There has been a burst of papers drawing further attention to the damage that glucose and insulin dysregulation does to the brain. A study just published in the journal Neurology investigates specifically…

“…the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia.”

The authors subjected 1,017 community-dwelling dementia-free subjects 60 years and older to an oral glucose tolerance test, then followed them for 15 years. The outcome measure was clinically diagnosed dementia. What did their data show?

The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74; AD: adjusted HR = 2.05; VaD: adjusted HR = 1.82). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L [120.6 mg/dl], the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L [140.4 to 198 mg/dl] or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L [199.8 mg/dl].”

This is striking. The risk of all-cause dementia doubled for those with diabetes, and there was a significant increase in the risk of all-cause dementia and Alzheimer’s disease with a 2 hour post-glucose load level of 140.4 mg/dl or more. Moreover, fasting glucose levels did not reveal the danger that was disclosed only by the functional OGTT. I always risk desensitizing my patients to the damage done to the brain by glucose and insulin dysregulation; better to let the authors’ conclusion do the talking:

“Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.”

Meanwhile, a time study just published in the journal Diabetic Medicine also examines the association of diabetes with Alzheimer’s disease. The authors’ intent was to determine…

“…whether diabetes mellitus influences functional status in patients with Alzheimer’s disease.”

They studied 608 community-dwelling patients with Alzheimer’s disease, assessing diabetes at the beginning. Functional status was examined twice yearly with the Activities of Daily Living scale. Each patient also had a baseline functional disability determined if their Activities of Daily Living score was less than 6. Decreases in these metrics over four years of follow-up exams was used to define worsening of functional disability due to AD. Their data also reveal the ruination of the brain by glucose intolerance:

“At baseline, diabetes was present in 63 participants (10.4%) and, compared with those without diabetes, was associated with functional impairment [age- and sex-adjusted OR = 2.73]. After controlling for confounders, the association remained significant [OR = 2.04]. Follow-up demonstrated a significant interaction between duration of Alzheimer’s disease and diabetes, which was associated with progression of functional impairment in patients who had been diagnosed with Alzheimer’s disease for less than 1 year, but not in those who had been diagnosed with Alzheimer’s disease for more than 1 year. Abnormal one-leg balance, polymedication and obesity seem to be important factors explaining the association between diabetes and functional status.”

Clinicians (non-neurologists), how often do you check one-leg balance? The authors’ data suggests that a year after a clear-cut Alzheimer’s diagnosis the damage is too extensive to discriminate the effect of diabetes, thus they conclude:

“At baseline, the presence of diabetes significantly increases the risk of functional disability in patients with Alzheimer’s disease; our longitudinal data confirm that in patients with a recent diagnosis of Alzheimer’s disease (but not in those who have had Alzheimer’s disease for longer than 1 year), diabetes continues to worsen functional status.”

Regarding mechanisms, an interesting paper just published in Current Diabetes Reviews examines recent findings illuminating the link between IGF-1 signaling and diabetes-associated dementia. The authors state:

“Patients with type 2 diabetes (T2DM) have a two- to three-fold increased risk for Alzheimer’s disease (AD), the most common form of dementia. Vascular complications might explain partially the increased incidence of neurodegeneration in patients with T2DM. Alternatively, neuronal resistance for insulin/insulin-like growth factor-1 (IGF-1) might represent a molecular link between T2DM and AD, characterizing AD as “brain-type diabetes”.”

They describe recent research findings that suggest decreased IGF-1 signaling (IIS) in the brain is a compensatory attempt to reduce the accumulation of toxic β-amyloid (Aβ):

“According to this hypothesis, brains from AD patients showed substantially downregulated expression of the Insulin receptor (IR), the IGF-1 receptor (IGF-1R), and the insulin receptor substrate (IRS) proteins…suggesting that decreased IIS [insulin/IGF-1 signaling] might be involved in the pathogenesis of both T2DM and AD. In contrast, type 2 diabetic patients suffering from AD accumulate less β-amyloid (Aβ) compared to non-diabetic AD patients raising the question, whether the changes in IIS are cause, consequence, or compensatory counterregulation to neurodegeneration. Recent data in C. elegans showed that reducing IIS decreases Aβ toxicity. This effect is accomplished via two transcription factors…suggesting that Insulin/IGF-1 transmitted signals influence Aβ proteotoxicity.”

