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Curr Opin Pharmacol. Author manuscript; available in PMC Dec 1, 2008.
Published in final edited form as:
PMCID: PMC2193628
NIHMSID: NIHMS36006

INSULIN SIGNALING FFECTS ON MEMORY AND MOOD

Abstract

The escalating obesity/diabetes epidemic is an important health care issue that has critical socio-economic ramifications. The complications of diabetes/obesity phenotypes extend to the central nervous system, including the hippocampus, a brain region that is particularly vulnerable to hyperglycemia and insulin resistance. Deficits in hippocampal synaptic plasticity observed in diabetes ultimately have deleterious consequences upon cognitive function. For example, recent studies using brain imaging technologies have identified cerebral atrophy in diabetic patients, suggesting that the neuroanatomical changes observed in experimental models of diabetes may accurately reflect what is occurring in the clinical setting. Deficits in insulin receptor signaling and impairments in hypothalamic-pituitary-adrenal (HPA) axis function also contribute to the neurological complications of diabetes phenotypes. The pathophysiological similarities between diabetes and stress-related mood disorders suggest that common mechanistic mediators may be involved in the etiology and progression of the neurological complications of these disorders. When combined with the accumulating evidence from pre-clinical models, these data support the hypothesis that a long-term consequence of diabetes/obesity phenotypes is accelerated brain aging that results in neuropsychological deficits and increased vulnerability to co-morbidities such as depressive illness.

Introduction

Ongoing epidemiological studies by the Centers for Disease Control determined that there is a significant increase in the incidence of obesity in the United States. The National Health and Nutrition Examination Survey (NHANES) estimates that greater than 60% of the adult US population may be categorized as either overweight or obese [1••]. These epidemiological results represent an important health-care issue that has profound socio-economic ramifications, especially in view of the complications that may arise from obesity phenotypes, such as insulin resistance and type 2 diabetes. Since current estimates report that one of every four Medicare dollars is spent on the treatment of diabetes, this growing population of diabetic patients will have a significant financial impact on public health costs. There is a growing appreciation that the complications of diabetes extend into the central nervous system (CNS), thereby leading to the development of diabetic encephalopathy and increased risk of neurological co-morbidities. In view of these observations, the goals of this review will be: 1) to discuss the impact of hyperglycemia and insulin resistance upon the structure and function of the hippocampus, a brain region that serves as a critical integration center for learning and memory in the mammalian brain; and 2) describe how deficits in hippocampal synaptic plasticity in diabetic subjects may adversely affect cognitive performance and increase neuronal vulnerability for stress-related disorders like depressive illness.

Is accelerated brain aging a consequence of diabetes?

The accumulated data from experimental models of diabetes suggest that a consequence of chronic hyperglycemia is accelerated brain aging, as proposed by Gispen, Biessels and co-workers [2]. Examples include neuroanatomical alterations, neurochemical changes, impairments in stress reactivity and HPA axis activity, as well as deficits in plasticity and insulin signaling, all of which may contribute to cognitive/behavioral deficits. For example, streptozotocin (STZ) diabetic rats, an experimental model of type 1 diabetes, rapidly exhibit dendritic remodeling in the CA3 region of the rat hippocampus [3]. Subsequent studies determined that hyperglycemia mediated morphological changes are more widespread in the hippocampus of STZ rats and include redistribution of synaptic proteins that may affect neurotransmission and plasticity [4]. An important consideration, especially in relation to hippocampal function, is whether these neuroanatomical changes represent the initiation of irreversible neuronal damage in diabetic subjects. Neuronal apoptosis and suppression of cell proliferation/neurogenesis are observed in the hippocampus of diabetic rodents [5-8], albeit under conditions of uncontrolled hyperglycemia. As such, the relationship of these findings to the clinical situation in which patients attempt to maintain tight glycmeic control remains to be determined. Indeed, previous studies illustrated that diabetes-induced morphological changes in the hippocampus [9], as well as deficits in hippocampal synaptic plasticity [10], are reversed with insulin replacement. Nonetheless, neuronal loss and apoptosis following extended periods of hyperglcycemia are suggestive of increased neuronal vulnerability that may have additive or synergistic effects when combined with the other neurological complications of diabetes.

