Mini-review: INSULIN RESISTANT BRAIN STATE AND ITS LINK TO DIABETES MELLITUS

M Šalković-Petrišić, Z. Lacković

Mini-review

INSULIN RESISTANT BRAIN STATE AND ITS LINK TO DIABETES MELLITUS

Running title:

brain insulin resistance

Melita Šalkovic-Petrišić*1, Zdravko Lacković1

*1Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Medical School & Croation Institute for Brain Research, University of Zagreb, Šalata 11, HR-10 000 Zagreb, Croatia.

telephone: +385-1-45 90 219

telefax: +385-1-45 66 843

e-mail:

melitas@mef.hr

* To whom the correspondence should be addressed

Abbreviations:

CNS, central nervous system; BBB, blood-brain barrier; IR, insulin receptor; IRS, insulin receptor substrate; PKB/Act, protein kinase B /Act; PI3, phosphatydilinositol–3 kinase; GSK-3, glycogen synthase kinase-3; APP, amyloid precursor protein; Aβs, amyloid-β peptides; GLUT, glucose transporter; MAPK, mitogen activated protein kinase; IGF-1, insulin-like growth factor-1

ABSTRACT

Insulin resistant brain state is a dysfunction of the neuronal insulin receptor (IR) signalling, demonstrated mostly in phosphatydilinositol-3 kinase pathway that resembles IR signaling dysfunction in the peripheral insulin resistance in type 2 diabetes mellitus. The resulted brain insulin dysfunction may be manifested as altered feeding behaviour and cognitive deficits in learning and memory in relation to aging, obesity, diabetes mellitus type 2, and late-onset sporadic Alzehimer’s disease. These conditions represent both, primarily central (aging and Alzheimer’s disease) and primarily peripheral (obesity and type diabetes) insulin resistance state. Current knowledge suggests a bi-directional communication between these two insulin resistant states, one increasing the risk for development of another and vice versa. In spite of reported genetic, metabolic, nutritional and environmental contributing factors, it is still not clear in which conditions insulin resistant brain state and the peripheral insulin resistance co-exist with manifested clinical symptoms of both disorders. Research is focused on discovering the trigger determining which target tissue, neuronal or non-neural, becomes first resistant to insulin and what initiates the afterwards development of insulin resistance in the left over target tissue.

INTRODUCTION

With a progression of brain research in diabetes mellitus, new perceptions have emerged revealing that within the brain, a condition of “cerebral” diabetes could develop. To set the stage for defining the “cerebral” diabetes in this review, it is necessary to turn first to the main features of diabetes mellitus.

Diabetes mellitus is a heterogeneous metabolic disorder characterized by an inappropriate glucose metabolism that leads to impaired removal of glucose from the circulation. The clearance of glucose from blood is mediated by insulin which following binding to insulin receptor (IR) activates cellular glucose uptake. Therefore, absolute or relative lack of insulin and/or impaired insulin action via IR causes delayed or almost absent metabolism of circulating glucose. Type 1 diabetes mellitus, in general, is caused by autoimmune destruction of insulin producing/secreting β cells in pancreas resulting in lack of insulin, while type 2 diabetes mellitus is associated with dysfunction of insulin intracellular signal transduction due to the cell does not couple insulin binding to IR with activation of the particular cell function, i.e. cell becomes resistant to the action of insulin (86). Insulin signaling within the cell is mediated in general by two functional cascades, one acting through phosphatidylinositol-3 (PI3) kinase pathway and mediating insulin effects on intermediary metabolism and glucose uptake, and one acting through mitogen activated protein kinase (MAPK) pathway, mediating cell growth and mitosis (50). Clinical insulin resistance seen in type 2 diabetes has been reported to involve inhibition of insulin-activated PI3 kinase pathway, that may be induced by products of fatty acid metabolism, cytokines and inflammatory cascade products (e.g. tumor necrosis factor-α /TNF-α/), etc. (25,27,56).

In line with these key features of diabetes mellitus, “cerebral” diabetes could be roughly define as a state of dysfunction of brain glucose metabolism and brain insulin system. Term “insulin resistant brain state” has recently been introduced instead of “cerebral diabetes”. Research of the brain insulin pathophysiology has been intensified in the last decade and dysregulation of insulin secretion and transport in the CNS along with insulin deficiency or resistance in the brain has been reported in relation to aging, obesity, diabetes mellitus and late-onset sporadic Alzheimer’s disease (32,47). This mini-review summarizes current knowledge about insulin resistant brain state and its relationship to diabetes mellitus, particularly type 2 diabetes.

