By now, many clinical researchers and practitioners recognize the strong association between cognitive impairment and type 2 diabetes, which, in its early stages, is characterized by hyperinsulinemia and insulin resistance. Although this relationship has not been observed uniformly, more than 20 large-scale epidemiologic studies have reported a link between type 2 diabetes and in creased risk of cognitive impairment and dementia, including Alzheimer disease (AD), the most common type of dementia.
By now, many clinical researchers and practitioners recognize the strong association between cognitive impairment and type 2 diabetes, which, in its early stages, is characterized by hyperinsulinemia and insulin resistance. Although this relationship has not been observed uniformly,1,2 more than 20 large-scale epidemiologic studies3-5 have reported a link between type 2 diabetes and in creased risk of cognitive impairment and dementia, including Alzheimer disease (AD), the most common type of dementia.
Recent attention has turned to the question of whether hyperinsulinemia itself may impact cognitive function--independent of diabetes or of the vascular complications that often accompany that disease. Indeed, accumulating biologic and epidemiologic evidence suggests an important contribution of high insulin levels to accelerated cognitive decline, even among those without diabetes.
This report will review the potential impact of abnormal insulin levels on the brain, present evidence on the association between hyperinsulinemia and cognitive impairment, and discuss the implications for clinical practice.
Basic Science Background Direct effects: neuromodulation
Insulin's action in the brain may influence both normal and abnormal memory function. Insulin receptors appear throughout the brain, and they are particularly dense in the hippocampus and entorhinal, perirhinal, and parahippo campal cortices-medial temporal lobe brain regions that are central to learning and memory. Insulin may modulate brain concentrations of several neurotransmitters and influence long-term potentiation, the molecular paradigm of learning.6
Numerous studies have demonstrated that acute infusion of insulin while maintaining normal blood glucose levels temporarily improves memory in human and animal subjects. In contrast, hyperinsulinemia over longer durations may have a negative impact on memory. For example, cultured rat neurons treated with insulin showed substantial decreases in activity of choline acetyltransferase (an enzyme in volved in forming acetylcholine, a key neurotransmitter in memory and learning).7 Thus, it appears that an important distinction should be made between the impact of acute or temporary increases in insulin levels in the setting of normal metabolic function and the effects associated with chronically elevated insulin levels, as observed with insulin resistance.8,9
Hyperinsulinemia may impact cognitive function indirectly through vascular mechanisms. It is commonly associated with cerebral microvascular and macrovascular damage, both of which contribute to cognitive decline and vascular dementia. Nevertheless, while the adverse effects of hyperinsulinemia on vascular health would provide a tempting explanation for its detrimental impact on cognition, there is grow ing evidence that some of the effects may be independent of vascular disease. For example, a recent MRI study involving men and women with and without diabetes showed that increased insulin resistance was associated with greater atrophy of the amygdala (a medial temporal lobe structure), but the association was not due to the more pronounced vascular morbidity among those with diabetes.10 Similarly, in studies of type 2 diabetes and cognition, adjustment for vascular morbidity has generally had a limited influence on results.3,11
In addition, elevated blood levels of insulin may promote increased production of one of its major counter-regulatory hormones, cortisol. Chronic hyper cortisolemia in humans has been associated with verbal memory impairment as well as diminished hippocampal volumes and regional cerebral glucose metabolism.8
Finally, hyperinsulinemia and in sulin resistance frequently accompany elevated markers of chronic inflammation, such as C-reactive protein (CRP) and interleukin 6 (IL-6).12 Sustained increases in levels of inflammatory response compounds have been implicat ed in the development of AD pathology.13
The amyloid b connection
Insulin may directly affect levels of amyloid b (Ab) peptide-the primary component of neuritic plaques (which are a central element of AD pathology14)-representing an alternative and intriguing pathway by which insulin may act to influence neurodegeneration. In vitro studies indicate that insulin causes a 3- to 4-fold increase in extracellular Ab levels as a result of enhanced Ab secretion as well as inhibited Ab degradation.15 A recent study in 16 healthy older adults found that on infusion of insulin, levels of Ab in cerebrospinal fluid were significantly increased compared with levels during infusion of saline in subjects older than 70 years.16