Insulin receptor expression and signaling: correlation with cognitive function

The insulin receptor (IR) is expressed in discrete neuronal populations in the CNS, including the hippocampus [11,12], where it is proposed to participate cognitive function [13]. Insulin improves cognitive performance in humans and animals in a wide variety of settings, including healthy subjects [14-16], aged subjects [17-19], Alzheimer’s disease (AD) patients [20-22] and in experimental models of insulin resistance [23]. Additionally, spatial learning of a hippocampal-dependent task, namely the Morris water maze, increases IR expression and signaling [24]. Physiologically-relevant increases in plasma insulin levels also stimulates the translocation of the insulin-sensitive glucose transporter GLUT4 to the plasma membrane in the rat hippocampus [25]. These data support the hypothesis that activation of insulin receptor signaling cascades improves cognitive/behavioral performance. The data regarding the relationship between insulin receptor activity and behavioral performance in experimental models of diabetes is less consistent. In experimental models of type 1 diabetes, STZ diabetic rats exhibit behavioral deficits in the water maze task that are associated with impairments in hippocampal long-term potentiation (LTP), a cellular correlate of learning and memory [10]. Conversely, other studies have failed to demonstrate deficits in water maze performance in hypoinsulinemic Akita mice [26]. These disparate findings may be related to the type of analyses performed since a study by Zhao and co-workers determined that STZ diabetic rats performed as well as non-diabetic controls in some aspects of water maze performance, but more poorly in others [27••]. Hippocampal IR expression [27], as well as plasma membrane association of GLUT4 [25], is reduced in STZ rats, suggesting that impairments in hippocampal IR expression and signaling contributes to deficits in hippocampal-dependent tasks. Interestingly, behavioral training strengthens IR signaling in the diabetic rat hippocampus [27], providing further evidence that at least some of the neurological complications of hyperglycemia represent plastic, not permanent, changes.

Analyses of behavioral performance and hippocampal synaptic plasticity in experimental models of type 2 diabetes have also yielded inconsistent findings, with some studies suggesting that water maze performance and hippocampal LTP are reduced [28], while others report that these measures are unaffected [29]. One important caveat associated with these studies is that performance in the water maze is dependent upon loco-motor activity, which may be adversely affected in diabetic animals that display decreases in muscle mass (such as type 1 models) or increases in adiposity (such as type 2 models). Evaluation of learning and memory performance in a task that is less dependent upon loco-motor activity, such as the variable interval delayed alternation (VIDA) task, may more directly assess behavioral performance in experimental models of diabetes. In this regard, type 2 Zucker diabetic rats effectively learn the VIDA task when intertrial intervals (ITI) are short. However, when the ITI is lengthened, which is dependent upon intact hippocampal function, behavioral performance deteriorates in the type 2 rats when compared to their lean littermates [30•]; these behavioral deficits in Zucker diabetic rats were associated with decreases in IR signaling. Such results support the hypothesis that decreases in hippocampal IR activities contribute to behavioral deficits in type 2 rodents. Nonetheless, the ‘take-home-message’ from these pre-clinical studies is that a variety of factors may impact of the outcome of behavior and hippocampal plasticity experiments in diabetic animals, ranging from the physiological/pathophysiological characteristics of the animal model to the selection and analysis of the particular behavioral tests.

Translation of animal studies to the clinical setting

One of the most critical questions that remains to be determined is whether these pre-clinical data translate to the clinical setting. The clinical literature that has described structural and functional changes in diabetic patients is somewhat equivocal in that the magnitude and significance of cognitive deficits in diabetic patients is a subject of debate. Neuroanatomical abnormalities have been reported in type 1 and type 2 patients (For review see [31]) and the advent of imaging technologies has confirmed and extended these previous observations. For example, while MRI techniques have not identified cerebral or hippocampal atrophy in type 1 patients [32,33], voxel-based morphometry (VBM) revealed decreases in grey matter density in type 1 patients [34]. Imaging studies in type 2 patients have yielded more consistent findings suggestive of cerebral atrophy, in that MRI analyses have identified structural atrophy [35], particularly in the limbic structures such as the hippocampus and amygdala [36]. Decreases in hippocampal formation volume in type 2 patients have also been identified using a combined MRI/VBM approach [37••]. Importantly, these structural changes are often associated with neuropsychological deficits in type 2 patients [35,37].

