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