Summary: the hormonal and menstrual irregularities, metabolic dysfunction and adverse cardiovascular changes of PCOS (polycystic ovary syndrome) can be effectively treated with the right dietary and lifestyle interventions according to two recent studies. This is not surprising considering that excessive levels of insulin promote the development of ovarian cysts.

A study recently published in The Journal of Clinical Endocrinology & Metabolism offers excellent evidence that the metabolic and cardiovascular irregularities of PCOS respond well to the appropriate lifestyle changes. The authors state:

“Polycystic ovarian syndrome (PCOS) is associated with cardiovascular risk factors (CRF). Lifestyle intervention is regarded as therapy of choice even if studies in adolescent girls with PCOS are scarce…Our objective was to analyze the impact of lifestyle intervention on menses irregularities, hyperandrogenemia, CRF, and intima-media thickness (IMT) in adolescent girls with PCOS.”

They examined 59 obese girls with PCOS aged 12–18 years for menstrual irregularities,IMT (thickening of the inner layer of the arteries), waist circumference, blood pressure, fasting lipids, insulin, glucose, testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and SHBG (sex hormone binding globulin) before and after a one year intervention of nutrition education, exercise training, and behavior therapy. The results were instructive:

“In contrast to the 33 girls without weight loss, the 26 girls reducing their body mass index during the lifestyle intervention (by a mean of −3.9 kg/m2) improved most CRF and decreased their IMT (by a mean of −0.01 cm). Testosterone concentrations decreased (by a mean of −0.3 nmol/liter) and SHBG concentrations increased (by a mean of +8 ng/ml) significantly in girls with weight loss in contrast to girls with increasing weight. The prevalence of amenorrhea (−42%) and oligoamenorrhea (−19%) decreased in the girls with weight loss. The changes in insulin in the 1-yr follow-up were significantly correlated to changes in testosterone and SHBG.”

These results illuminate the role of insulin resistance and its association with obesity and PCOS. The authors conclude:

“Weight loss due to lifestyle intervention is effective to treat menses irregularities, normalize androgens, and improve CRF and IMT in obese adolescent girls with PCOS.”

These results add savor to another study published shortly afterward in The American Journal of Clinical Nutrition that offers evidence for the most effective protein/carbohydrate ratio for PCOS. The authors state:

“Some evidence has suggested that a diet with a higher ratio of protein to carbohydrates has metabolic advantages in the treatment of polycystic ovary syndrome (PCOS)…The objective of this study was to compare the effect of a high-protein (HP) diet to a standard-protein (SP) diet in women with PCOS.”

They assigned 57 PCOS women to either a high protein (HP) diet (>40% of energy from protein and 30% of energy from fat) or a standard protein (SP) diet (<15% of energy from protein and 30% of energy from fat). Both diets were without caloric restriction, but dietary counseling was given monthly. At baseline and 3 and 6 mo, They took anthropometric measurements and collected blood samples at the beginning and after 3 and 6 months. The results support the replacement of carbohydrates with protein for women with PCOS:

“The HP diet produced a greater weight loss (mean: 4.4 kg) and body fat loss (mean: 4.3 kg) than the SP diet after 6 mo. Waist circumference was reduced more by the HP diet than by the SP diet. The HP diet produced greater decreases in glucose than did the SP diet, which persisted after adjustment for weight changes. There were no differences in testosterone, sex hormone–binding globulin, and blood lipids between the groups after 6 mo. However, adjustment for weight changes led to significantly lower testosterone concentrations in the SP-diet group than in the HP-diet group.”

Considering that PCOS is driven by elevated insulin levels associated with insulin resistance the authors’ conclusion offers sound guidance:

“Replacement of carbohydrates with protein in ad libitum diets improves weight loss and improves glucose metabolism by an effect that seems to be independent of the weight loss and, thus, seems to offer an improved dietary treatment of PCOS women.”

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Summary: the stress of oxygen starvation that occurs with sleep disordered breathing (sleep apnea and hypopnea) contributes to metabolic syndrome and high blood pressure. CPAP (continuous positive airway pressure) can help .

I have been finding that people coming to our practice who have been struggling with the depredations of metabolic syndrome including overweight, hypertension, elevated lipids and HgbA1c, etc. have not been evaluated for sleep disordered breathing. A study recently published in The New England Journal of Medicine offers evidence that treatment for sleep apnea can provide significant benefit. The authors state:

“Obstructive sleep apnea is associated with an increased prevalence of the metabolic syndrome and its components…In our double-blind, placebo-controlled trial, we randomly assigned patients with obstructive sleep apnea syndrome to undergo 3 months of therapeutic CPAP followed by 3 months of sham CPAP, or vice versa, with a washout period of 1 month in between.”

