Magnesium and the risk of type 2 diabetes

Posted on October 31, 2011 by Dr. Jonathan

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.

Inflammation caused by allergy promotes weight gain and obesity

Posted on June 29, 2011 by Dr. Jonathan

As clinicians and most lay readers know, healthy weight loss and weight maintenance require healthy insulin signaling. Insulin receptor resistance due to excessive glycemic stimulation results in higher compensatory insulin levels that force the storage of calories as fat. Inflammation also contributes to insulin resistance, with metabolic syndrome and its associated weight gain and eventual type 2 diabetes. A fascinating study just published in the journal Obesity describes how B cell-activating factor (BAFF) contributes to the development of insulin resistance. BAFF can be induced by food hypersensitivity and allergic reactions. The authors state:

“Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell-activating factor (BAFF) in the induction of insulin resistance.”

They examined BAFF levels in the blood and visceral fat of obese mice, which they found to be increased compared to normal control mice…

“Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes.”

In other words, BAFF not only directly induced insulin resistance, but altered the expression of genes related to insulin receptor function and fat inflammatory cytokine (adipokine) production. The authors concluded:

“We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF-R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.”

We can also appreciate an earlier paper published in the journal Experimental & Molecular Medicine that also identifies BAFF as an adipokine that links inflammation with obesity. The authors state:

“In the current study, we verified that BAFF expression is increased during adipocyte differentiation…We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation…BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions…”

They also demonstrated that the BAFF receptors BAFF-R and BCMA were downregulated by rosigliatazone treatment. (Rosigliatzone, trade name Avandia, is a thiazolidinedione type anti-diabetic drug with anti-inflammatory properties whose use has been complicated by serious side effects.) In other words, inflammation associated with BAFF signaling promoted insulin resistance and obesity. The authors conclude:

“Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.”

Incidentally, as the authors of a review just published in the Journal of Clinical Investigation note, obesity-associated inflammation has serious global effects:

“The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity…The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases.”

Moreover…

“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…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.”

Clinicians should never overlook the role of the gut-associated immune tissue (GALT) in disorders of chronic inflammation. A paper just published in Current Opinion in Clinical Nutrition & Metabolic Care highlights this in the link between intestinal inflammation, obesity and insulin resistance. The authors state:

“Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity…”

They go on to summarize…

“…the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms.”

Of course, food allergy and hypersensitivity are major causes of intestinal inflammation. Regrettably, many practitioners may wrongly assume that the phenomenon of inflammation triggered by food sensitivity is limited to the classically defined IgE-mediated acute hypersensitivity reaction. In fact, there are a number of pathways by which food sensitivity can elicit an inflammatory response. A very important study just published in Alimentary Pharmacology & Therapeutics makes this clear in regard to BAFF, which we now understand to be linked to obesity and insulin resistance. The authors first note that…

“Medically confirmed hypersensitivity reactions to food are usually IgE-mediated. Non-IgE-mediated reactions are not only seldom recognized but also more difficult to diagnose.”

They set out to…

“…examine B cell-activating factor (BAFF) in serum and gut lavage fluid of patients with self-reported food hypersensitivity, and to study its relationship to atopic disease.”

So they examined the gut lavage fluid obtained from 60 patients with self-reported food hypersensitivity and the serum from 17 others. From 20 healthy control subjects they obtained gut lavage fluid, along with serum from 11 of them. They then measured BAFF in both serum and the gut lavage fluid. Their findings are most interesting:

“B cell-activating factor levels in serum and gut lavage fluid were significantly higher in patients than in controls…There was no significant correlation between serum levels of BAFF and IgE.”

In other words, patients with food hypersensitivity produced significantly higher levels of BAFF–and IgE failed as an indicator of BAFF associated inflammation with food hypersensitivity. The authors add in their conclusion:

“The results suggest that BAFF might be a new mediating mechanism in food hypersensitivity reactions. Significantly higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be involved particularly in non-IgE-mediated reactions.”