The complexity of the pathophysiological causes and consequences of diabetes may contribute to the dissimilar findings in clinical studies. For example, a variety of factors have been proposed to negatively influence the structural and functional integrity of the brain in diabetes patients, including the degree of glycemic control, the number and severity of hypoglycemic episodes, the age of onset and the duration of diabetes (For reviews, see [38,39]). A consequence of these metabolic deficits is impairments in HPA axis function, which may further exacerbate the neurological complications of diabetes. Indeed, impairments in HPA axis function and elevated basal GCs are implicated in the neurological complications observed of type 1 and type 2 diabetic animals [3,30,40-42]. Clinical studies have yielded inconsistent findings regarding HPA axis activity in diabetic patients, although a recent study by Convit and co-workers demonstrated an association between glycemic control, HPA axis dysfunction and cognitive performance in type 2 diabetes patients [43•].

Some investigators suggest that CNS structural and functional deficits in diabetic patients are subtle and do not represent a significant cognitive burden in diabetic individuals compared to the general population. Irrespective of the ‘significance’ of cognitive impairments identified in diabetes, the life-long complications of hyperglycemia predispose diabetic patients to co-morbidities such as dementia, AD and recurrent depressive illness [44-46]. For instance, epidemiological studies suggest that diabetic patients are two to three-fold more likely to develop depressive illness when compared to non-diabetic individuals [47•]. It is interesting to note that there are striking similarities between the neurological consequences of diabetes and depressive illness, including decreases in hippocampal formation volume [46]. In addition to HPA axis dysfunction and hypercortisolemia, a variety of other endocrine factors may predispose diabetic patients to depressive illness, including elevations in plasma leptin levels and/or leptin resistance (as in type 2 diabetes) and increased plasma levels of pro-inflammatory cytokines [48•]. Indeed, cytokines are implicated in the pathogenesis of type 1 diabetes and the progression of type 2 diabetes. Therefore, while the magnitude of cognitive deficits observed in diabetic subjects may remain a subject of debate, the significance of the underlying neuroendocrinological, neurophysiological and neuroanatomical changes that may ultimately produce cognitive deficits and co-morbidities in diabetes subjects should not be overlooked or marginalized.

Conclusions

The long-term consequences of hyperglycemia upon the CNS are an important health care issue in view of the growing obesity and diabetes patient populations. While clinical and pre-clinical studies have failed to reach a consensus, the accumulated data suggest that the neurological complications of diabetes include deficits include hippocampal synaptic plasticity, as well as structural and cognitive deficits. Less debate surrounds the increased incidence of co-morbidities in diabetic patients, including increased risk for Alzheimer’s disease [49] and depressive illness [47•]. As a result, diabetic encephalopathy could surpass renal failure, heart disease and retinopathy as the major complication of diabetes. The good news for diabetic patients is the emergence of innovative transplantation strategies and pharmacological treatments that have the potential to significantly reduce or eliminate diabetes-related complications. These include new approaches to enhance current pancreatic islet cell transplantation strategies for type 1 patients [50••], as well as the advancement of novel drug strategies such as insulin mimetics [51] and incretin mimetics [52] for the treatment of type 2 diabetes and obesity. When combined with lifestyle changes, including diet and exercise, these developing technologies offer hope to clinicians and patients for the successful treatment of the neurological consequences of diabetes and obesity.

Acknowledgments

The author’s work is supported in part by Juvenile Diabetes Research Foundation grant number 2-03-675, NIH grant number NS047728 and the University of South Carolina Research Foundation.

Footnotes

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