation analyses indicated that beneficial effects of lower HbA1c on memory are in part mediated by hippocampal volume and microstructure.”

There is really no excuse for clinicians to not make glucose and insulin regulation a top priority in case management for healthy aging and prevention of cognitive decline. The authors conclude:

“Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials.”


Biological PharmacologyThe authors of a paper published in Biological Pharmacology associate insulin with the crucial issue of neuroinflammation.

“The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer’s disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill-equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of α-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients’ cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer’s disease, and the treatment approaches they provide.”

Altered cytokine-insulin axis in neurodegenerative diseaseThey underline a connection between inflammatory cytokines, insulin resistance in the brain and neurodegeneration:

“A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier.”


Neuroscience ResearchCommenting on the importance of neuroinflammation, the authors of a paper published in Neuroscience Research state:

Neuroinflammation is central to the common pathology of several acute and chronic brain diseases. This review examines the consequences of excessive and prolonged neuroinflammation, particularly its damaging effects on cellular and/or brain function, as well as its relevance to disease progression and possible interventions. The evidence gathered here indicates that neuroinflammation causes and accelerates long-term neurodegenerative disease, playing a central role in the very early development of chronic conditions including dementia. The wide scope and numerous complexities of neuroinflammation suggest that combinations of different preventative and therapeutic approaches may be efficacious.”

They articulate these critical highlights:

  • Neuroinflammation is central to the common pathology of diseases/disorders.
  • Neuroinflammation causes acute brain cell death.
  • Neuroinflammation causes and accelerates long-term neurodegenerative disease.
  • Preventative and therapeutic approaches are needed to dampen-down neuroinflammation.


Frontiers In Integrative NeuroscienceA paper recently published in Frontiers In Integrative Neuroscience expands of the role of neuroinflammation in Alzheimer’s disease:

“Although there are different genetic and environmental causes, all patients have a similar clinical behavior and develop identical brain lesions: NFTs (neurofibrillary tangles) consisting of Tau (τ) protein and NPs (neuritic plaques) consisting of amyloid-β (Aβ) peptides. These alterations are the final result of post-translational modifications and involve different genes and render AD as a complex multigenic neurodegenerative disorder.”

The identify the activation of inflammation by amyloid-β as a pivotal step:

“In addition to this multi-genic complexity in AD, now we know that Aβ promotes an inflammatory response mediated by microglia and astrocytes, thus activating signaling pathways that could lead to neurodegeneration…Although it was previously thought that the central nervous system (CNS) was an immune-privileged site, now is well known that certain features of inflammatory processes occur normally in response to an injury, infection or disease. The resident CNS cells generate inflammatory mediators, such as pro-inflammatory cytokines, prostaglandins (PGs), free radicals, complement factors, and simultaneously induce the production of adhesion molecules and chemokines, which could recruit peripheral immune cells. This review describes the cellular and molecular mediators involved in the inflammatory process associated with AD and several possible therapeutic approaches describe recently.”

Inflammation in Alzheimer's diseaseThey summarize their extensive review of this topic:

“…inflammation induced by Aβ has an important role in the neurodegenerative process. The inflammatory process itself is driven by microglial and astrocytic activation through the induction of pro-inflammatory molecules and related signaling pathways, thus leading to synaptic damage, neuronal loss, and the activation of other inflammatory participants… Although, the role of amyloid as a potential initiator of inflammation is not obvious, its accumulation exerts an indirect effect by activating caspases and transcription factors, such as NF-κ B and AP-1, which produce numerous inflammation amplifiers (IL-1β, TNF-α, and IL-6). Pro-inflammatory cytokines, such as TNF-α and IL-1β and IL-6, could act directly on the neuron and induce apoptosis. Similarly, TNF-α and IL-1β can activate astrocytes, which could release factors that have the capacity to activate microglia… Furthermore, APP, BACE1, and PSEN expression is governed by factors such as NF-κ B. The genes encoding these proteins have sites in their promoter regions, which are recognized by NF-κ B; in turn, the expression of these factors is upregulated by the presence of pro-inflammatory cytokines.”

Neuronal damage and Aβ deposition trigger inflammationMoreover…

Inflammatory mediators acting on neurons contribute to an increase in amyloid production and activate microglia-mediated inflammation. The microglia-neuron communication amplifies the production of factors that contribute to AD-type pathology.”