Unfortunately, food hypersensitivity is too often dismissed by many in the medical community as a poorly understood phenomenon that ends up being ignored in clinical practice. A clinical study review recently published in the Scandinavian Journal of Gastroenterology investigates this issue and observes the role of BAFF:

“Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years’ interdisciplinary research program dealing with such patients.”

The studies included more than 400 adults who were referred to a university hospital because of gastrointestinal complaints that they attributed to food hypersensitivity. Most not only fulfilled criteria for irritable bowel syndrome…

“…In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life.”

Sadly…

“Despite extensive examinations, food allergy was seldom diagnosed…However, psychological factors could explain only approximately 10% of the variance in the patients’ symptom severity and 90% of the variance thus remained unexplained.”

Moreover…

“Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and “IgE-armed” mast cells.”

Atopic dermatitis (the most common form or eczema, also linked to food sensitivity) has been shown to be associated with high levels of B cell-activating factor (BAFF) in a paper published not long ago in the journal Clinical and Experimental Dermatology. In order to investigate the role of BAFF in serum of patients with atopic dermatitis (AD)…

“Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.”

Their data showed a distinct association:

“Patients were characterized as having atopic eczema (AE); the remainder were healthy control subjects. Serum BAFF level in children with AE was significantly higher than in non-AE children or healthy controls.“

Not surprisingly considering immune function in the common mucosal barrier system, there is also evidence that B-cell activating factor is induced by airborne hypersensitivity reactions. A study published in The Journal of Allergy and Clinical Immunology documents the increased production of BAFF in the airway tissues after exposure to antigen. The authors state:

“The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B cell survival and immunoglobulin class switch recombination, in bronchoalveolar lavage (BAL) fluid after segmental allergen challenge (SAC) of allergic subjects.”

They measured the amount of B cell-active cytokines including BAFF in bronchoalveolar lavage (BAL) fluid after 16 adult allergic subjects where challenged with allergens or saline. The data showed a clear result:

“BAFF protein was significantly elevated in BAL fluid after allergen challenge compared with those at saline sites…BAFF levels were also significantly correlated with other B cell-activating cytokines, IL-6 and IL-13.”

As in the gut, inflammation due to allergen exposure elevated BAFF levels. The authors conclude:

“These findings imply that exposure to antigen in the airway activates a process that stimulates the release of cytokines, including BAFF and others, that are known to promote CSR [class switch recombination = a change in antibody production by B cells] and immunoglobulin synthesis by B cells.”

Finally, B cell-activating factor expression due to gluten sensitivity deserves special mention because of the insidious and distinctively injurious nature of gluten reactions. An interesting study published in the Scandinavian Journal of Gastroenterology investigates this phenomenon, while referring to the link between celiac disease, BAFF and lymphoma. The authors state:

“The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD.”

They examined serum BAFF levels, anti-transglutaminase (a-tTG) and endomysial antibodies in 73 patients with celiac disease confirmed by biopsy and laboratory tests before starting a gluten free diet (GFD), while using 77 blood donors as controls. Their data painted a most interesting and dramatic picture:

“Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels…”

And happily…

“…there was a significant reduction of BAFF after introduction of a GFD [gluten-free diet].”

To summarize the significance for obesity and weight loss:

B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
A sucessful and physiologically sound weight loss and maintenance program should have a strategy to control inflammation and BAFF signaling. This includes the diagnosis of food allergy or sensitivity, with special emphasis on proper screening for reactions to gluten.

As insulin goes up so does the danger of arterial plaques

Posted on April 15, 2011 by Dr. Jonathan

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.

Trans-palmitoleate, a good fat in dairy products

Posted on February 7, 2011 by Dr. Jonathan

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.”

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

Posted on November 21, 2010 by Dr. Jonathan

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.“

Coffee polyphenols may suppress body fat accumulation

Posted on November 14, 2010 by Dr. Jonathan

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

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

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

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

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

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

Most US doctors are still not paying proper attention to blood sugar

Posted on October 30, 2010 by Dr. Jonathan

It’s disturbing and worrisome to see how few doctors seem to be alert to the blood sugar dysregulation that precedes type 2 diabetes and many other chronic diseases in their patients as evidenced by a study just published in the journal Diabetes Care. The authors conducted their investigation to…

“…estimate the rates of prevalence, diagnosis, and treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).”