BRAIN INSULIN

Insulin and IR are found throughout the central nervous system (CNS) (83). Since the main feature of the insulin resistant brain state is disorder of the IR signaling cascade (47), the review is focused primarily to this aspect and therefore, brain insulin and IR distribution, regulation, function and dissimilarities to the peripheral insulin system will be briefly summarized.

Insulin origin. The source of insulin in the brain might be either peripheral or local in origin, or both (3,83). Insulin from the blood crosses the blood brain barrier (BBB) by a saturable transport mechanism, but all regions of the BBB are not equally permeable to insulin. Namely, BBB transports insulin into the pons-medulla and hypothalamus twice time (4), and into the olfactory bulb two to eight times (5) faster than into the whole brain. This is consistent with finding of regionally specific distribution of insulin in the CNS with the olfactory bulb and hypothalamus containing the highest concentration of insulin (6). There are also several lines of evidence consistent with a local synthesis of insulin in the brain. Insulin mRNA is distributed in a highly specific pattern with the highest density in pyramidal cells of the hippocampus and a high density in the medial prefrontal cortex, the enthorinal cortex, perirhinal cortex, thalamus, granule cell layer of the olfactory bulb, and hypothalamus (24,104). Synthesized insulin was shown to be secreted into the extracellular space specifically by neurones (35).

Insulin receptor and its signalling. Two different types of IR have been found in adult mammalian brain; a peripheral type, detected in lower density on glia cells, and a neuron-specific type of IR that has been widely distributed in the CNS on the regionally specific basis (6). High concentrations of this neuronal IR mRNA (the following text refers to this type of IR) were found in the chorioid plexus, olfactory bulb, piryform cortex, amygdaloid nucleus, hippocampus, hypothalamic nucleus and cerebellar cortex (60). Expression of IR protein levels is in accordance with its mRNA levels in most areas, but significant discrepancy is found in the hippocampus and cerebellar cortex, suggesting a higher stability of IR in the hippocampus and probably a rapid turnover of the receptor in the cerebellar cortex neurons (106). The mayor molecular structure and most of the biochemical properties of the neuronal IR are indistinguishable from those found in the periphery, but some structural and functional differences between the CNS and the peripheral IR have been suggested; the molecular mass of alpha and beta subunits of the brain IR is slightly lower than that in the peripheral tissue (42), and high concentrations of insulin downregulate the peripheral IR, but have no effect on the brain IR (12). It has to be mentioned that two insulin receptor isoforms (IR-A and IR-B) generated by alternative mRNA splicing have been identified at the periphery, and their expression found to be highly regulated in tissue specific fashion (7). Namely, IR exists in two isoforms differing by the absence (Ex11-) or presence (Ex11+) of 12 amino acids in the C-terminus of the alpha-subunit due to alternative splicing of exon 11.Ex11- binds insulin with two-fold higher affinity than Ex11+. This difference is paralleled by a decreased sensitivity for metabolic actions of insulin. However, data reported so far suggest that heterogeneity of IR in different tissues including brain is unrelated to alternative splicing of IR gene (13,51). Also, inconsistent data have been reported regarding the abundance of the two isoforms in relation to insulin resistance in type 2 diabetes in humans (84).

Insulin signal transduction in the brain is similar to that at the periphery. Insulin receptor belongs to the receptor tyrosine kinase superfamily. Briefly, activated IR recruits insulin receptor substrate (IRS-1/2) adapter protein (also regionally specifically distributed in the CNS and co-expressed with IR in certain population of neurones /29/) to its phosphorylated docking site, which then becomes phosphorylated on tyrosine residues and capable to recruit various SH2 domain-containing signaling molecules, among which are PI3 kinase and adapter proteins for MAPK pathway (Fig. 1) (50). Activation of MAPK pathway leads to insulin-induced mitogenic effects. Activation of PI3 kinase pathway transduces the signal to protein kinase B (PKB/Act), that in the peripheral insulin-sensitive tissue and as also shown in some brain regions, triggers glucose transporter GLUT4 translocation and consequently cellular glucose uptake (50,98). In addition, PKB/Act can modulate the glycogen synthase kinase (GSK-3) pathway that in the peripheral insulin-sensitive tissue leads to glycogen synthesis (50). In the brain, beside other roles, GSK-3 has been related to the regulation of amyloid-β peptides (Aβs) and tau-protein phosphorylation (47). Therefore, metabolism of amyloid precursor protein (APP), the intracellular formation of secreted APPs and Aβs, and the release of APPs and Aβs into the extracellular space, as well as the balanced phosphorylation of tau-protein, are under control of insulin/IR signal transduction (47). Factors that affect phosphorylation/dephosphorylation homeostasis of elements in insulin signal transduction are capable of modifying this cascade causing its dysfunction, e.g., phosphorylation of particular serine and threonine residues of IRS protein reduces insulin-stimulated IRS-1 associated PI3 kinase activity that at the periphery has been causative of insulin resistance and type 2 diabetes (27).

