Category Archives: Insulin & Diabetes

Metabolic syndrome promotes cognitive decline

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More evidence that metabolic syndrome, and its root causal factor insulin resistance, are damaging to the brain and promote cognitive decline appears in a study just published in the journal Neurology. The authors set out to…

“…examine associations between metabolic syndrome (MetS) and its individual components with risk of cognitive decline on specific cognitive functions.”

The assessed 4,323 women and 2,764 men aged 65 and over for cognitive decline and metabolic syndrome (possessing at least 3 of 5 cardio-metabolic abnormalities: hypertension, high waist circumference, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, hyperglycemia). The risk evaluation was adjusted for a number of variables including the APOE4 genotype. What did their data show?

“MetS at baseline was associated with an increased risk of cognitive decline on MMSE [Mini-Mental State Examination for global cognitive function]…. Among MetS components, hypertriglyceridemia and low HDL cholesterol were significantly associated with higher decline on MMSE; diabetes, but not elevated fasting glycemia, was significantly associated with higher decline on BVRT [Benton Visual Retention Test for visual working memory]and IST [Isaacs Set Test for verbal fluency].”

The practical message for clinicians and the public is that blood sugar and insulin regulation are critical factors for brain health. Management begins with diet and lifestyle factors including exercise and encompasses specific needs for supplementation as determined by reliable laboratory investigations that disclose individual genetic and epigenetic factors. The authors conclude:

“MetS as a whole and several of its components had a negative impact on global cognitive decline and specific cognitive functions in older persons.“

Pro-aging signaling, cancer and diabetes are reduced with LESS growth hormone effect

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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.”

Trans-palmitoleate, a good fat in dairy products

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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.”

Children with sleep schedule irregularity or shorter sleep duration more prone to obesity

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Sleep disorders are well known to have metabolic consequences for adults, but what about children? A study just published in the journal Pediatrics suggests that suboptimal sleep timing and duration have adverse effects on the metabolism of children too that promote obesity and metabolic dysfunction. The authors state:

“The goal was to explore the effects of duration and regularity of sleep schedules on BMI [body mass index] and the impact on metabolic regulation in children.”

The examined the sleep patterns of 308 children ages 4 to 10 for associations with BMI; fasting glucose, insulin, lipids (blood fats), and hsCRP (high sensitivity C-reactive protein, a marker for vascular inflammation). Their data support the importance of sleep for the pediatric metabolism:

“For obese children, sleep duration was shorter and showed more variability on weekends, compared with school days. For overweight children, a mixed sleep pattern emerged. The presence of high variance in sleep duration or short sleep duration was more likely associated with altered insulin, low-density lipoprotein, and high-sensitivity C-reactive protein plasma levels. Children whose sleep patterns were at the lower end of sleep duration, particularly in the presence of irregular sleep schedules, exhibited the greatest health risk.”

The authors’ conclusion supports a public health effort to reduce obesity and metabolic dysfunction in children by promoting regular sleep schedules:

“…the combination of shorter sleep duration and more-variable sleep patterns was associated with adverse metabolic outcomes. Educational campaigns, aimed at families, regarding longer and more-regular sleep may promote decreases in obesity rates and may improve metabolic dysfunction trends in school-aged children.”

Magnesium improves insulin sensitivity

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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.

Body fat distribution, insulin and breast cancer

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A report just published in the Journal of the National Cancer Institute adds more evidence to the importance of insulin regulation in ER (estrogen receptor) negative breast cancer. The authors first note a conundrum in breast cancer epidemiology:

“Body mass index is inversely associated with risk of premenopausal breast cancer, but the underlying mechanisms for this association are poorly understood. Abdominal adiposity is associated with metabolic and hormonal changes, many of which have been associated with the risk of premenopausal breast cancer.”

They investigated the association between body fat distribution, hip circumference, and waist to hip ratio, and the incidence of premenopausal breast cancer in the Nurses’ Health Study II:

“During 426 164 person-years of follow-up from 1993 to 2005, 620 cases of breast cancer were diagnosed among 45 799 women. Hormone receptor status information was available for 84% of the breast cancers.”

When they looked at the group as a whole, no statistically significant associations were found. However…

“…each of the three body fat distribution measures was statistically significantly associated with greater incidence of estrogen receptor (ER)–negative breast cancer.”