This important point should not go unnoticed by those who are contemplating therapies that increase IGF-1—they may increase risk factors for Alzheimer’s disease and dementia.

And another paper recently published in Neurology highlights the damage done to the brain by advanced glycation end products due to poor glucose tolerance. The authors observe:

“Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging.”

They studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose, and examined baseline AGE concentration by urine pentosidine in association with performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. What did the data show?

“On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level [more AGEs] compared to those in the lowest tertile. Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile.”

We are probably just beginning to understand the ways that glucose and insulin regulation, whose profound leverage on the physiology is evolutionarily preserved from relatively primitive organisms to humans, has on the brain. Regarding damage done by excessive glucose interaction with tissues, it is not necessary for glucose dysregulation to have progressed to diabetes as the authors conclude:

“High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.”

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There is an accumulation of fascinating scientific evidence that intermittent calorie restriction (ICR) offers a number of advantages over continuous calorie restriction (CCR) for successful long term weight loss and the ‘turning on’ of genes that favor longevity. Consider a study published recently in the International Journal of Obesity in which the investigators compared ICR and CCR for weight loss and metabolic disease risk markers in overweight women. The authors state:

“Excess weight and weight gain during adult life increases the risk of several diseases including diabetes, cardiovascular disease (CVD), dementia, certain forms of cancer including breast cancer, and can contribute to premature death. Observational and some randomised trials indicate that modest weight reduction (>5% of body weight) reduces the incidence and progression of many of these diseases. Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known.”

Moreover…

“Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation. Sustainable and effective energy restriction strategies are thus required.”

In other words, a method that can be comfortable enough to be accepted into daily life for the long that also avoids loss of improvements due to adaption is required.

“One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction.”

So the authors set out to…

“…compare the feasibility and effectiveness of IER with CER for weight loss, insulin sensitivity and other metabolic disease risk markers…This is the largest randomised comparison of an isocalorific intermittent vs. continuous energy restriction to date in free living humans..”

They designed a randomised comparison of a 25% energy restriction as IER (~2266 kJ/day which equals 541 calories per day for 2 days/week) or CER (~6276 kJ/day equaling 1499 calories each day for 7 days/week) in 107 overweight or obese premenopausal women for a 6 month study period. They measured an extensive list of biomarkers at baseline and after 1, 3 and 6 months: weight, anthropometry (size, weight and proportions), biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, IGF-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain derived neurotrophic factor. What did the data show?

“Last observation carried forward analysis showed IER and CER are equally effective for weight loss, mean weight change for IER was −6.4 kg vs. −5.6 kg for CER. Both groups experienced comparable reductions in leptin, free androgen index, high sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than CER; difference between groups for fasting insulin −1.2 μU/ml, and insulin resistance −1.2 μU/mmol/L.”

Regarding concerns about tolerance…

“A recent blinded trial of a 2 day VLCD [very low calorie diet] (1311 kJ/day [313 calories per day!]) reported no adverse effects on cognition, energy levels, sleep or mood, suggesting symptoms are expected with VLCD and therefore experienced and could potentially be overcome with appropriate counselling. Importantly IER did not lead to overeating on non-VLCD days.”

The authors briefly summarize the results of their comparison of IER and CER by concluding:

“IER is as effective as CER in regards to weight loss, insulin sensitivity and other health biomarkers and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.”