IL-1β plays a key role:

“This cascade is primarily mediated by the pro-inflammatory cytokine IL-1β, which is expressed by microglia cells. IL-1β may cause neuronal death via various pathways, which activate microglia and consequently increase the release of IL-1β, thus generating a self-sustaining mechanism that is amplified by itself. This slow but steady inflammation state, generated for long periods in the brain eventually can destroy neurons and contribute to the clinical symptoms observed in the disease.”


Journal of Alzheimer's DiseaseAutoimmunity in cognitive decline and dementia is a major topic on its own and will be featured in forthcoming posts. For now, an interesting study just published in the Journal of Alzheimer’s Disease describes how early changes in cognitive function due to autoimmune inflammation precede amyloid-β or tau pathologies. The authors set out to discriminate whether autoimmunity is causal or consquential:

“Immune system activation is frequently reported in patients with Alzheimer’s disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration… The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology.”

They assessed behavioral performance and autoimmune/inflammatory markers in a group of study animals genetically predisposed to Alzheimer’s disease and a control group, and found an association between cognitive impairment that predated the onset of AD and autoimmune inflammation:

“Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first six months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology.”

In other words, they found that Alzheimer’s disease is a smoldering process that coincides with systemic inflammation and takes years to evolve:

The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior.”


Journal of NeuroinflammationA fascinating paper recently published in the Journal of Neuroinflammation demonstrates how Down syndrome (DS) and Alzheimer’s disease share similar cytokine-driven neuroinflammatory gial activity:

“In the brain, neuritic amyloid-β (Aβ) plaques – a characteristic neuropathological feature of Alzheimer’s disease (AD) – are a virtually certain finding in adults with DS and have been noted in some children with DS. For instance, among 12 children with DS, two (ages 8 and 9 years) had Aβ plaques, and among those between the ages of 35 and 45 years, all had neuritic Aβ plaques and other AD pathologies, such as neurofibrillary tangles and glial activation… the prediction of AD neuropathological changes at middle age is reported to be a virtual certainty in those with DS.”

The process starts right away in Down syndrome:

“Three such early events have been reported in DS fetuses and each is related to the others as they induce, and are induced by each other and by cytokines subsequent to neuroinflammatory changes. In particular, these include overexpression of two chromosome 21 gene products – APP and S100B – and the resultant overexpression of the pluripotent neuroinflammatory cytokine IL-1, which is encoded by chromosome 2 genes IL-1A and IL-1B. Complex interactions between APP, glial activation, S100B, and IL-1 include upregulation of the expression of IL-1α and β by both APP and S100B, and induction of both APP and S100B by IL-1β. Such interactions have been shown to be elicited by multiple neural insults, each of which is characterized by gliosis-related neuroinflammation and risk for development of the characteristic neuropathological changes of AD… Such glial activation and cytokine overexpression occurs years before the virtually certain appearance at middle age of the Aβ plaques in DS.”

They note that this process is not confined to DS and AD, but associated with cognitive decline in other conditions:

“By analogy, without regard to the diversity of the source of neuronal stress, for example, traumatic brain injury, epilepsy, aging, or AIDS, the downstream consequence is increased risk for development of the neuropathological changes of AD marked by increased expression of neuronal APP, activation of glia, and neuroinflammatory cytokine expression.”

Inflammation-associated genes in the promotion of Alzheimer neuropathogenesis in trisomy 21And a particularly evil aspect of this process is that it is self-propagating, that is it feeds on itself:

“The danger of chronic induction of neuroinflammation with its manifestation of glial activation and cytokine overexpression is related to the capacity of proinflammatory cytokines such as IL-1β to self-propagate as they, themselves, activate microglia and astrocytes and further excess expression of IL-1β. In addition to IL-1β induction of the precursors of the principal neuropathological changes in AD, viz., APP for Aβ plaques, S100B for non-sensical growth of dystrophic neurites in plaques, synthesis and activation of MAPK-p38 for hyperphosphorylation of tau, favors formation of neurofibrillary tangles. In addition to favoring formation of these anomalies, IL-1β induces the synthesis and the activity of acetylcholinesterase, thus favoring the breakdown of acetylcholine, an important neurotransmitter in learning and memory, which is known to be decreased in AD. Similarly devastating, excess IL-1β, as observed in DS and AD, is associated in vitro and in vivo with decreases in the expression of synaptophysin, which is a hallmark of the synaptic loss in AD. Such neuropathophysiological changes would be expected to further stress neurons, promote more neuroinflammation, and in this way create a self-propagating cycle of ever increasing neuronal stress, dysfunction, and loss.”