Role of insulin in the brain. The biological effects of brain insulin depend on the availability of the hormone in the brain, its binding and activating specific brain IR with related signaling pathways, and to a minor extent also on regulation of the brain insulin that is synthesized within the CNS. Regional and state-dependent differences in transport across the BBB and in its distribution within the CNS have been suggested as possible factors that may explain how brain insulin can have so diverse effects (3). Namely, while the insulin/IR associated with the hypothalamus plays important role in regulation of the body energy homeostasis and feeding, the hippocampus- and cerebral cortex-distributed insulin/IR has been shown to be involved in brain cognitive function, including learning and memory (75,105).

Glucose is the primary fuel for the brain and cerebral metabolism of glucose requires its transport across the BBB by insulin-insensitive glucose transport GLUT1 (64), that has been found downregulated in uncontrolled diabetes (69), and upregulated in chronic hypoglycaemia (63). Majority of glucose utilization within the CNS appears to be mediated through glucose transporters GLUT1 and GLUT3, both insulin-insensitive (28). However, rapid and transient changes in cerebral glucose utilization may occur via insulin-sensitive glucose transporters GLUT4 and GLUT8, found in the brain (76,77,98). Glucose transporter GLUT4 is the main transporter type responsible for glucose uptake in the peripheral insulin target cell, and in the brain neuronal localization of GLUT4 mRNA and protein in hypothalamus, cerebellum, cortex and hippocampus exhibits overlapping distribution with IR, as well (57,65). Activation of brain IR leads to stimulation of the glycolytic key enzymes and pyruvate oxidation in the brain (48,78).

Growing evidence suggests that insulin interacts with both orexigenic and anorexigenic peptides in the brain in the control of feeding behaviour, maintenance of body weight and energy homeostasis, but most of the research has been focused on insulin “cross-talk” with leptin in the hypothalamus, as reviewed elsewhere (36,72). Both insulin and leptin acutely regulate the membrane potential and firing rates of a specific subset of hypothalamic neurones, the effect being dependent on signaling through PI3 kinase (89,90). Genetic studies demonstrated that brain-specific knockouts of the IR and animals lacking IRS-2 show a phenotype of obesity and reproductive dysfunction (14,16), and knockdown of IR expression locally in the hypothalamus resulted in cumulative food intake of 152% and fat mass of 186% relative to controls (73). These findings support the conclusion that insulin action in the hypothalamus is essential in the regulation of energy homeostasis. It has been suggested that central insulin has fundamentally catabolic (i.e. reducing food intake and body weight), whereas peripheral insulin has anabolic (i.e. increasing energy storage and potentially increasing body weight if an individual has too much insulin) activity (72). Like most physiological systems, the peripheral and central actions of insulin regarding this issue are balanced. Therefore, the lack of catabolic insulin action in the brain (coupled with disturbances like the decrease in serum leptin) leads to marked increases in food intake and obesity that is often associated with insulin resistance and hyperinsulinemia (72).

Insulin receptor signaling plays a role in synaptic plasticity in hippocampus by modulating activity of excitatory and inhibitory receptors and consequently affecting cognitive functions like learning and memory (105). During learning insulin binds to its receptors, and activated IR may be involved in memory formation via potentiation of glutamatergic NMDA receptor channel activity leading to increase in Ca 2+ influx and long-term potentiation (85). Via PI3 kinase it may be involved in long-term depression by internalisation of glutamatergic AMPA receptors (59), or via recruiting of functional GABA receptors to the postsynaptic membrane (99). Additionally, IR induced activation of MAPK pathway after learning may lead to regulation of gene expression that is required for long-term memory storage, while IR interaction with G-protein coupled receptor may activate protein kinase C leading to facilitation of short-term memory encoding (105). Also, IR-IRS-PI3 kinase pathway may trigger endothelial nitric oxide synthase (eNOS) activity and generation of nitric oxide that acts as a retrograde messenger for release of neurotransmitters involved in learning and synaptic plasticity (26,68).