They examined a representative sample of the U.S. population that included 1,547 nondiabetic adults without a history of heart attack to determine the proportion who met the criteria for IFG/IGT, and the proportion of them who: 1) received a diagnosis from their physicians; 2) were prescribed lifestyle modification or medication for blood sugar; or 3) were currently on therapy. Their data painted a dismal picture:

“Of the 1,547 subjects, 34.6% had pre-diabetes; 19.4% had IFG only; 5.4% had IGT only, and 9.8% had both IFG and IGT. Only 4.8% of those with pre-diabetes reported having received a formal diagnosis from their physicians. No subjects with pre-diabetes received oral antihyperglycemics, and the rates of recommendation for exercise or diet were 31.7% and 33.5%, respectively.”

Yikes. It’s really up to the patient to be informed (one of the purposes of this blog) and seek proper care. Blood sugar dysregulation wrecks almost everything that clinicians practicing according to the functional model try to do to correct brain, hormone and immune dysregulation. It’s importance as a clinical focus is hard to over-emphasize. The authors’ disappointment is almost palpable in their conclusion:

“Three years after a major clinical trial demonstrated that interventions could greatly reduce progression from IFG/IGT to type 2 diabetes, the majority of the U.S. population with IFG/IGT was undiagnosed and untreated with interventions. Whether this is due to physicians being unaware of the evidence, unconvinced by the evidence, or clinical inertia is unclear.”

Perhaps this says something about why the scientists who authored another paper in the same issue of Diabetes Care saw fit to ask whether sugar-sweetened beverages would contribute to the risk of metabolic syndrome and type 2 diabetes (!):

“Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.”

Their meta-analysis included 310,819 participants from 11 acceptable studies. It’s troubling to allow that there may be physicians who might not anticipate the conclusion that their data defined:

“In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.”

It seems that even fewer physicians and their patients are aware of the role of glucose in ‘feeding’ cancer and the research being done to block the metabolism of sugar by tumor cells as described in a paper just published in the journal Oncogene. The authors state:

“Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials.”

While research investigates possible interventions to aggressively interrupt the glycolytic metabolism of tumor cells, doctors should assist their patients in controlling blood sugar and insulin (another tumor promoter) with the appropriate tools:

“Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels…Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death…”

Blood sugar dysregulation contributes to most chronic diseases including cardiovascular, autoimmune, neurodegenerative and malignant conditions. Supporting healthy blood sugar and insulin regulation is one of the most important things that practitioners and their patients can do together.

Alzheimer’s disease and insulin resistance

Posted on September 23, 2010 by Dr. Jonathan

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

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

They structured their investigation by setting out to…

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

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

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

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

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

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

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

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

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

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

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

Type 2 diabetes in children can have an autoimmune component

Posted on September 14, 2010 by Dr. Jonathan

Most practitioners and parents think of type 2 diabetes (T2DM) as a metabolic disorder that emerges when the pancreas can no longer keep up with the increasing need for insulin as receptor resistance grows worse. There is growing evidence that T2DM in children and adults is in many cases complicated by the same autoimmune phenomena as in type 1 diabetes. A study just published in the journal Diabetes Care adds to the evidence. The authors set out to:

“…determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.”

They screened 1,206 children ages (10-17) who were known to have type 2 diabetes for GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, performed physical examinations, and measured fasting lipids, C-peptide, and HgbA1C. What did the data show?

“Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive…Diabetes autoantibody (DAA) positivity was significantly associated with race, with positive subjects more likely to be white (40.7 vs. 19% and male (51.7 vs. 35.7%. BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype…”

A clinical ‘pearl’ embedded here is that if a youth with T2DM does not have the characteristics of metabolic syndrome (overweight, etc.), there is strong suspicion of an autoimmune component to their condition. This must, however, be determined by a blood test for the autoantibodies. The authors conclude:

“Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.”