That’s not all though. The authors additionally note an extremely interesting observation with profound implications and potential for benefit regarding additional benefits of an intermittent very low calorie method:

“Recent reviews speculate that IER may be associated with greater disease prevention than CER due to increased cellular stress resistance, in particular increased resistance to oxidative stress. This is thought to be mediated by ‘hormesis’ whereby the moderate stress of energy restriction increases the production of cytoprotective, restorative proteins, antioxidant enzymes and protein chaperones. Alternate day fasting has been linked to increased SIRT-1 gene expression in muscle, and to greater neuronal resistance to injury compared to CER in C57BL/6 mice. The tendency for greater improvements in oxidative stress markers in our IER than in the CER group may support these assertions. Declines in long term protein oxidation product aggregates suggest IER as a possible activator of catabolism and autophagy.”

In other words, intermittent calorie restriction can be as effective as continuous calorie restriction for weight loss, but have the added advantage of ‘turning on’ genes beneficial for health and longevity and preventing adaptation that would result in regaining weight.

Other investigators also have compared intermittent with continuous calorie (daily) calorie restriction as in a study published recently in the journal Obesity Reviews. The authors set out to…

“…evaluate and compare the effects of daily CR versus intermittent CR on weight loss, fat mass loss, lean mass retention and visceral fat mass reduction, in overweight and obese adults.”

They undertook a review of studies that were randomized control trials, had a primary endpoint of weight loss and/or body composition changes, used daily CR or intermittent CR as the primary focus of the intervention; had a study duration of 4–24 weeks, and involved adult populations who were overweight or obese subjects but not diabetic. These included 11 daily continuous calorie restriction trials and five intermittent CR trials published between 2000 and 2010, along with two unpublished trials of intermittent CR from their own lab. What did all these studies add up to?

“Results reveal similar weight loss and fat mass loss with 3 to 12 weeks’ intermittent CR (4–8%, 11–16%, respectively) and daily CR (5–8%, 10–20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR.”

This is a significant advantage of ICR over CCR (continuous = daily calorie restriction). The authors conclude by stating:

“In sum, intermittent CR and daily CR diets appear to be equally as effective in decreasing body weight, fat mass, and potentially, visceral fat mass. However, intermittent restriction regimens may be superior to daily restriction regimens in that they help conserve lean mass at the expense of fat mass. These findings add to the growing body of evidence showing that intermittent CR may be implemented as another viable option for weight loss in overweight and obese populations.”

Numerous other studies have examined the distinctive benefits of intermittent calorie restriction. A paper published recently in the journal Oncogene investigates the positive effects of brief ICR compared to CCR for cancer patients. The authors state:

“The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.”

They point out that cancer cells are unable to respond to the positive stimuli of calorie restriction:

“Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells.”

Moreover…

“Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans.”

They go on to review studies on fasting, cellular protection and chemotherapy resistance, and futher compare them to those on continuous calorie restriction and cancer treatment. The authors conclude:

“Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.”

A study published in the Journal of Molecular and Cellular Cardiology offers evidence that intermittent calorie restriction activates genes that help in the recovery from heart damage. The authors state:

“Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI).“

Two weeks after myocardial ischemia was induced in their study animals, they were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks the authors evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival. The results were truly striking:

“Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4 ± 0.17 versus 3.9 ± 0.18. Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group. Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-α (3010 ± 350% versus 650 ± 151%), BDNF (523 ± 32% versus 110 ± 12%), and VEGF (450 ± 21% versus 170 ± 30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone.”

This is a dramatic indication that intermittent calorie restriction can be used to protect and repair heart tissue. The authors conclude:

“Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.”

Another fascinating study published recently in the journal Cancer Prevention Research demonstrates that intermittent calorie restriction is clearly superior to both continuous calorie restriction and an unrestricted diet for breast cancer prevention. Specifically, the authors studied…

“The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels…in relation to mammary tumorigenesis.”

Their subjects were assigned to ad libitum fed, ICR (3-week 50% caloric restriction followed by 3-wks 100% AL consumption), and CCR groups.

“Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad.”

This amounts to an impressive ‘turning on’ of genes that protect against breast cancer for ICR. In conclusion…

“…we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.”

A paper published in the journal Nutrition and Cancer demonstrates that ICR offers a greater protective effect than CCR for prostate cancer. The authors state:

“Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development.”