Regulation of brain insulin. It is still a controversial issue if the effects of insulin on the brain should mainly be regarded as an extension of its peripheral action, or insulin effects on the brain that are clearly independent from its peripheral metabolic effects. If the latter is the case, how can these peripheral and central effects of insulin be regulated independent from each other, assuming that circulating insulin is the major source of insulin in the brain. This suggests not only the complexity of brain insulin regulation, but also the potential significance of the centrally originated portion of brain insulin.

Brain insulin is subject to a multifactorial control exerted at various levels. It can be regulated both peripherally and centrally; biosynthesis and secretion in the pancreas along with transport in the brain, internalisation, storage, stability, as well as its local synthesis and release within the CNS may be affected by numerous metabolites, circulating hormones, regulatory peptides and neurotransmitters (36). The molecular mechanisms involved in the production and release of insulin in the CNS seem to share similarities to that in the periphery: structures specific for glucose sensing and metabolizing at the level of beta cells, such as glucose transporter GLUT2 and glucokinase, have been demonstrated co-localized in particular hypothalamic cells (49); both beta cells and hypothalamic neurons contain ATP-sensitive-K+ channels, a key protein in the glucose response mechanism and insulin secretion (2,97). Furthermore, insulin released from adult rat brain synaptosomes under depolarising conditions depends on calcium influx, suggesting that insulin is stored in the adult rat brain in synaptic vesicles within nerve endings from which it can be mobilized by exocytosis in association to neural activity (101).

Regulation of brain insulin, in particular its release, has been investigated at the level of hypothalamus. Increased insulin release in hypothalamus has been found in relation to carbohydrate meals (37), and local glucose (38,82) and serotonin (74) increament, respectively. This regulation showed regional specificity, since the modifications induced in the hypothalamus were not observed in the cerebellum, and neither insulinemia nor glycemia were affected. Leptin may interact with insulin directly or via other neuromodulators (serotonin, melanocortin, etc.) and there is also a cross-talk of insulin and leptin receptors in the CNS (72). The potential effects of glucocorticoids on brain insulin could be a result of both peripheral and central action, where local regulation has been suggested to involve effects via glucose and serotonin (72). Participation of other hormones and regulatory peptides in regulation of brain insulin is also being investigated.

INSULIN RESISTANT BRAIN STATE AND AGING

It has been clinically demonstrated that with physiological aging a resistance to the action of insulin develops at the periphery, leading to slightly increased glycemia and insulin levels, as reviewed elsewhere (32). Several causes have been postulated for this insulin resistance with aging, among them also the alteration of peripheral IR signal transduction, such as decrease in IRS-1 protein level and its tyrosine residua phosphorylation (18), decrease in IRS-1 association with PI3 kinase and decrease in insulin-stimulated MAPK activity (33,67). The regulation of neuronal glucose metabolism during aging is diminished in the brain, as a result of complex age-associated alterations, but mainly because of the decreased neuronal insulin signal transduction (31). Namely, insulin and C-peptide concentrations decrease with aging (30%-45%) in all brain regions, while brain IR density decreases (38%-49%) in regionally specific manner, particularly stressed in frontal and parietal cortex, with IR tyrosine kinase activity also being decreased, particularly in the temporal region (31).