They measured anthropometric variables, blood pressure, fasting blood glucose levels, insulin resistance, fasting blood lipids, glycated hemoglobin, carotid intima–media thickness, and visceral fat before and after the real and sham CPAP interventions. Their data showed a worthwhile effect:

“A total of 86 patients completed the study, 75 (87%) of whom had the metabolic syndrome. CPAP treatment (vs. sham CPAP) was associated with significant mean decreases in systolic blood pressure (3.9 mm Hg), serum total cholesterol (13.3 mg per deciliter), non–high-density lipoprotein cholesterol (13.3 mg per deciliter), low-density lipoprotein cholesterol (9.6 mg per deciliter), triglycerides (18.7 mg per deciliter), and glycated hemoglobin (0.2%). The frequency of the metabolic syndrome was reduced after CPAP therapy (reversal found in 11 of 86 patients [13%] undergoing CPAP therapy vs. 1 of 86 [1%] undergoing sham CPAP).”

Clinicians should not fail to consider the possibility of sleep disordered breathing when managing hypertension, overweight and other components of metabolic syndrome. Do you snore or wake in the morning unrefreshed and fall asleep inappropriately during the day? If so, a screening may be appropriate. The authors conclude:

“In patients with moderate-to-severe obstructive sleep apnea syndrome, 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities.”

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Summary: In a double-blind crossover study 140 mg per day of resveratrol improved a cluster of markers for metabolism and inflammation that corresponded to the known benefits of caloric restriction.

A study published recently in the journal Cell Metabolism adds more evidence for the beneficial metabolic effects of resveratrol. The authors state:

“Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity.”

They gave 150 mg/day of resveratrol alternating with placebo to eleven obese men in a randomized double-blind crossover study for 30 days. This is quite a small dose (in practice 500 mg two times per day is common). Nonetheless, the benefits were robust:

“Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased.”

In other words, there were meaningful improvements in cellular energy metabolism, liver and blood fats, blood sugar, inflammation, blood pressure and insulin sensitivity (HOMA index). These benefits are similar to those gained from restricting calories. The authors conclude:

“…we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.”

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Summary: women in the highest third of blood glucose levels were almost twice as likely to develop colorectal cancer over the course of the study.

More evidence that high blood sugar contributes to cancer is presented in a study just published in the British Journal of Cancer that examines the link between elevated fasting glucose and colorectal cancer in postmenopausal women. The authors state:

“It is unclear whether circulating insulin or glucose levels are associated with increased risk of colorectal cancer. Few prospective studies have examined this question, and only one study had repeated measurements.”

So they examined baseline fasting serum insulin and glucose values for 4902 non-diabetic women over 12 years, during which 81 cases of colorectal cancer turned up. The data showed a significant trend:

“Baseline glucose levels were positively associated with colorectal cancer and colon cancer risk: multivariable-adjusted hazard ratio (HR) comparing the highest (greater than or equal to 99.5 mg dl−1) with the lowest tertile (<89.5 mg dl−1): 1.74 and 2.25, respectively. Serum insulin and homeostasis model assessment were not associated with risk.”

In other words, glucose in the highest third almost doubles the risk. In this non-diabetic group an association with fasting insulin levels was not observed. However, I can say through extensive experience over 2-3 years having patients suffer through an extended glucose + insulin tolerance test that insulin can be often elevated later in the test but not in the fasting sample. The authors conclude:

“These data suggest that elevated serum glucose levels may be a risk factor for colorectal cancer in postmenopausal women.”

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Summary: in this study prostate size correlated with fasting blood sugar. Elevated fasting glucose is a risk factor for prostate disease.

A study recently published in the Journal of Korean Medical Science offers further evidence for the association between blood glucose regulation and prostate disease. The authors state:

“We evaluated the correlations between BMI, fasting glucose, insulin, testosterone level, insulin resistance, and prostate size in non-diabetic benign prostatic hyperplasia (BPH) patients with normal testosterone levels.”

They examined ata from 212 non-diabetic BPH patients with normal testosterone levels, excluding those with diabetes or serum testosterone levels less than 3.50 ng/mL. Their data showed that…

“Prostate size correlated positively with age, PSA , and fasting glucose level, but not with BMI, testosterone, insulin level, or HOMA-IR.Testosterone level inversely correlated with BMI, insulin level, and HOMA-IR [insulin resistance], but not with age, prostate size, PSA, or fasting glucose. HOMA-IR significantly correlated with BMI, fasting glucose, and insulin level, but not with age, PSA, or prostate size.”