The risk for ER-negative breast cancer was increased by 275% for waist circumference, 240% for hip circumference, and 195% for waist to hip ratio (comparing the highest to the lowest quintile). The authors state:

“These findings may suggest that an insulin-related pathway of abdominal adiposity is involved in the etiology of premenopausal breast cancer.“

The implication is that factors associated with increased abdominal adiposity influence the development of breast cancer through estrogen independent pathways, specifically the influence of excess levels of insulin on tumor growth that also promote the accumulation of fat around the waist. As experienced clinicians know, tumors often have mixed cell types. The role of insulin as a tumor promoter should never overlooked in case management, with careful attention to the regulation of blood sugar and insulin.

Choice of breakfast staple impacts brain size and cognition in children

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A fascinating study conducted by Japanese researchers just published in PLoS One (Public Library of Science) demonstrates a significantly larger brain volume and a higher IQ in healthy children depending on whether their breakfast staple was rice or bread. The authors state:

“Childhood diet is important for brain development. Furthermore, the quality of breakfast is thought to affect the cognitive functioning of well-nourished children. To analyze the relationship among breakfast staple type, gray matter volume, and intelligence quotient (IQ) in 290 healthy children, we used magnetic resonance images and applied voxel-based morphometry.”

They divided their study groups into those children who consumed rice, bread or both as their breakfast staple, controlled for a range of dietary, biological and socioeconomic variables, and analyzed the data.

“We showed that the rice group had a significantly larger gray matter ratio (gray matter volume percentage divided by intracranial volume) and significantly larger regional gray matter volumes of several regions, including the left superior temporal gyrus…The perceptual organization index (POI; IQ subcomponent) of the rice group was significantly higher than that of the bread group.”

Their study didn’t investigate what would be the underlying causes of such a difference, but they speculated that glycemic index may play a role:

“Although several factors may have affected the results, one possible mechanism underlying the difference between the bread and the rice groups may be the difference in the glycemic index (GI) of these two substances; foods with a low GI are associated with less blood-glucose fluctuation than are those with a high GI.”

However, the glycemic index of both rice and bread is relatively high compared to eggs. Drawing on a large body of published research, we can rationally advance the idea that gluten may be the decisive factor in the documented differences in brain volume and IQ. It is difficult to argue with their conclusion:

“Our study suggests that breakfast staple type affects brain gray and white matter volumes and cognitive function in healthy children; therefore, a diet of optimal nutrition is important for brain maturation during childhood and adolescence.”

Which diet is better for keeping weight off?

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An international study just published in The New England Journal of Medicine provides the most robust evidence so far that a high protein + low glycemic index diet is best for weight maintenance. The authors observe:

“Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power.”

773 overweight adults from eight European countries who completed an initial low-calorie weight loss phase were randomized to follow one of five diets for weight maintenance: a low-protein and low-glycemic-index diet, a low-protein and high-glycemic-index diet, a high-protein and low-glycemic-index diet, a high-protein and high-glycemic-index diet, or a control diet. The diets were ‘ad libitum’, meaning they were allowed to eat freely within the constraints of their diet plan. What did the data show?

“…only the low-protein–high-glycemic-index diet was associated with subsequent significant weight regain. In an intention-to-treat analysis, the weight regain was 0.93 kg less in the groups assigned to a high-protein diet than in those assigned to a low-protein diet and 0.95 kg less in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet.”

Moreover, it seems that the high-protein and low-glycemic-index groups were more comfortable:

“Fewer participants in the high-protein and the low-glycemic-index groups than in the low-protein–high-glycemic-index group dropped out of the study.”

Thus the authors conclude:

“In this large European study, a modest increase in protein content and a modest reduction in the glycemic index led to an improvement in study completion and maintenance of weight loss.”

Blood sugar dysregulation damages learning and memory

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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.”

Insulin resistance marks Alzheimer’s disease risk at the earliest stage

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An important paper recently published in the Archives of Neurology offers evidence that insulin resistance is a causal factor for Alzheimer’s disease at its earliest stages. The authors observe:

“Insulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fludeoxyglucose F 18–positron emission tomography (FDG-PET) in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset.“

With this in mind they set out to…

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

In other words, the authors correlated glucose and insulin measurements, brain scans of glucose metabolism and a radioactive emission brain scan (fludeoxyglucose F 18–positron emission tomography)  during a memory encoding task. What did the data show?

“Greater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D…During the memory encoding task, healthy adults showed activation in right anterior and inferior prefrontal cortices, right inferior temporal cortex, and medial and posterior cingulate regions. Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.“

The authors’ conclusion adds to the weight of evidence indicating that blood sugar dysregulation and insulin resistance are fundamental causal factors and early risk indicators for Alzheimer’s disease:

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