Additionally, IR signaling pathway in the brain interacts with signaling pathway of other factors, such as insulin growth factor I (IGF-I) and brain-derived neurotrophic factor (BDNF), the alteration of which may therefore contribute to brain insulin dysfunction. As previously mentioned, insulin plays a significant role in cognitive functions and significant decline in cognitive functions has been found with aging (22). Aging itself appears to be associated with decreased brain signaling of BDNF which is known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain (62). The receptor for BDNF belongs to tyrosine kinase superfamily and exerts its effects on neurones via a signal transduction mechanism similar to the insulin signaling pathway (30). When activated, BDNF receptor involves IRS-1 and -2 signaling pathway and stimulation of PI3 kinase which then activates PKB/Act. Activation of this pathway enhances learning and memory, can promote the survival of neurones in metabolic and oxidative stress, and also an important role in regulating glucose metabolism and possibly lifespan has been suggested (61). Alterations of BDNF and its overlapping with the part of insulin intracellular signaling may contribute to insulin resistant brain state in aging. Aging is also associated with a reduced activity of IGF-I in the CNS (91). In spite of relatively constant levels of mRNA in different brain regions, cortical IGF-I protein levels decrease significantly during aging process in rats (71). IGF-I and insulin share a common signal transduction mechanism involving IRS proteins and subsequent signaling pathway, moreover, IR and IGF-I receptors show relative promiscuity and can bind both IGF-I and insulin. There is ample evidence that IGF-I plays a role in cognitive functions, further supporting involvement of insulin signaling pathway dysfunction in age-related decline in cognitive functions (11,91).

There is a clear evidence that the function of the neuronal insulin/IR signal transduction is of a pivotal significance to maintain normal cerebral blood flow and oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and the cell cycle in terminally differentiated neurones no longer in the cell cycle (46). It has become evident that normal metabolism of both APP and tau-protein is a part of interactive processes controlled by the normal insulin/IR signal transduction. In physiological brain aging, the malfunction of this cascade starts, leading to various adverse effects that due to their multifolding and permanency may become severe and may increase the vulnerability of the aging brain, facilitating thus the generation of some age-related disorders, such as dementia and the late-onset sporadic Alzheimer’s disease (46).

INSULIN RESISTANT BRAIN STATE AND ALZHEIMER’S DISEASE

Alzheimer’s disease is the most common form of dementia among older adults. In spite of indistinguishable clinical dementia symptoms, there two types of origin-based Alzheimer’s disease. In a small proportion (familial early-onset Alzheimer’s disease), the disease is caused by missense mutations in three genes, resulting in permanent generation of APP derivative Aβ which aggregates forming amyloid and plaques, while in the great majority of people (late-onset Alzheimer’s disease), it is sporadic in origin with old age as main risk factor, where Aβ has not been proven to be necessary for the generation and development of the disease (47). Among other more or less known neurochemical alterations in the brain that are beyond the scope of this review, growing evidence has identified a potential association among Alzheimer’s disease, glucose metabolism, and insulin activity (47). Patients with Alzheimer’s disease may have decreased cerebrospinal fluid levels and decreased cerebrospinal fluid to plasma insulin ratio related to impaired transport of insulin across the BBB (21), but neuronal insulin signal transduction in this disease has been in the focus of the current research. In contrast to the more localised abnormalities in the early-onset type, the late-onset type of Alzheimer’s disease is associated with glucose utilization abnormalities distributed all over the cerebral cortex, and particularly in parietotemporal and frontal areas, in structures with both high glucose demands and high insulin sensitivity (43). Since it has become obvious that neuronal glucose metabolism is under the control of the neuronal insulin, the abnormalities in neuronal glucose metabolism in Alzheimer’s disease have been suggested to be caused at the level of insulin signal transduction (46).

The up-regulation of IR density observed in hippocampus and associated with reduced activity of IR tyrosine kinase in the brain of people with sporadic Alzheimer’s disease indicates a desensitization of the neuronal IR (21,31). Proposed mechanism of inhibition of neuronal IR in the late-onset sporadic Alzheimer’s disease is related to age-induced increase in cortisol and catecholamine levels that may compromise the phosphorylation of tyrosine residues in IR (39,47). This leads to a dysfunction of subsequent insulin signal transduction, which at the level of GSK-3 kinase (α and β subtypes) results in two main pathophysiological events. In the physiological condition, PKB/Act acts to phosphorylate GSK-3 at its serine 9 residue, thereby inactivating it. Insulin normally exerts a double-sided effect on Aβs, stimulating their neuronal release (mediated through GSK-3α kinase) and in the same time contributing to extraneuronal accumulation of Aβs by competing for insulin-degrading enzyme that degrades both insulin and Aβs (34). The net action of insulin is to increase extracellular levels of Aβs in the brain. Therefore, insulin resistance-induced disinhibition of GSK-3α function in the sporadic Alzheimer’s disease leads to increased storage of APP and Aβs in neurons which then undergo lysis to form amyloid plaques, one of the main pathological features of the Alzheimer’s disease (47). These Aβs in turn reduce the binding of insulin to its receptor and receptor autophosphorylation, which in the early-onset type of Alzheimer’s disease may be the cause of triggering the dysfunction of brain insulin signal transduction (103). Also, with the fall in extracellular APPs, its mediated functions in memory enhancement may be assumed to fail, contributing to cognitive deficits (66). On the other side, insulin resistance-induced disinhibition of GSK-3β function leads to uncontrolled hyperphosphorylation of tau-protein (47). Tau is a neuronal cytoskeletal protein that binds to microtubules and promotes tubulin polymerisation and stabilization. The binding of tau to microtubules is regulated through phosphorylation by protein kinases, including GSK-3β (47). In physiological condition, insulin inhibits GSK-3β and consequently reduces tau phosphorylation, promoting binding of tau to microtubules (44). Following brain insulin dysfunction hyperphosphorylated form of tau protein builds neurofibrillary tangles, the other important pathological feature of the Alzheimer’s disease.