This is one important reason why once ‘the train leaves the station and gets up to full speed’ it’s so hard to treat.


Food and Chemical ToxicologyA paper recently published in Food and Chemical Toxicology directs attention to the contribution of oxidative stress and glycation along with inflammation. In measuring markers of oxidative stress and endothelial dysfunction in the blood of 21 AD patients under standard treatment for AD compared with 10 controls, they saw significant differences in the ability to manage oxidative damage with glutathione and in levels of glycation end-products due to poor blood glucose regulation:

“Results indicate that IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients. Protein carbonyls levels were higher in AD group, while glutathione reductase and total antioxidant capacity were lower, depicting decreased defense ability against reactive oxygen species. Besides, a higher level of advanced glycation end-products was observed in AD patients. Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed: in Rivastigmine-treated group, IL6 levels were 47% lower than the average value of the remaining AD patients; homocysteine and glutathione reductase were statistically unchanged in the Rivastigmine and Donepezil–Memantine, respectively Donepezil group.”

They highlighted these conclusions:

  • IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients compared to controls.
  • Protein carbonyls levels were increased in AD patients.
  • GSH (glutathione) level and TAC (total antioxidant capacity) were lower in AD patients, suggesting an impaired self-defense ability against oxidative stress.
  • Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed.


Journal of Alzheimer's Disease & Other DementiasReaders of earlier posts on histamine intolerance will be particularly interested in a paper published this summer in the American Journal of Alzheimer’s Diseaes & Other Dementias in which the authors describe the role of histamine regulation in AD:

“Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H1 receptor (H4R). The histaminergic system has a role in the treatment of brain disorders by the development of histamine receptor agonists, antagonists. The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy. In this review, we focus on the role of histamine and its receptors in the treatment of AD, and we hope that histamine could be an effective therapeutic factor in the treatment of AD.”


Ageing Research ReviewsPrevention and treatment of cognitive decline is a huge topic that invites forthcoming posts. A nod in that direction considers the use of polyphenols such as resveratrol and curcumin that are shown to help quench neuroinflammation, as recognized in a paper just published in Ageing Research Reviews:

“Alzheimer’s disease (AD) is characterised by extracellular amyloid deposits, neurofibrillary tangles, synaptic loss, inflammation and extensive oxidative stress. Polyphenols, which include resveratrol, epigallocatechin gallate and curcumin, have gained considerable interest for their ability to reduce these hallmarks of disease and their potential to slow down cognitive decline. Although their antioxidant and free radical scavenging properties are well established, more recently polyphenols have been shown to produce other important effects including anti-amyloidogenic activity, cell signalling modulation, effects on telomere length and modulation of the sirtuin proteins.”


Brain accessible polyphenols with multiple effects on pathways involved in neurodegeneration and ageing may therefore prove efficacious in the treatment of age-related diseases such as AD, although the evidence for this so far is limited. This review aims to explore the known effects of polyphenols from various natural and synthetic sources on brain ageing and neurodegeneration, and to examine their multiple mechanisms of action, with an emphasis on the role that the sirtuin pathway may play and the implications this may have for the treatment of AD.”

They draw these highlights from their findings:

  • Polyphenols have been shown to act on many of the pathways involved in the pathogenesis of Alzheimer’s disease.
  • Polyphenols activate members of the sirtuin family of proteins which play an important role in cell survival and longevity.
  • Polyphenols positively influence oxidative stress, amyloid aggregation, inflammation, mitochondrial function and telomere maintenance.
  • Utilising synergistic combinations of polyphenols may prove beneficial in developing treatment strategies for Alzheimer’s disease.


The FASEB Journal Vol 27 Num 9Concerns for cognitive decline certainly come to the fore on the occasion of hospitalization for major surgery or illness. The authors of a study published in The FASEB Journal describe how a compound derived from aspirin can play a therapeutic role:

Hospitalization for major surgery or critical illness often associates with cognitive decline. Inflammation and dysregulation of the innate immune system can exert broad effects in the periphery and central nervous system (CNS)… Endogenous regulation of acute inflammation is providing novel approaches to treat several disease states including sepsis, pain, obesity and diabetes.”

