High Glucose Linked to Poorer Memory, Even in People Without Diabetes.

Higher levels of both short-term and long-term blood glucose markers are significantly associated with poorer memory and with decreased volume and microstructure of the hippocampus in persons without diabetes or impaired glucose tolerance (IGT), according to a new study.

The results imply that lowering blood glucose levels, possibly even to relatively low levels, might help preserve cognition, study author Agnes Flöel, MD, Department of Neurology and Center for Stroke Research Berlin, Charite-University Medicine, Berlin, Germany, toldMedscape Medical News.

Strategies that help lower blood glucose levels include a healthy Mediterranean-type diet and regular physical activity, she added.

The study is published online October 23 in Neurology.

Direct Relationship

The cross-sectional study included 141 healthy persons (mean age, 63.1 years) who were recruited through advertising. Persons with diabetes, IGT, or neurologic disorders and those taking antidepressants were excluded.

Researchers obtained blood measurements, including glycosylated hemoglobin (HbA1c), which reflects peripheral glucose levels of the preceding 8 to 12 weeks; fasting glucose; and insulin. They also carried out apolipoprotein E (APOE) genotyping.

Participants underwent cognitive testing using the German version of the Rey Auditory Verbal Learning Test. Researchers calculated hippocampal volume from MRI scans and assessed hippocampal microstructure by mean diffusivity (MD) estimated by using diffusion tensor imaging.

According to Dr. Flöel, this was the first time that this MD method provided data on the association between hippocampal microstructure and glucose metabolism.

The investigators found that lower performance on 3 memory tasks (delayed recall, learning ability, and consolidation) was associated with higher levels of both the long-term marker of glucose control (HbA1c) and the short-term glucose marker (all P ≤ .01).

For insulin, there was a “general trend going in the same direction” but correlations were less clear, and without the same direct relationship, said Dr. Flöel.

Potential Mechanisms

Memory performance was correlated with hippocampal volume (P = .001) and lower MD (P = .01), lower age, and, in part, lower blood pressure and female sex. Researchers did not find a statistically significant association between memory performance and APOE genotype, body mass index, Beck Depression Inventory score, physical activity, or smoking.

Lower levels of HbA1c were associated with larger hippocampal volume (nonsignificant trend; P = .06). The associations between lower fasting glucose levels and higher hippocampal volume did reach significance (P = .01). There was no significant relationship between hippocampal volume and insulin.

As for hippocampal microstructure, the researchers noted that lower levels of all 3 markers of glucose metabolism significantly correlated with lower MD within the hippocampus.

There was no significant association between glucose markers and volume or MD in brain areas other than the hippocampus (eg, gray matter and thalamus).

The hippocampus is particularly vulnerable to disturbances in metabolic supply, including glucose, said Dr. Flöel.

“Elevated blood sugar levels may damage the outer membrane of the cells, or decrease neurotransmitter levels, which would disturb signaling within and between hippocampal cells. Information transfer between cells, which is indispensable for memory encoding, storage and retrieval, would then be compromised.”

Elevated blood sugar levels may also damage small and large vessels in the brain, leading to decreased blood and nutrient flow to brain cells or even brain infarcts, and this may further damage memory-relevant brain structures, added Dr. Flöel.

The current findings are in line with studies of patients with type 2 diabetes mellitus and IGT, but earlier research was unable to confirm the deleterious effects of nondiabetic glucose levels on cognition. This, said the authors, may be because of different methods for classifying glucose levels and varying cognitive tests used.

Prevention Research

The authors also pointed out that the current study used MRI with higher magnetic field strength, which offers a higher sensitivity of hippocampal volumetry and greater statistical power to observe significant associations.

Following a diet high in lean protein and complex carbohydrates (such as whole grains, vegetables, fruits, and fiber) and low in heavily refined foods will help lower blood glucose, said Dr. Flöel. Another important lifestyle strategy is regular physical activity.

How low is it safe to go in terms of blood glucose levels? According to Dr. Flöel, that depends in part on lifestyle. “If you’re used to low blood sugar levels, you can go quite low,” she said.

She likened this to the situation with blood pressure. “At one time, it was assumed that you needed a certain level to function, but that actually is not true. You can go very low and still maintain normal function, and it might actually be better in the long run.”