Their animal models for prostate cancer were assigned to ad libitum (AL), ICR, and CCR groups. There were distinctive differences according to the manner of calorie restriction that dramatically favored the ICR over both the AL and CCR cohorts:

“ICR mice were older at tumor detection than AL and CCR mice. There was no difference for age of tumor detection between AL and CCR mice. Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups.”

Not only did the subjects on CCR live longer with healthier biomarkers than the ones on either the free diet or CCR, there was no difference between the AL and CCR groups for age of tumor detection or survival. The implication is exciting: the benefits were due not to the weight loss component but to the way in which ICR affects gene expression. The authors conclude:

“These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.”

A paper published in the The Journal of Nutritional Biochemistry also offers evidence that intermittent calorie restriction protects heart tissue:

“It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats.”

The authors showed by echocardiographic analysis of heart structur and function that intermittent fasting attenuates the disease related increase in heart thickness, end systolic and diastolic volumes, and ejection fraction. Additionally…

“The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI.”

There is now a large body of evidence showing that ICR increases the protective hormone adiponectin much more than CCR. The authors conclude:

“Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.”

A paper published in the journal Ageing Research Reviews discusses how IFR and CCR can protect the brain from accelerated neurodegeneration associated with aging. The authors note:

“The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span.”

As we’ve seen regarding cardioprotection and tumorigenesis…

“CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease.”

These studies comprise the first post that illustrates the scientific basis for the Lapis Light Weight Loss & Gene Modulation Program that customizes intermittent calorie restriction according to the individual’s weight management and other health needs. Subsequent posts will offer additional scientific evidence important for other aspects of the program.

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I always include GGT (Serum γ-Glutamyltransferase) in our basic screening blood panel, but find often that this is not included in lab work that patients bring from elsewhere. A study recently published in the journal Obesity shows that, besides being associated with fatty liver,  GGT is an important metric for predicting metabolic syndrome, diabetes and hypertension. The authors state:

“Serum γ-glutamyltransferase (GGT) is associated with oxidative stress and hepatic steatosis. The extent to which its value in determining incident cardiometabolic risk (coronary heart disease (CHD), metabolic syndrome (MetS), hypertension and type 2 diabetes) is independent of obesity needs to be further explored in ethnicities.”

They examined a cohort of 1,667 adults from a general population age 52 to 63 with 4 year’s follow-up, measuring GGT activity in association with metabolic syndrome (identified by Adult Treatment Panel-III criteria modified for male abdominal obesity) and multiple markers for cardiovascular disease. Their data bolsters the use of GGT for case management:

“Median GGT activity was 24.9 U/l in men, 17.0 U/l in women…while smoking status was not associated, (male) sex, sex-dependent age, alcohol usage, BMI, fasting triglycerides and C-reactive protein (CRP) were significant independent determinants of circulating GGT. Each 1-s.d. increment in (= 0.53 ln GGT) GGT activity significantly predicted in each sex incident hypertension (hazard ratio (HR) 1.20), and similarly MetS, after adjustment for age, alcohol usage, smoking status, BMI and menopause. Strongest independent association existed with diabetes (HR 1.3) whereas GGT activity tended to marginally predict CHD independent of total bilirubin but not of BMI.”

Interestingly…

“Higher serum total bilirubin levels were protective against CHD risk in women.”

While not any stronger a risk predictor for coronary heart disease (CHD) than body mass index (BMI), GTT is a valuable and underutilized marker to use for the case management of cardiometabolic disorders. The authors conclude:

“We conclude that elevated serum GGT confers, additively to BMI, risk of hypertension, MetS, and type 2 diabetes but only mediates adiposity against CHD risk.”

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Most readers of these posts, practitioner and layperson alike, have probably long been aware of the role of insulin resistance in cardiovascular disease, chronic inflammation and cancer as described in last week’s New York Times article. A fascinating study that adds to the mountain of scientific evidence was just published in the Public Library of Science (PLoS One) in which the authors show that higher insulin levels are associated with the unstable form of carotid artery plaque:

“The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric 14C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques.”

