Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”


Magnesium mediates insulin resistance, diabetes risk

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

Magnesium and diabetes

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

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

 Prediabetes and insulin resistance

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

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

Condensing these results they state:

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

In the clinic

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

The authors conclude:

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

HgbA1c (hemoglobin A1c) predicts prediabetes better than glucose

HgbA1c predicts prediabetesHgbA1c (hemoglobin A1c) is hemoglobin that has been ruined by glycation (bonding with sugar). It has long been recognized as a biomarker for average glucose over an approximately three month time span as well as a metric for the degree of damaging glycation occurring throughout the body. Now further evidence for its superior value as a predictor for prediabetes is presented in a study just published in The Lancet Diabetes & Endocrinology.The authors…

“…compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions.”

HgbA1c compared to fasting and 2 hour glucose

They compared several prediabetes definitions in their ability to predict major long-term health problems. They analyzed data from over seven thousand subjects drawn from four communities across the USA who participated in the Atherosclerosis Risk in Communities (ARIC) study. HgbA1c was pitted against fasting and 2 hour postprandial glucose:

“Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6–6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1–6·9 mmol/L), HbA1c (ADA HbA1ccutoff 5·7–6·4% [39–46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0–6·4% [42–46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8–11·0 mmol/L).”

HgbA1c better identifies those at risk for diabetes and serious complications

Chronic kidney disease, cardiovascular disease and death were more accurately predicted by HgbA1c than by fasting glucose:

“After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories. The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions.”

Clinical Significance

HgbA1c study reviewed in Medscape Family Medicine

Medscape Family Medicine remarks:

“The researchers found that using an HbA1c-based definition, those identified as having prediabetes were 50% more likely to develop kidney disease, twice as likely to develop CVD, and 60% more likely to die from any cause compared with those with normal HbA1c.”

The authors, quoted in Medscape Family Medicine, comment on the practical significance of their findings:

“When someone is told they have prediabetes, we hope it will cause them to make changes to their habits in order to prevent the development of diabetes and its complications,” added the study’s senior author, Elizabeth Selvin, PhD, MPH, a professor in the Bloomberg School’s department of epidemiology.

“Being identified as having prediabetes can also make it easier to receive weight-loss and nutritional counseling as well as reimbursement for these services. Intensive lifestyle changes and weight loss can reduce the risk of diabetes, so it is critically important we identify those persons who are at high risk.

At the same time, we also don’t want to overdiagnose people. Using the hemoglobin A1c test allows us to more accurately identify those persons at highest risk,” she added.

This is important information for physicians and it is also important information for professional organizations. Coming to a global consensus on how to define and diagnose prediabetes would really help move the field forward — and help patients all over the world,” she concluded.”

The authors conclude:

“Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall.”

Stroke risk reduced by magnesium

StrokeStroke risk is reduced by higher plasma magnesium levels according to data from 32,826 women in the Nurses’ Health Study presented in a paper just published in the journal Stroke. The authors note:

Lower plasma magnesium levels may be associated with higher blood pressure and endothelial dysfunction, but sparse prospective data are available for stroke.”

So they compared plasma magnesium in stroke cases with controls matched for age, race/ethnicity, smoking status, date of blood draw, fasting status, menopausal status, and hormone use. Women with magnesium levels* that I see in lab reports had a signficantly increased risk for stroke:

“Conditional on matching factors, women in the lowest magnesium quintile had a relative risk of 1.34 for total ischemic stroke compared with women in the highest quintile. Additional adjustment for risk factors and confounders did not substantially alter the risk estimates for total ischemic stroke. Women with magnesium levels <0.82 mmol/L* had significantly greater risk of total ischemic stroke (multivariable relative risk, 1.57) and thrombotic stroke (multivariable relative risk, 1.66) compared with women with magnesium levels ≥0.82 mmol/L. No significant effect modification was observed by age, body mass index, hypertension, or diabetes mellitus.”

Magnesium is an anti-inflammatory agent

Clinical key  point: Cardiovascular and cerebrovascular disease have a well-known inflammatory component. Besides lowering blood pressure and promoting healthy endothelial function, magnesium is ‘nature’s anti-inflammatory mineral’ that supports parasympathetic nervous system function with a calming, anti-spasmodic effect.

* Plasma magnesium <0.82 mmol/L = 2.0 mg/dL.

The authors conclude:

Lower plasma magnesium levels may contribute to higher risk of ischemic stroke among women.”