Although the study uncovers the protective potential of lower blood glucose levels, the relationship between high blood glucose and poor memory “seems to be more linear” and changing recommended cutoffs may not make much of a difference, said Dr. Flöel.

On the other hand, what could be key is prevention, she said.

“There have been some initiatives to put prevention more on the agenda of dementia research,” she said. “There has been so much money spent on treatment of Alzheimer’s disease and it has already been established that this is not very successful. “

Dementia prevention strategies could include taking measures at an earlier stage to encourage physical fitness and control hypertension, blood lipids (including cholesterol and triglycerides), and now, possibly, blood glucose levels, she said.

Patients should have their fasting glucose and HbA1c levels measured as part of a regular medical check-up starting at age 55 years, unless there’s a personal or family history of diabetes or the patient is obese, in which case the family doctor may opt for earlier and more intense monitoring, said Dr. Flöel. She pointed out that such tests are easy to do and are already carried out regularly in pregnant women.

Fresh Eyes

Commenting on the findings for Medscape Medical News, Marwan N. Sabbagh, director, Banner Sun Health Research Institute, Sun City, Arizona, said that the study looks at the link between glucose metabolism and cognition with fresh eyes.

“This is saying that immediate learning and A1c levels, and potentially even blood sugars, interact even in people who are nondemented, and I don’t think anyone has looked at it that way before,” said Dr. Sabbagh.

“The idea is that the lower the A1c the better your brain function. This is a very exciting development and clearly helps put a frame around the Alzheimer’s discussion, but more importantly, it talks about how blood sugar metabolism and cognitive function directly interact.”

The study opens “a whole new territory” because until now, HbA1c and blood glucose have been looked at only in the context of diabetes and the risk for diabetes, added Dr. Sabbagh. “Maybe we need to rethink our normalization of glucose with an eye toward cognition and not simply a diabetes risk.”

Identifying post-partum diabetes after gestational diabetes mellitus: the right test.

Post-partum glucose testing is recommended for women who had gestational diabetes mellitus during pregnancy to identify those with persistent glucose intolerance. Guidelines from several medical organisations disagree about which glucose test should be used and when.

Traditionally, glucose testing in women who had gestational diabetes is done 6 weeks post partum, because of the coincident health-care visit and, theoretically, to allow the temporary increases in glucose during pregnancy to return to normal. However, Lawrence and colleagues1 reported that fasting plasma glucose (FPG) and postprandial glucose (measured by a 75 g, 2 h oral glucose tolerance test [OGTT]) concentrations assessed before 6 weeks are not higher than those obtained 6—12 weeks post partum, suggesting that earlier testing would not lead to falsely increased measurements. After the first measurement, testing is recommended from annually to every 3 years (table). Although few studies have compared the benefits of testing every year or every 3 years, mathematical models suggest that, if FPG is measured, annual testing might yield the lowest cost per case, whereas if OGTT is used, testing every 3 years would have the lowest cost.2

The HbA1c test can identify individuals at risk for future diabetes and diabetes complications, is easily done, and has little intra-individual variation in people who have not recently given birth.3 Additionally, HbA1c concentration is not known to be affected by breastfeeding during the actual blood draw, unlike fasting or postprandial glucose.4 However, because HbA1cconcentrations 6 weeks post partum could be affected by perinatal haemoglobin shifts and prenatal treatments, HbA1cmeasured post partum correlates weakly with glucose concentrations.5 Therefore, the American Diabetes Association has recommended that HbA1c should not be used as a measure of blood glucose concentration at the first post-partum visit (table).3 Whether or not it is used at subsequent visits was not addressed in the guidelines,3 because data for several years after pregnancy are scarce. Notably, measurement of HbA1c in addition to FPG does not increase sensitivity or specificity 1 year post partum.6

Thus, the primary choice for post-partum glucose testing should be either FPG measurements or the OGTT. The postprandial glucose test identifies a different population of women with glucose dysregulation from the FPG test,7 and therefore the OGTT will always have greater sensitivity than FPG measurements alone. However, values obtained by the postprandial glucose test show variability—sometimes exceeding 15% within individuals.8 Moreover, the OGTT has logistical difficulties, such as a glucose challenge and the need for at least two blood draws in 2 h as opposed to one draw after fasting with FPG measurements.