Blood sugar and the brain in learning and behavioral disorders

Posted on September 5, 2010 by Dr. Jonathan

The brain needs a steady supply of glucose to work normally. Disorders of blood sugar regulation, whether hypoglycemia or insulin resistance (precursor to type 2 diabetes), deprives the brains cells of the fuel to produce the energy they need to function. Research just published in the journal Diabetologia examines the cognitive impairments present in adolescents when insulin resistance and overweight have progressed to type 2 diabetes.

“Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes…Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops.”

The authors compared two groups of overweight adolescents, one with and the other without type 2 diabetes. The depredations of insulin resistance on the brain were stunning:

“Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency…[and] executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular… In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity.”

The authors conclusion places both clinicians and parents on the alert:

“These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease.”

On the hypoglycemic pole of glucose regulation we can appreciate earlier fascinating research published Pediatric Research documenting an impaired neurotransmitter response to falling blood sugar in children with ADD (the catecholamines epinephrine and norepinephrine attenuate the drop in blood sugar).

“Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children with attention deficit disorder (ADD)…metabolic, hormonal, and cognitive responses to a standard oral glucose load (1.75 g/kg) were compared in 17 children with ADD and 11 control children.”

Their data showed a significant difference between ADD and control children:

“The late glucose fall stimulated a rise in plasma epinephrine that was nearly 50% lower in ADD than in control children. Plasma norepinephrine levels were also lower in ADD than in control children…”

The authors’ conclusion indicates the need for conscientious blood sugar management through dietary and other measures:

“These data suggest that children with ADD have a general impairment of sympathetic activation involving adrenomedullary as well as well as central catecholamine regulation [of blood sugar].”

Similar phenomena are presented in a paper published in the Journal of the American Academy of Child & Adolescent Psychiatry describing abnormalities of brain metabolism in girls with ADHD:

“This study assesses the effect of attention-deficit hyperactivity disorder (ADHD) and gender on cerebral glucose metabolism (CMRglu), using positron emission tomography and 18F-fluorodeoxyglucose.”

An interesting gender difference emerged from the data:

“However, the global CMRglu in ADHD girls was 15.0% lower than in normal girls, while global CMRglu in ADHD boys was not different than in normal boys. Furthermore, global CMRglu in ADHD girls was 19.6% lower than in ADHD boys and was not different between normal girls and normal boys.”

Gender differences that must be respected are pronounced here and throughout medicine and biology:

“The greater brain metabolism abnormalities in females than males strongly stress that more attention be given to the study of girls with ADHD.”

Addressing the dysfunctions in blood sugar dysregulation associated with disorders of learning and behavior requires understanding that deleterious eating conducts can manifest as a form of self-medication. A paper recently published in Current Psychiatry Reports brings attention to this:

“In the past decade, we have become increasingly aware of strong associations between overweight/obesity and symptoms of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults.”

The need to satisfy imperious physiological urges on a cellular level when an individuals genetic needs are not being met can overwhelm all advice and intention to acquire more wholesome and sustainable habits:

“It is also proposed—based on the compelling evidence that foods high in fat, sugar, and salt are as addictive as some drugs of abuse—that excessive food consumption could be a form of self-medication. This view conforms with the well-established evidence that drug use and abuse are substantially higher among those with ADHD than among the general population.”

True remediation demands a functional medicine approach to resolve the underlying cellular and metabolic needs that are not being met so they can be supported in a physiological and sustainable manner to restore normal function.

A paper published in the Journal of Nutrition, Health & Aging brings us back to the fundamental importance of glucose regulation for the brain.

“The regulation of glycaemia (thanks to the ingestion of food with a low glycaemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the brain consumes more than 50% of dietary carbohydrates, approximately 80% of which are used only for energy purpose. In infants, adults and aged, as well as in diabetes, poorer glycaemic control is associated with lower performances, for instance on tests of memory. At all ages, and more specifically in aged people, some cognitive functions appear sensitive to short term variations in glucose availability.“