This impairment of the insulin signal transduction causing insulin resistant brain state is similar to condition of systemic insulin resistance in non-neuronal tissues in type 2 diabetes mellitus, suggesting a hypothesis that sporadic Alzheimer’s disease is the brain equivalent of type 2 diabetes mellitus, in other words, a kind of “cerebral” diabetes (45). Comparable to type 2 diabetes mellitus, susceptibility genes in combination with the main risk factor aging dysregulate the function of insulin signaling cascade. In addition to insulin resistance, Alzheimer’s disease (familial and sporadic) and diabetes mellitus (type 1 and 2) share the similarity in fact that both diseases are heterogenic in origin and homogenic in clinical appearance of their respective subtypes (46). It has been proposed that whether type 2 diabetes or Alzheimer’s dementia develops as a consequence of loss of sensitivity to insulin, may depend on what target tissue, neuronal or non-neuronal, becomes resistant to it (17).

INSULIN RESISTANT BRAIN STATE AND DIABETES MELLITUS

Type 2 diabetes mellitus is associated with dysfunction of insulin intracellular signal transduction due to the cell does not couple insulin binding to IR with activation of the particular cell function, i.e. cell becomes resistant to the action of insulin. The intriguing question is whether peripheral insulin resistant state (type 2 diabetes) and central insulin resistant states (presented here as e.g. aging and sporadic Alzheimer’s disease) are two different, separated entities or just one condition that, like in the physics “Law of connected containers”, metaphorically speaking, can “overflow” from one container to another. In other words, does peripheral insulin resistance lead to development of central insulin resistance and vice versa? Due to insufficient level of current knowledge, answers to these questions could only be speculative ones.

Growing evidence indicates that these conditions may be connected; effects of diabetes and aging on the brain may interact, and both conditions may interact with the appearance of sporadic late-onset Alzheimer’s disease (8). Summarizing the aforementioned data, brain glucose metabolism and insulin signal transduction in the brain seem to be the interconnecting link. Decreased brain glucose metabolism and decreased brain insulin content have been demonstrated in diabetes (1) as well as in aging and in the sporadic Alzheimer’s disease, accompanied by dysfunction of brain IR signalling cascade (31). Disturbances in transducing the signal from IR to the intraneuronal structures in the brain can be caused by various factors that may inhibit the tyrosine phosphorylation of IRSs and PI3 kinase subunits, among which advanced glycation end products (AGEs) and oxidative stress were frequently mentioned (10,27,70). AGEs have been generated by glucose-induced reaction of glycation of long-lived macromolecules and tend to accumulate both in the periphery and in the brain with aging, as well as in diabetes and in Alzheimer’s disease (52,81,87). During the formation of AGEs free radicals are produced, and they all may interfere with the IR functioning and signal transduction by diminishing the tyrosine phosphorylation of IRS-1/2, which then is unable to activate PI3 kinase – PKB/Act pathway, leading to altered glucose/glycogen metabolism and insulin resistance (32). Contributing factor could also be oxidative stress mediated by free radicals (10). Preclinical and clinical data demonstrate that aging, diabetes and Alzheimer’s disease are all associated with increased oxidative stress both at the periphery and in the CNS (41,53,70). Chronic oxidative stress may cause chronic oxidizing of tyrosine phosphatase PTP-1B, enzyme that dephosphorylates IR tyrosine residues and reduces its activity, leading thus to insulin resistance (32). In the context of human aging, an association between the IR and the longevity can be drawn, since altered IR signaling and marked insulin resistance are associated with physiological aging. This may suggest that not only aging increases the risk for type 2 diabetes, but also that type 2 diabetes may lead to premature aging (32).