There seems to be a disconnect here regarding the association of prostate size with fasting glucose but not the calculated insulin resistance that requires further investigation. The authors, however, are clear in their conclusion regarding blood sugar and prostate hypertrophy:

“In non-DM BPH patients with normal testosterone levels, fasting glucose level is an independent risk factor for prostate hyperplasia.”

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Summary: Brazil nuts protect against vascular disease in overweight female adolescents.

Recent research published in the journal Nutrition & Metabolism offers evidence that Brazil nuts, besides being more effective at raising serum selenium levels than selenium taken as a supplement, improve the lipid profile and protect against blood vessel damage. The authors state:

“Obesity is a chronic disease associated to an inflammatory process resulting in oxidative stress that leads to morpho-functional microvascular damage that could be improved by some dietary interventions. In this study, the intake of Brazil nuts (Bertholletia excelsa), composed of bioactive substances like selenium, α- e γ- tocopherol, folate and polyunsaturated fatty acids, have been investigated on antioxidant capacity, lipid and metabolic profiles and nutritive skin microcirculation in obese adolescents.”

Their study subjects comprising obese female adolescents were randomized to a group that consumed 15-25 g/day of Brazil nuts in capsules for 16 weeks and a placebo group. Anthropometry, metabolic-lipid profiles, oxidative stress, capillary diameters, functional capillary density, red blood cell velocity (RBCV) were measured at baseline (T0) and after the Brazil nut intervention (T1). What did the data show?

“At T1, BNG [the Brazil nut group] had increased selenium levels, RBCV and RBCVmax and reduced total (TC) and LDL-cholesterol. Compared to PG [placebo group], Brazil nuts intake reduced TC, triglycerides and LDL-ox and increased RBCV.”

In other words, compared to the placebo group, the Brazil nut cohort had better blood vessel function, lower total and LDL cholesterol and, importantly, reduced oxidized cholesterol (LDL-ox, the truly ‘bad’ cholesterol). Naturally, they also had higher selenium levels. The authors conclude:

“Brazil nuts intake improved the lipid profile and microvascular function in obese adolescents, possibly due to its high level of unsaturated fatty acids and bioactive substances.

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Summary: chronic low-grade inflammation is both a damaging result of and a fundamental cause promoting obesity. Management of both weight loss programs and the medical complications of obesity should address the inflammatory component.

An important paper was recently published in the Journal of Clinical Investigation that discusses the role of inflammation in obesity, obesity-related disorders, and metabolic dysfunction. The chronic inflammatory response associated with obesity is has been termed metainflammation:

“Over the past decade, the search for a potential unifying mechanism behind the pathogenesis of obesity-associated diseases has revealed a close relationship between nutrient excess and derangements in the cellular and molecular mediators of immunity and inflammation. This has given birth to the concept of “metainflammation” to describe the chronic low-grade inflammatory response to obesity.”

The authors describe characteristics of the metainflammation of obesity:

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time. Childhood obesity may place individuals at risk for lifelong metainflammation, since inflammatory markers are elevated in obese children as young as 3 years old. Superimposed on this chronic inflammation are recurrent acute episodes of nutrition-related immune activation induced by nutrient availability (fasting or high-fat meals)…Non-biased assessments of gene expression networks in adipose tissue identify a robust pattern of overexpressed inflammatory genes associated with obesity and metabolic disease and enriched for macrophage genes…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Importantly, inflammation itself induces insulin resistance that further promotes obesity:

“Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines, decreases in protective factors (e.g., adiponectin), and communication between inflammatory and metabolic cells. For example, direct and paracrine signals from M1 classically activated macrophages can impair insulin signaling and adipogenesis in adipocytes…Similar effects on adipocyte inflammation and glucose transport are generated by signals from activated conventional T cells such as IFN-γ. In parallel, dysregulated macrophage-myocyte and macrophage-hepatocyte signaling can influence insulin sensitivity.”

They discuss the fascinating observation that obesity is associated with an imbalance of immune regulation characterized by the dominance of Th1 (cell-mediated, with a classical proinflammatory macrophage activation state = M1) over Th2 (antibod-mediated, M2) immune inflammatory activity:

“While ATMs [adipose tissue macrophages] likely assume a number of states along the M1/M2 spectrum depending on fat depot location and nutritional status, increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate.”