Magnesium, inflammation and endothelial function

American Journal of Clinical NutritionRegarding additional mechanisms by which magnesium status is linked to stroke and cardiovascular disease, a study published in the American Journal of Clinical Nutrition provides evidence that magnesium is important for endothelial (blood vessel lining) health:

“We conducted a cross-sectional study of 657 women from the Nurses’ Health Study cohort who were aged 43-69 y and free of cardiovascular disease, cancer, and diabetes mellitus when blood was drawn in 1989 and 1990. Plasma concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor alpha receptor 2 (sTNF-R2), E-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. Estimates from 2 semiquantitative food-frequency questionnaires, administered in 1986 and 1990, were averaged to assess dietary intakes.”

E-selectin recruits white blood cells to engage in the endothelial inflammatory process. The authors demonstrated a  role for magnesium significant for stroke:

“…magnesium intake was inversely associated with plasma concentrations of CRP, E-selectin, and sICAM-1. After further adjustment for physical activity, smoking status, alcohol use, postmenopausal hormone use, and body mass index, dietary magnesium intake remained inversely associated with CRP and E-selectin. Multivariate-adjusted geometric means for women in the highest quintile of dietary magnesium intake were 24% lower for CRP and 14% lower for E-selectin than those for women in the lowest quintile.”

Magnesium reduces CRP

Archives of Medical ResearchA recent study published in Archives of Medical Research also shows anti-inflammatory effect of magnesium in lowering CRP:

“It has been suggested that magnesium deficiency is associated with the triggering of acute phase response, which may contribute to type 2 diabetes and cardiovascular disease risk. We undertook this study to determine whether oral magnesium supplementation modifies serum levels of high-sensitivity C-reactive protein (hsCRP) in apparently healthy subjects with prediabetes and hypomagnesemia.”

The authors examined the effect of magnesium supplementation on 62 men and non-pregnant women aged 18–65 years who were newly diagnosed with prediabetes and hypomagnesemia (serum magnesium levels <0.74 mmol/L/1.8 mg/dL) for the effects of daily supplementation with magnesium in a double-blind placebo-controlled trial, leading to their conclusion…

Oral magnesium supplementation decreases hsCRP levels in apparently healthy subjects with prediabetes and hypomagnesemia.”

Prediabetes also damages the heart

CirculationPrediabetes—elevation of blood glucose still within the ‘normal’ range—was recently reported to increase cancer risk; now a study just published in the journal Circulation demonstrates that prediabetes causes unfelt damage to the heart that substantially raises the risk of future coronary artery disease and heart failure regardless of cholesterol levels. The authors…

“…measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at two time points, 6 years apart, among 9,331 participants…with no diabetes, prediabetes, or diabetes but without cardiovascular disease including silent MI by ECG. First, we examined incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ~14 years of follow-up among persons with and without incident elevated hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes, prediabetes, and diabetes were 3.7%, 6.4%, and 10.8%, respectively. Compared to normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.38 for prediabetes and 2.46 for diabetes. Persons with diabetes and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (HR 6.37), death (HR 4.36) and coronary heart disease (HR 3.84) compared to persons without diabetes and no incident elevation in hs-cTnT. “

DG NewsThat’s a 600% increase in risk of heart failure, 400% increase in death and 380% increase in coronary artery disease. Lead author Elizabeth Selvin, PhD of the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland was quoted in DG News:

It puts what we know about heart damage in diabetes on its head…It looks like diabetes may be slowly killing heart muscle in ways we had not thought of before.”

Regardless of cholesterol and without symptoms

Because the risk of cardiovascular disease associated with prediabetes and diabetes may have nothing to do with cholesterol:

Statin treatment may not be sufficient to prevent damage to the heart in people with diabetes.”

It’s important for clinicians and patients to keep mind that this kind of damages goes on ‘under the hood’ without apparent symptoms:

Even though there may be no symptoms yet, our research suggests there is microvascular damage being done to the heart which is leading to heart failure and even death.”

The authors of the study state in conclusion:

Prediabetes and diabetes were independently associated with development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular etiology. “

Prediabetes increases cancer risk

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

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

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

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

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

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

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

Hyperglycemia, advanced glycation end-products and oxidative damage

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

Insulin resistance

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


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

The public health implications of their results are enormous:

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

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

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

Inflammation and diabetes

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

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

Breast cancer and glucose intolerance

PLOS ONEBreast cancer, insulin resistance and blood sugar dysregulation are associated, and more evidence for the breast cancer link with glucose intolerance is presented in a study just published in PLOS ONE (Public Library of Science). The authors used oral glucose tolerance tests (OGTT) to assess breast cancer patients at their initial diagnosis and during chemotherapy and found a persistent association:

“The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5%, 50.6% and 28.1%, and 25.3% and 33.3%, respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT.”

It is fundamentally important to regulate blood glucose and insulin in oncologic case management since high glycation and insulin promote disease progression. The authors conclude:

Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.”

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

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.