The authors dissected the cores of carotid plaques from 29 patients with carotid stenosis and analyzed them for 14C. Their findings are fascinating:

“The average plaque age (i.e. formation time) was 9.6±3.3 years. All but two plaques had formed within 5–15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels…plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages…Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation.”

As readers here know, a heart attack or stroke occurs when a vulnerable plaque ruptures and blocks a smaller vessel downstream. These investigators show that unstable plaque is associated with higher insulin levels. Intervening to reduce insulin resistance is one of the most important things that clinicians and patients can do for a host of conditions. The authors conclude:

“Our results show, for the first time, that plaque age, as judge[d] by relative incorporation of 14C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.”

Regarding laboratory testing to determine the presence of inflamed vulnerable plaque, see the earlier post on Lp-PLA2.

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It’s by far best to prevent type 2 diabetes by acting on the earliest signs of metabolic syndrome with appropriate lifestyle changes and evidence-based support for genetic and epigenetic needs based on objective laboratory data. All too often, however, this isn’t accomplished and the case advances to type 2 diabetes as insulin resistance mounts and insulin production can no longer compensate. When we enter the realm of pharmaceuticals for T2DM there are choices. A huge study just published in the European Heart Journal offers valuable evidence that metformin is associated with much less risk of cardiovascular disease and all-cause mortality. The authors state:

“The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.”

The authors examined the data for all Danish residents over 20 years old who starting taking an a single-agent insulin secretagogue (medication that provokes the secretion of insulin, ISs) or metformin between 1997 and 2006, a total of 107,806 subjects. They were followed for up to 9 years (3.3 years on average) for all-cause mortality, cardiovascular mortality, and the combination of myocardial infarction (MI), stroke, and cardiovascular mortality. This was correlated with the use of individual ISs. What did their data show?

“Compared with metformin, glimepiride: 1.32, glibenclamide: 1.19, glipizide: 1.27, and tolbutamide: 1.28 were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30, glibenclamide: 1.47, glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47. Results for gliclazide and repaglinide and were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.”

In other words, for example, patients (who had never had a heart attack) taking glimepiride had a 32% increased chance of dying compared with taking metformin. The authors conclude by stating:

“Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.”

This outcome is not unexpected when we consider that, in addition to suppressing hepatic glucose production, metformin acts to increase insulin receptor sensitivity. The authors of an editorial published in the same journal comment on the gravity of this study:

“While this is not the first study to evaluate outcomes with these drug classes comparatively, the observations are among the most robust published based on the very large sample of patients with drug choices largely free of selection bias, sufficient numbers of events ascertained to yield substantial statistical power to analyse outcomes for each insulin secretagogue individually, with additional stratification by history of previous myocardial infarction.”

Important: metformin is known to interfere with vitamin B12 absorption (see previous posts). Patients should be followed carefully for indications of suboptimal vitamin B12 levels, preferably by urine or serum methylmalonic acid assays.

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Research just published in the journal Science Translational Medicine is a further reminder of the critical need  for caution and sound physiological thinking when considering the use of growth hormone. The authors note in their introduction:

“Reduced activity of growth hormone (GH) and insulin-like growth factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman organisms…contribute to extended life span and protection against age-dependent damage or diseases…”

Pursuant to these earlier observations they formulated an important investigative objective:

“Mutations in growth signaling pathways [that diminish the GH effect] extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies.”

Combining this information with surveys that identified the cause and age of death for their subjects who died before this period, the data paint a compelling picture:

“The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects.“

They describe earlier studies that help explain the very low incidence of cancer. In one, serum from subjects with GHR deficiency had reduced DNA breakage yet increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. In others, serum from GHR-deficient subjects caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells. These changes in signaling promote cellular protection and life-span extension in model organisms.

Importantly, in their present study the authors also observed:

“……reduced insulin concentrations and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects.”