The draw attention to the activity of resolvins:

Resolvins are potent endogenous lipid mediators biosynthesized during the resolution phase of acute inflammation that display immunoresolvent actions. Here, using a mouse model of surgery-induced cognitive decline we report that orthopedic surgery affects hippocampal neuronal-glial function, including synaptic transmission and plasticity. Systemic prophylaxis with aspirin-triggered resolvin D1 (AT-RvD1: 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, as little as 100 ng dose per mouse) improved memory decline following surgery and abolished signs of synaptic dysfunction. Moreover, delayed administration 24 h after surgery also attenuated signs of neuronal dysfunction postoperatively. AT-RvD1 also limited peripheral damage by modulating the release of systemic interleukin (IL)-6 and improved other clinical markers of tissue injury.”

The authors conclude:

“Collectively, these results demonstrate a novel role of AT-RvD1 in modulating the proinflammatory milieu after aseptic injury and protecting the brain from neuroinflammation, synaptic dysfunction and cognitive decline. These findings provide novel and safer approaches to treat postoperative cognitive decline and potentially other forms of memory dysfunctions.”


Note: Prevention and treatment of cognitive decline in its various manifestations is a complex and demanding clinical challenge emerging as one of the key responsibilities of any clinician. It requires a working familiarity with every facet of clinical systems biology. Forthcoming posts will highlight the emerging science in this critical area.

Insulin resistance is a risk factor for breast cancer even with normal fasting glucose and insulin

Journal of Experimental & Clinical Cancer ResearchWell before fasting glucose and insulin rise out of the normal range, background surges of insulin associated with decreased insulin receptor sensitivity do harm throughout the body and, as confirmed by a study just published in the Journal of Experimental & Clinical Cancer Research shows, promote breast cancer. The authors observe:

“Metabolic Syndrome (MS) has been correlated to breast carcinogenesis [development of breast cancer]. MS is common in the general population (34%) and increases with age and body mass index. Although the link between obesity, MS and hormone related cancers incidence is now widely recognized, the molecular mechanisms at the basis of such increase are still poorly characterized. Crucial role is supposed to be played by the altered insulin signalling, occurring in obese patients, which fuels cancer cell growth, proliferation and survival. Therefore we focused specifically on insulin resistance to investigate clinically the potential role of insulin in breast carcinogenesis.”

They investigated the role of insulin resistance in the development of breast cancer by examining data for 975 women, specifically measuring insulin resistance with the Homeostasis Model Assessment score (HOMA-IR) in 975 women. Using the cut off value HOMA-IR >= 2.50 to define insulin resistance there was a clear connection:

“Higher prevalence of MS [metabolic syndrome] (35%) was found among postmenopausal women with breast cancer compared to postmenopausal healthy women (19%). A broad range of BMI spanning 19–48 Kg/m2 was calculated. Both cases and controls were characterized by BMI >= 25 Kg/m2 (58% of cases compared to 61% of controls). Waist circumference >88 cm was measured in 53% of cases and in 46% of controls. Hyperinsulinemia was detected in 7% of cases and only in 3% of controls. HOMA-IR score was elevated in 49% of cases compared to 34% of controls. That means insulin resistance can nearly double the risk of breast cancer development. Interestingly 61% of women operated for breast cancer (cases) with HOMA-IR >= 2.5 presented subclinical insulin resistance with fasting plasma glucose levels and fasting plasma insulin levels in the normal range. Both android fat distribution and insulin resistance correlated to MS in the subgroup of postmenopausal women affected by breast cancer.”

Practitioners should savor the significance of this: (1) insulin resistance nearly doubles the risk of breast cancer; (2) breast cancer-promoting insulin resistance can be subclinical, that is with normal fasting glucose and insulin. The authors elaborate:

Insulin resistance can often be defined as a subclinical condition. Consistently, most of our patients (68%) had levels of fasting plasma glucose in the normal range, and, interestingly, only through the use of HOMA score we classified them as insulin resistant. Similarly, fasting plasma insulin levels were diagnosed as normal in 88% of cases. These patients were identified as insulin resistant only by means of the HOMA score. HOMA-IR is widely-used in epidemiologic studies as a measure of insulin resistance, and has been shown to reflect euglycemic clamp insulin resistance more accurately than fasting insulin levels alone.”