Insulin degrading enzyme
Findings about the insulin-degrading enzyme (IDE) provide a possible explanation for the observation that hyperinsulinemia leads to elevated levels of Ab. IDE is the major enzyme responsible for insulin degradation in the body,17 as well as the first protease dem onstrated to degrade Ab.18
In human cell lines, over-expression of IDE protein markedly reduced levels of both extracellular and intra cellular Ab.19,20 In addition, in animal studies, IDE proteolysis of Ab eliminated the neurotoxic effects of this peptide in rat neuronal cultures.21 In versely, in a mouse model with homozygous deletions of the IDE gene, cerebral accumulation of Ab was increased by up to 64% in the mice with IDE double deletion, compared with wild-type mice (hyperinsulinemia was also induced); IDE deficiency was as sociated with a greater than 50% reduction in Ab degradation in primary neuronal cultures.22
Furthermore, IDE binds more readily to insulin relative to other sub strates,17 and insulin acts as a competitive in hibitor of Ab degradation. Thus, hyperinsulinemia may potentially interfere with peripheral Ab clearance, resulting in higher Ab concentrations in the brain.9
A good way to distinguish between the impact of abnormally elevated insulin itself and that associated with diabetes is to evaluate risk of dementia and age-related cognitive impairment in persons without diabetes. A few recent epidemiologic studies have done precisely that.
AD and dementia
In contrast to the abundant literature on type 2 diabetes and cognitive im pairment and dementia, there are very few prospective studies that have in vestigated the relationship between hyperinsulinemia in persons without diabetes and the risk of actual clinical dementia or AD. However, Luchsing er and colleagues23 recently reported findings from the Washington Heights-Inwood Columbia Aging Project. The data from this trial of 531 men and women without diabetes suggested a doubling of the risk of developing AD (hazard ratio [HR] = 2.3; 95% confidence interval [CI], 1.5-3.6) with plasma fasting in sulin levels that were above versus be low the upper limit of normal.
Early cognitive impairment and decline
Recent data support an association between elevated insulin and early cognitive decline in older persons without diabetes. Mild cognitive decline is an increasingly active area of research: small, early impairments in cognitive function in healthy older individuals strongly predict later development of AD and dementia24; thus, identifying and addressing modifiable factors for the earliest stages of decline may be most critical for effective dementia prevention.
Early cross-sectional epidemiologic data suggested that hyperinsulinemia may be adversely related to cognitive performance.11,25 In the Zutphen Elderly Study of 386 men without diabetes, those in the highest quartile of fasting insulin had 25% more errors on the Mini-mental State Exam (MMSE) compared with those in the bottom quartile (95% CI, 4%-50%); there was a trend of increasing errors with increasing quartile (P trend = .02).25
There are limited prospective data available on this question. However, our research group recently completed investigations of the relationship of mid life elevated insulin secretion, as represented by plasma C-peptide levels, and late-life cognitive function in 2 population-based cohorts. Among 718 women without diabetes in the Nurses' Health Study, higher plasma C-peptide levels were consistently associated with significantly worse performance on tests of global cognitive function and verbal memory an average of 10 years later.26 On a global cognitive summary score, odds of cognitive impairment (defined as the worst 10% of the distribution of performance) were 3-fold higher among women in the top versus bottom quartile of plasma C-peptide (95% CI, 1.3-7.8); on verbal memory, the odds of impairment were 2.8-fold higher (95% CI, 1.1-7.0) for women in the top quartile compared with those in the lowest quartile.
In a comparable study involving 367 male participants in the Physicians Health Study II, midlife plasma C-peptide levels were similarly associated with worse late-life general cognitive performance an average of 18 years later.27 On the Telephone Interview of Cognitive Status (a telephone-administered assessment of general cognition analogous to the MMSE), men in the top tertile of C-peptide levels performed significantly worse than those in the bottom tertile (multivariable-adjusted mean difference –1.01 points; 95% CI, –1.78 to –0.24); this apparent impact of C-peptide on cognition was equivalent to the cognitive differences we observed between men aged 6 years apart. However, in contrast to our findings with women, increasing C-peptide levels were not statistically signifily associated with worse late-life verbal memory, although scores appeared generally lower in those with increased levels.