Most importantly there are a number points where we may intervene to ‘perturb the system’ in the direction of more balanced immune function, thus reducing inflammation and supporting weight loss:

“…maintaining metabolic homeostasis requires a balanced immune response and an integrated network of multiple cell types. Adipose tissue also contains potent tolerogenic CD4+ Tregs that are downregulated by obesity, a potential initiating event in metainflammation. Likewise, there appear to be innate systems by which nutrient signals are utilized to self-limit inflammation. For example, the obesity-induced increase in expression of GPR120, an omega-3 fatty acid (FA) receptor on macrophages capable of attenuating M1 macrophage activation and increasing M2 gene expression, limits inflammation…”

Also of great interest is the role of brain inflammation in promoting obesity:

“The effects of brain inflammation on the metabolic function of peripheral tissues are broad. Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension. Many of these effects are generated by signals from the sympathetic nervous system, which is also capable of inducing inflammatory changes in adipose tissue in response to neuronal injury…The dynamic interplay between hypothalamic inflammation and obesity suggest additional targets for antiinflammatory therapies in obesity. A key extension of these observations is the potential that antiinflammatory pathways may counteract these CNS inflammatory events and improve leptin sensitivity.”

Obesity must be understood as an active agent, both as cause and result, in the web of chronic inflammation. The greatest clinical success in managing weight loss and chronic inflammatory disorders comes from determining and treating the pro-inflammatory factors involved according to each individual case.

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Summary: Magnesium is important for the prevention and treatment of type 2 diabetes.

The frequency of suboptimal levels of magnesium almost compares to the many critical functions it plays a role in throughout the body. A study just published in the journal Diabetes Care offers fresh evidence of the link between magnesium intake and type 2 diabetes. The authors state:

“Emerging epidemiological evidence suggests that higher magnesium intake may reduce diabetes incidence. We aimed to examine the association between magnesium intake and risk of type 2 diabetes by conducting a meta-analysis of prospective cohort studies.”

They conducted a database search to identify prospective cohort studies of magnesium intake and risk of type 2 diabetes, and applied a random-effects model to compute the summary risk estimates. Data crunching yielded a significant result:

“Meta-analysis of 13 prospective cohort studies involving 536,318 participants and 24,516 cases detected a significant inverse association between magnesium intake and risk of type 2 diabetes (relative risk [RR] 0.78)…In the dose-response analysis, the summary RR of type 2 diabetes for every 100 mg/day increment in magnesium intake was 0.86. Sensitivity analyses restricted to studies with adjustment for cereal fiber intake yielded similar results. Little evidence of publication bias was observed.”

In other words, there was an overall decrease in risk of 22%, and a 14% drop in risk for very 100 mg/day of magnesium consumed. The authors conclude:

“This meta-analysis provides further evidence supporting that magnesium intake is significantly inversely associated with risk of type 2 diabetes in a dose-response manner.”

Clinicians, wondering whether your patient has a significant deficiency but aware that serum and erythrocyte magnesium are poor indicators of intracellular levels? X-ray fluorescence is a validated method for determining reliable tissue levels of magnesium. And it’s easy to collect cellular specimen in the office.

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Summary: the insulin receptor resistance and higher insulin levels of metabolic syndrome are a significant risk factor for kidney disease.

We’ve long known that the kidneys are exquisitely sensitive to damage from higher levels of insulin. A study recently published in the Clinical Journal of the American Society of Nephrology further reveals the contribution metabolic syndrome to chronic kidney disease. Since MetS is on the rise, chronic kidney may too. The authors state:

“Observational studies have reported an association between metabolic syndrome (MetS) and microalbuminuria or proteinuria and chronic kidney disease (CKD) with varying risk estimates. We aimed to systematically review the association between MetS, its components, and development of microalbuminuria or proteinuria and CKD.”

The authors undertook an analysis of eleven studies encompassing 30,146 subjects that reported the development of microalbuminuria or proteinuria and/or CKD in subjects with MetS, with attention to eGFR (estimated glomerular filtration rate, a metric for kidney function). Their data present a clear picture:

“MetS was significantly associated with the development of eGFR <60 ml/min per 1.73 m2 [impaired kidney function]. The strength of this association seemed to increase as the number of components of MetS increased. In patients with MetS, the odds ratios for development of eGFR <60 ml/min per 1.73 m2 for individual components of MetS were: elevated blood pressure 1.61, elevated triglycerides 1.27, low HDL cholesterol 1.23, abdominal obesity 1.19, and impaired fasting glucose 1.14. Three studies reported an increased risk for development of microalbuminuria or overt proteinuria with MetS.”

The ‘take home’ message for clinicians and patients is don’t wait until the onset of type 2 diabetes; bear in mind the authors’ conclusion and take decisive action before delicate kidney tissue is irrevocably lost:

“MetS and its components are associated with the development of eGFR <60 ml/min per 1.73 m2 and microalbuminuria or overt proteinuria.”

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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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