These comments, along with an earlier post on growth hormone research, are a plea for caution along with sound thinking. There seem to be good reasons why we have evolved to reduce growth hormone activity with age. The authors advance the idea that blocking growth hormone receptor function may…

“…prevent or reduce the incidence of cancer, diabetes, and other age-related diseases, including inflammatory disorders, stroke, and neurodegenerative diseases.”

Clinicians and individuals tempted to experiment with growth hormone therapy should consider the authors’ conclusion:

“Our finding that human GHRD [growth hormone receptor deficient] subjects are protected against age-related pathologies is consistent with the elevated cellular protection in both yeast and human cells with reduced expression of specific pro-growth genes and with the effect of serum from GHRD subjects in lowering their expression. The results from the human cohort also show similarities with those from GHRD- and GH-deficient mice, which display lower incidence (49%) or delayed occurrence of fatal neoplasms and increased insulin sensitivity… These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.”

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Original research published recently in the Annals of Internal Medicine offers evidence that trans-palmitoleate, a fat present in milk, is responsible for metabolic benefits observed with dairy consumption. The authors set out to…

“…To investigate whether circulating trans-palmitoleate is independently related to lower metabolic risk and incident type 2 diabetes.”

They examined 3736 adults in the Cardiovascular Health Study for plasma phospholipid fatty acids, blood lipids, inflammatory markers, and glucose–insulin and dietary habits, taking into consideration relevant demographic, clinical, and lifestyle factors. They then determined how trans-palmitoleate related to major metabolic risk factors. Their data tell an interesting story of a helpful fat:

“In multivariate analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate levels. Higher trans-palmitoleate levels were associated with slightly lower adiposity and, independently, with higher high-density lipoprotein cholesterol levels, lower triglyceride levels, a lower total cholesterol–HDL cholesterol ratio, lower C-reactive protein levels, and lower insulin resistance. Trans-palmitoleate was also associated with a substantially lower incidence of diabetes…Protective associations with metabolic risk factors were confirmed in the validation cohort.”

Of course, this study does address the widespread problem of dairy allergy, nor does it discriminate between the widely varying qualities of dairy (organic from grass-fed free-range animals versus industrial dairy). But it does caution against the wholesale discrimination against fats in general and the dairy food group in particular. As always, clinical and lifestyle decisions depend on the needs of the individual which can be verified by objective outcome markers. Practitioners and health conscious individuals can consider the authors’ conclusion:

“Circulating trans-palmitoleate is associated with lower insulin resistance, presence of atherogenic dyslipidemia, and incident diabetes. Our findings may explain previously observed metabolic benefits of dairy consumption and support the need for detailed further experimental and clinical investigation.”

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Oral corticosteroids such as prednisone have well-known side effects that include increased insulin resistance and risk for diabetes, but what if they are inhaled for chronic inflammatory respiratory conditions such as asthma? A study recently published in The American Journal of Medicine addresses this question. The authors first observe:

“Systemic corticosteroids are known to increase diabetes risk, but the effects of high-dose inhaled corticosteroids are unknown. We assessed whether the use and dose of inhaled corticosteroids increase the risk of diabetes onset and progression.”

The authors examined a cohort of 388,584 patients treated for respiratory disease during 1990-2005, then followed them through 2007 or until diabetes onset. (A subcohort treated with oral blood sugar lowering medication was followed until they developed diabetes.) They evaluated their data to estimate the rate ratios of diabetes onset and progression associated with ‘current’ inhaled corticosteroid use and adjusted for the relevant variables. Their data showed that among their study cohort…

“…30,167 had diabetes onset during 5.5 years of follow-up (incidence rate 14.2/1000/year), and 2099 subsequently progressed from oral hypoglycemic treatment to insulin (incidence rate 19.8/1000/year). Current use of inhaled corticosteroids was associated with a 34% increase in the rate of diabetes and in the rate of diabetes progression. The risk increases were greatest with the highest inhaled corticosteroid doses, equivalent to fluticasone 1000 μg per day or more.”

