There has been a burst of papers drawing further attention to the damage that glucose and insulin dysregulation does to the brain. A study just published in the journal Neurology investigates specifically…

“…the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia.”

The authors subjected 1,017 community-dwelling dementia-free subjects 60 years and older to an oral glucose tolerance test, then followed them for 15 years. The outcome measure was clinically diagnosed dementia. What did their data show?

The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74; AD: adjusted HR = 2.05; VaD: adjusted HR = 1.82). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L [120.6 mg/dl], the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L [140.4 to 198 mg/dl] or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L [199.8 mg/dl].”

This is striking. The risk of all-cause dementia doubled for those with diabetes, and there was a significant increase in the risk of all-cause dementia and Alzheimer’s disease with a 2 hour post-glucose load level of 140.4 mg/dl or more. Moreover, fasting glucose levels did not reveal the danger that was disclosed only by the functional OGTT. I always risk desensitizing my patients to the damage done to the brain by glucose and insulin dysregulation; better to let the authors’ conclusion do the talking:

“Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.”

Meanwhile, a time study just published in the journal Diabetic Medicine also examines the association of diabetes with Alzheimer’s disease. The authors’ intent was to determine…

“…whether diabetes mellitus influences functional status in patients with Alzheimer’s disease.”

They studied 608 community-dwelling patients with Alzheimer’s disease, assessing diabetes at the beginning. Functional status was examined twice yearly with the Activities of Daily Living scale. Each patient also had a baseline functional disability determined if their Activities of Daily Living score was less than 6. Decreases in these metrics over four years of follow-up exams was used to define worsening of functional disability due to AD. Their data also reveal the ruination of the brain by glucose intolerance:

“At baseline, diabetes was present in 63 participants (10.4%) and, compared with those without diabetes, was associated with functional impairment [age- and sex-adjusted OR = 2.73]. After controlling for confounders, the association remained significant [OR = 2.04]. Follow-up demonstrated a significant interaction between duration of Alzheimer’s disease and diabetes, which was associated with progression of functional impairment in patients who had been diagnosed with Alzheimer’s disease for less than 1 year, but not in those who had been diagnosed with Alzheimer’s disease for more than 1 year. Abnormal one-leg balance, polymedication and obesity seem to be important factors explaining the association between diabetes and functional status.”

Clinicians (non-neurologists), how often do you check one-leg balance? The authors’ data suggests that a year after a clear-cut Alzheimer’s diagnosis the damage is too extensive to discriminate the effect of diabetes, thus they conclude:

“At baseline, the presence of diabetes significantly increases the risk of functional disability in patients with Alzheimer’s disease; our longitudinal data confirm that in patients with a recent diagnosis of Alzheimer’s disease (but not in those who have had Alzheimer’s disease for longer than 1 year), diabetes continues to worsen functional status.”

Regarding mechanisms, an interesting paper just published in Current Diabetes Reviews examines recent findings illuminating the link between IGF-1 signaling and diabetes-associated dementia. The authors state:

“Patients with type 2 diabetes (T2DM) have a two- to three-fold increased risk for Alzheimer’s disease (AD), the most common form of dementia. Vascular complications might explain partially the increased incidence of neurodegeneration in patients with T2DM. Alternatively, neuronal resistance for insulin/insulin-like growth factor-1 (IGF-1) might represent a molecular link between T2DM and AD, characterizing AD as “brain-type diabetes”.”

They describe recent research findings that suggest decreased IGF-1 signaling (IIS) in the brain is a compensatory attempt to reduce the accumulation of toxic β-amyloid (Aβ):

“According to this hypothesis, brains from AD patients showed substantially downregulated expression of the Insulin receptor (IR), the IGF-1 receptor (IGF-1R), and the insulin receptor substrate (IRS) proteins…suggesting that decreased IIS [insulin/IGF-1 signaling] might be involved in the pathogenesis of both T2DM and AD. In contrast, type 2 diabetic patients suffering from AD accumulate less β-amyloid (Aβ) compared to non-diabetic AD patients raising the question, whether the changes in IIS are cause, consequence, or compensatory counterregulation to neurodegeneration. Recent data in C. elegans showed that reducing IIS decreases Aβ toxicity. This effect is accomplished via two transcription factors…suggesting that Insulin/IGF-1 transmitted signals influence Aβ proteotoxicity.”

This important point should not go unnoticed by those who are contemplating therapies that increase IGF-1—they may increase risk factors for Alzheimer’s disease and dementia.

And another paper recently published in Neurology highlights the damage done to the brain by advanced glycation end products due to poor glucose tolerance. The authors observe:

“Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging.”

They studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose, and examined baseline AGE concentration by urine pentosidine in association with performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. What did the data show?

“On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level [more AGEs] compared to those in the lowest tertile. Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile.”

We are probably just beginning to understand the ways that glucose and insulin regulation, whose profound leverage on the physiology is evolutionarily preserved from relatively primitive organisms to humans, has on the brain. Regarding damage done by excessive glucose interaction with tissues, it is not necessary for glucose dysregulation to have progressed to diabetes as the authors conclude:

“High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.”

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This compelling research published recently in the journal Diabetes discloses that loss of insulin sensitivity (increased insulin resistance) related to increase in adiposity (fat) and, “In contrast, age had no independent effect on insulin sensitivity.” Astute readers will recall that insulin resistance is a causal factor in overweight, so the main messages here are: Chronological age and biological age are different (this goes for men too, of course); and life-style behaviors that support healthy insulin regulation are good for a lifetime.

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A study published recently in the American Journal of Clinical Nutrition documents longer telomere length in women taking multivitamins. Telomere length is a fundamental factor in the ability of cells to renew tissue, a marker of biological aging. Although I don’t recommend multivitamins to people taking a functional approach because your unique personalized protocol fulfills those needs much more effectively, this is more evidence that reducing oxidative stress and chronic inflammation with key micronutrients slows age-related degeneration.

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