Finally, there is evidence that the metabolic syndrome-which has been variably defined but typically involves obesity (particularly, central obesity), dyslipidemia, hypertension, and evi dence of insulin resistance or impaired glucose tolerance28-may be related to increased risk for cognitive impairment. In a large, prospective study in volving more than 2600 black and white community-dwelling elderly persons, the metabolic syndrome was as sociated with a 20% increased risk for cognitive decline.29 However, the increased likelihood of cognitive impairment was strongly modified by the presence of high blood levels of inflammatory markers (CRP and IL-6), sug gesting an important role for inflammation in the relationship between hyperinsulinemia and cognitive decline.
Early Clinical Trial Evidence
Not surprisingly, the basic and population science findings mentioned above have inspired investigation into classes of diabetes drugs as potential treatments for cognitive impairment and dementia in older persons, even in the absence of clinical diabetes. This area of inquiry is particularly important and exciting because existing pharmacotherapies for AD and dementia have demonstrated only modest benefit, and existing prevention trial data have been somewhat disappointing.
Watson and colleagues30 recently reported data from their group on the potential role of a class of diabetes drugs called peroxisome proliferator-activated receptor-g (PPAR-g) agonists. These drugs enhance insulin sensitivity and significantly reduce blood levels of inflammatory markers, such as CRP and IL-6, even in persons without diabetes.31 In a double-blind placebo-controlled study that involved 30 patients with mild AD or amnestic mild cognitive impairment, those who received rosiglitazone (a PPAR-g agonist) had better performance on a task of delayed recall, compared with those who received placebo, by the end of the 6-month study period.30 In addition, after 6 months, plas ma levels of Ab42 (Ab peptide in 42-amino acid form is considered more toxic and highly correlated with AD) for rosiglitazone recipients remained stable but declined for those in the placebo group, which is consistent with the concept of increased Ab42 sequestration in the brain (and a subsequent drop in plasma) with disease progression.
Overall, there has been an exciting confluence of basic science, epidemiologic, and preliminary clinical data pointing to a possible role of abnormal insulin levels in cognitive decline and dementia.
Recent findings indicate that even in the absence of diabetes, excess insulin levels may have a deleterious impact on late-life cognition. Such evidence provides yet another compelling reason for physicians to encourage patient adherence to current public health recom mendations regarding physical activity, healthy diet (specifically, an appropriate balance of carbohydrates and minimization of refined sugars), and weight reduction/control-all of which have substantial influence on insulin action and secretion and on the risk for diabetes.
Regular physical activity promotes insulin sensitivity and reduces hyperinsulinemia.32 Dietary replacement of high glycemic index carbohydrates (refined cereals, products made with white flour, potatoes) with minimally refined cereals and whole grains reduces the risk for insulin resistance and diabetes.33 Obesity also provokes insulin resistance; thus, maintaining a healthy body weight and avoiding weight gain during adulthood is considered "the cornerstone of diabetes prevention."34 Besides these lifestyle strategies, additional research on potential risk-modifying agents, such as the PPAR-g agonists, may provide an avenue for further preventive benefit.
Even in the absence of a major culprit such as obesity, however, older people are at risk for abnormal insulin levels because insulin resistance in creases with age.35 According to data from the Third National Health and Nutrition Examination Survey, the prevalence of type 2 diabetes in Americans aged 60 to 74 years is greater than 20%; however, an additional 20% of this age group meets criteria for im paired glucose tolerance, although they do not have frank diabetes.36 These older men and women without diabetes, but with growing insulin resistance, may represent a large population at additional risk for later cognitive impairment and dementia, as well as for the health, economic, and societal costs these disorders entail. Thus, as the proportion of older persons continues to rise in this country-along with the prevalence of age-related cognitive decline and dementia-careful attention to potential risk factors, such as abnormal insulin levels, is of the utmost importance. Geriatric psychiatrists can play an important role by closely monitoring the cognitive function of older patients who already have diabetes and by encouraging all of their patients to address and modify risk factors for insulin resistance and hyperinsulinemia.
Dr Okereke is an instructor in psychiatry at Harvard Medical School and an associate physician in the department of medicine and psychiatry at Brigham and Women's Hospital in Boston. She reports that she has no conflicts of interest concerning the subject matter of this article.
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