The authors’ conclusion should be considered not only for the case management of asthma (before significant markers for pre-diabetes and diabetes emerge), but for the metabolic and endocrine effects beyond respiratory disease:

“In patients with respiratory disease, inhaled corticosteroid use is associated with modest increases in the risks of diabetes onset and diabetes progression. The risks are more pronounced at the higher doses currently prescribed in the treatment of chronic obstructive pulmonary disease.”

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More evidence that magnesium improves insulin function to treat metabolic syndrome and prevent type 2 diabetes is presented in a study just published in the journal Diabetes, Obesity and Metabolism. The authors note:

“The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects.”

Note that the study subjects were ‘normal’ (normomagnesemic) according to the standard blood (serum) test for magnesium. Their study subjects were screened for eligibility with an oral glucose tolerance test and randomized to either a magnesium supplement or placebo. After 6 months they were evaluated for several insulin sensitivity indices (ISI), plasma glucose, serum insulin, blood pressure and lipids. After the intervention period…

“Mg supplementation resulted in a significant improvement of fasting plasma glucose and some ISI compared to placebo…Several mechanisms may be responsible for the beneficial effect of magnesium on insulin resistance…These include direct effects of magnesium on the insulin receptor and its downstream signaling processes, enhanced enzyme activities involved in glucose utilization, prevention of an intracellular calcium overload supposed to negatively affect insulin sensitivity, and finally, anti-inflammatory effects known to improve insulin resistance.”

The authors’ conclusion adds to the mountain of documentation for the potential value of magnesium supplementation:

“The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimisation of Mg status to prevent insulin resistance and subsequently type 2 diabetes.“

The magnesium blood test used commonly reported and used in this study is not a reliable marker. It is sensitive only to the most severe magnesium deficiencies and does not accurately reflect tissue content. I suggest to the clinicians reading this that they consider testing sublingual epithelial cell magnesium [Mg]i. This can be performed on a simple buccal scrape by IntraCellular Diagnostics, Inc.

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More evidence for the deleterious effects on the brain of hyperglycemia and hypoglycemia is presented in a study just published in the journal Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. The authors’ research was designed to…

“…evaluate the effects of streptozotocin (STZ)-induced hyperglycemia and insulin-induced hypoglycemia in cortical and hippocampal mitochondria bioenergetics and oxidative status.”

The hippocampus is the seat of short-term memory and a regulatory center for adrenal function. STZ-induced hyperglycemia and insulin-induced hypoglycemia are standard methods employed to examine the physiological repercussions of high and low blood sugar respectively. They analyzed the respiratory chain and phosphorylation system for the capacity to produce energy in the mitochondria (cellular energy ‘factories’), thiobarbituric acid reactive substances (TBARS) levels and the hydrogen peroxide (H2O2) production rate for oxidative stress, and non-enzymatic and enzymatic antioxidant defenses. What did their data show?

“Cortical mitochondria from insulin-induced hypoglycemic rats present a significant decrease in the ADP/O index, a significant increase in the repolarization lag phase and a decrease in GSH/GSSG ratio when compared with STZ and control mitochondria. Both STZ-induced diabetes and insulin-induced hypoglycemia promote a significant increase in TBARS levels and a decrease in glutathione disulfide reductase activity. Diabetic cortical mitochondria present a significant decrease in glutathione peroxidase (GPx) activity compared to control mitochondria. In turn, insulin-induced hypoglycemia induced a significant increase in GPx and manganese superoxide dismutase (MnSOD) activities. In hippocampal mitochondria, insulin-induced hypoglycemia increases the respiratory control ratio whereas both situations, hyper- and hypoglycemia, potentiate H2O2 production and decrease the activity of MnSOD.”

In other words, both hyper- and hypoglycemia impair cortical and hippocampal function deranging energy production, increasing damage due to oxidative stress. In reference to type 1 diabetes, the authors state in conclusion:

“These results suggest that the poor glycemic control that occurs in type 1 diabetic patients undergoing insulin therapy may have detrimental effects in brain areas involved in learning and memory.”

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