Several questions about whether FPG measurement or the OGTT should be used are relevant. Will more women comply with a FPG test than an OGTT? What proportion of women who refuse an OGTT but agree to an FPG test is identified as having impaired fasting glucose or diabetes? Do these women justify not identifying those who have an isolated 2 h glucose measurement, as measured by OGTT? Systematic information about who refuses an OGTT but accepts an FPG test is not available. In one series, a third of women with glucose dysregulation had normal FPG concentrations.7 This finding implies that testing of post-partum glucose concentration by FPG only is justified only if about 30% more women with impaired fasting glucose are identified as a result of the more straightforward logistics involved in an FPG test than by the OGTT.

The diagnostic test used for gestational diabetes is relevant to the choice of post-partum glucose test. Specifically, when less stringent criteria (ie, lower cutoff for glucose concentration) are used, more women will be diagnosed with gestational diabetes, and the overall population of patients with gestational diabetes will have lower glucose levels and be at lower risk for post-partum diabetes. Indeed, prevalence of post-partum glucose intolerance decreases from 16% when Carpenter and Coustan criteria (lower glucose cutoffs) are used to 8% when National Diabetes Data Group criteria (higher glucose cutoffs) are used.1 Thus, if more women are diagnosed with gestational diabetes—ie, the glucose cutoffs are decreased during pregnancy—the benefit of a post-partum OGTT as opposed to an FPG test only will be reduced. Because International Association of Diabetes and Pregnancy Study Group criteria identify more women with gestational diabetes than did previous criteria,3 these women will, on average, have less severe glucose intolerance, and the relative benefit of an OGTT post partum might be decreased. Notably, women diagnosed with gestational diabetes by postprandial values alone would be most likely to be identified with a post-partum OGTT.

When deciding on a post-partum glucose testing strategy, the provider and patient should also consider whether the woman plans on becoming pregnant again; a more sensitive test for glucose intolerance (ie, the OGTT) could lead to changes in lifestyle or medication use that will reduce risk in future pregnancies. The provider and patient should also consider whether the woman had isolated increases in postprandial glucose concentrations during pregnancy; if so, the OGTT would be a more sensitive diagnostic strategy post partum. The answers to these questions will help to establish the frequency and choice of test, while uniformity in the guidelines for diagnosis of gestational diabetes, and data from randomised trials and cohort studies that quantify post-partum diabetes risk in affected women are awaited.

Source: Lancet


IGT ups risk for abnormal retinal vascular reactivity CVD.

Researchers in the United Kingdom have found a link between impaired glucose tolerance and microvascular and macrovascular function, as well as a direct association between retinal microcirculatory changes and established plasma markers for cardiovascular disease.

Sunni R. Patel, PhD, a postdoctoral fellow at University Health Network in Toronto and former researcher for the Vascular Research Laboratory and Ophthalmic Research Group at the School of Life and Health Sciences at Aston University in Birmingham, United Kingdom, and colleagues conducted a study involving 60 age- and sex-matched white European adults, 30 with IGT and 30 with normal glucose tolerance.

Patients with IGT had higher blood pressure values (P<.001), fasting triglyceride levels and triglyceride-to-HDL ratios (P<.001) vs. patients with normal glucose tolerance. According to data, blood glutathione levels were lower (reduced glutathione, P<.001; glutathione disulfide, P=.039; and total glutathione, P<.001), whereas plasma von Willebrand factor was increased in patients with IGT when compared with the control group (P=.014).

Moreover, patients with IGT displayed higher intima-media thickness in the right (P=.017) and left carotid arteries (P=.005) and larger brachial artery diameter (P=.015). Patients with IGT also had lower flow-mediated dilation percentage (P=.026) and glyceryl trinitrate-induced dilation (P=.012) than healthy control patients.

“The results of our pilot study suggest that IGT individuals demonstrate signs of early vascular dysfunction as measured by functional (at macro- and microcirculatory levels) and circulatory markers. Moreover, in addition to a relationship between functional macro- and microvascular parameters, there appears to be a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD risk,” the researchers wrote.

Due to these observations, researchers wrote that there should be a possible emphasis on early CV screenings and interventions for those with a prediabetes diagnosis, including those with IGT.

“Retinal vascular imaging could emerge as a possible future option for individual risk stratification in diseased patients but also in individuals at risk for metabolic and CV pathologies,” the researchers wrote.

Source: Endocrine Today.