Their conclusions are of the first importance for the prevention of breast cancer:

“Our results further support the hypothesis that MS, in particular insulin resistance and abdominal fat, can be considered as risk factors for developing breast cancer after menopause. We suggest that HOMA-IR, rather than fasting plasma glucose and fasting plasma insulin levels alone, could be a valuable tool to identify patients with subclinical insulin resistance, which could be relevant for primary prevention and for high risk patients screening…In conclusion, our experience suggests that insulin resistance and abdominal fat (more than BMI alone) represent the most important criteria of MS on which primary prevention should be concentrated. Interestingly, Homeostasis Model Assessment of insulin resistance promises to be a valuable tool for primary prevention, particularly for patients with subclinical insulin resistance, presenting fasting plasma glucose levels and fasting plasma insulin levels in the normal range. Our findings suggest that HOMA-IR could be useful in screening patients at higher risk of developing breast cancer.

Clinicians wishing to calculate model-derived estimates of insulin sensitivity and beta cell function derived from fasting plasma glucose and insulin can use the HOMA2 Calculator made available by the University of Oxford Centre for Diabetes, Endocrinology and Metabolism.

Weight loss and insulin resistance improved by branched-chain amino acids

Diabetologia Vol 55 Issue 2Weight loss and improvement in insulin resistance naturally go hand in hand, and a study just published in the journal Diabetologia confirms that consumption of branched-chain amino acids (BCAAs) helps both. Isoleucine, leucine and valine are already known to promote muscle growth and repair, influence brain signaling for appetite and metabolic rate, help with burn recovery, and be remedial for autism when it includes genetic mutations in BCAA pathways. The investigators’ intent was to discern biomarkers for weight loss and insulin resistance:

Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss.”

They cast a wide net to assay 60 metabolites, including non-essential fatty acids (NEFA), β-hydroxybutyrate, ketones, insulin and glucose at the beginning of their study and after 6 months for 500 subjects who had lost at least 4 kg of weight during Phase I of the Weight Loss Maintenance (WLM) trial. They also calculated the standard metric for insulin resistance, the homeostatic model assessment of insulin resistance (HOMA-IR) and added the change in HOMA-IR with weight loss (∆HOMA-IR).” BCAAs stood out from the pack of metabolites in association with weight loss and improvement in insulin resistance:

“Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was −0.80 ± 1.73. Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR and independently associated with ∆HOMA-IR. ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR. These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR.”

Fpr clinicians, this evidence supports the use of BCAAs in case management of weight loss and recovery of insulin sensitivity. The authors conclude:

A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.”

A low carbohydrate diet can increase cardiovascular disease

Research just published in BMJ (the British Journal of Medicine) presents substantial evidence that a low carbohydrate high protein diet can increase the risk of cardiovascular disease. The authors’ intent was to…

“…study the long term consequences of low carbohydrate diets, generally characterised by concomitant increases in protein intake, on cardiovascular health.”

They followed a cohort of 43,396 Swedish women, ages of 30-49 years at the beginning of the study, for an average of 15.7 years, then correlated data on incident cardiovascular diseases with decreasing carbohydrate intake, increasing protein intake, and a combination of these to give a low carbohydrate-high protein score. This was adjusted for intake of energy, intake of saturated and unsaturated fat, and several non-dietary variables. The results show that there are better ways to reap the cardiovascular benefits of a low glycemic diet than a low carbohydrate high protein regimen:

A one tenth decrease in carbohydrate intake or increase in protein intake or a 2 unit increase in the low carbohydrate-high protein score were all statistically significantly associated with increasing incidence of cardiovascular disease overall. No heterogeneity existed in the association of any of these scores with the five studied cardiovascular outcomes: ischaemic heart disease, ischaemic stroke, haemorrhagic stroke , subarachnoid haemorrhage, and peripheral arterial disease.”

Key clinical point: there is abundant evidence that regulating blood glucose and insulin with a wholesome low glycemic diet (such as with the ‘modified Mediterranean’ or ‘paleo-Mediterranean’ diets) confers important benefits. Sacrificing healthy low glycemic carbohydrates replete with anti-inflammatory flavonoids for an across-the-board low carbohydrate regimen with increased protein can, as we see here, promote rather than diminish chronic inflammation. The authors conclude:

Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are associated with increased risk of cardiovascular disease.”