Increasing evidence supports the hypothesis that type 2 diabetes may increase the risk for Alzheimer’s disease. This involves not only those at the signal transduction level representing insulin resistance and those at the behavioural level representing cognitive deficits, but also at the morphological level demonstrating hippocampal and amygdalar atrophy on magnetic resonance imaging (which is a good, early marker of the degree of Alzheimer’s neuropathology) in type 2 diabetic patients (23), and at the structural level, demonstrating deposits of islet amyloid polypeptide in pancreas of diabetic patients, that share a 90% structural similarity with APP which forms deposits in brain of patients with Alzheimer’s disease. Conversely, patients with Alzheimer’s disease have an increased risk for aberrations in peripheral glucose metabolism exhibiting less efficient glucoregulation with slightly but significantly decreased basal arterial glucose concentration and increased plasma insulin concentration resembling partly to the type 2 diabetes condition (15,20). Another study also suggested that patients with Alzheimer’s disease may have abnormal insulin activity in the CNS as well as at the periphery (21).

Regardless the cause, insulin resistance in the brain leads to brain insulin dysfunction. Cognitive deficits, particularly manifested as memory and learning deficits, are well known and documented in relation to age and Alzheimer’s disease as well, and it has been demonstrated that insulin administration can facilitate memory in such individuals (100). Cognitive impairments associated with diabetes mellitus have been reported more consistently in type 2 diabetes characterised by increased insulin resistance, and individuals suffering from type 2 diabetes show an increased prevalence of dementia (19,79). Memory deficits are not usually evident in insulin-dependent type 1 diabetes in humans, and if they occur, are often associated with hypoglycaemia (80,88). In experimental type 1 (streptozotocin-induced) diabetes cognitive deficits have not been consistently reported (9). However, duration and severity dependent distinct changes in hippocampal synaptic plasticity, associated with deficits in NMDA-dependent long-term potentiation probably related to insulin dysfunction, have been reported in streptozotocin-diabetic animals (40).

Beside cognitive deficit discrepancies between type 1 and type 2 diabetes, in general similar changes of monoaminergic neurotransmission at the neurochemical level were observed in streptozotocin-diabetic animals (representing type 1 diabetes) and in streptozotocin-intracerebroventricularly (icv) treated animals (representing an experimental model for sporadic Alzheimer’s disease and brain type 2 diabetes) (54,55,93-96). However, while changes of monoamines and their metabolite content, monoamine turnover rate, as well of monoamine synaptic transporters and dopaminergic receptors were irreversible and tend to progress with the duration of streptozotocin-induced diabetes, in streptozotocin icv-treated animals they seem to be reversible. Bearing in mind that streptozotocin is selectively toxic for insulin producing/secreting cells (92), and that insulin (possibly co-localised in catecholamine-containing neurons) has a neuromodulatory role in synaptic monoaminergic transmission (83,102), these results may suggest similar, insulin-related mechanism of induction the neurochemical changes in brain (at least at the level of monoamine transmission), regardless whether peripheral or central insulin-producing cells have been affecting. The tendency of reversibility of streptozotocin icv-induced changes may suggest that either the damage of brain producing/secreting cells alone is not enough for brain insulin dysfunction to be persistent, or that brain cell damage can somehow be compensated (reversibility depending possibly on streptozotocin dose, or other mechanisms including molecules that share the signalling pathway with insulin, like IGF-1).

Molecular biology and genetic studies give support to the hypothesis that brain insulin dysfunction could have consequences spreading to the periphery, as well. Neuron-specific disruption of the IR gene in mice results in development of diet-sensitive obesity with increases in body fat and plasma leptin levels, insulin resistance, hyperinsulinemia and hypertriglyceridemia, features seen in type 2 diabetes (14). The phenotype of a knock-out mouse model lacking the IRS-2 is similar to model with neuron-specific deletion of IR characterized by increased food intake, body fat content and impaired hypothalamic control of reproduction (16,36). Very recent data indicated that conditional knockout of IRS-2 in mouse pancreas β cells and parts of brain including hypothalamus caused obesity and insulin resistance that progressed to diabetes (58).However, diabetes resolved when functional β cells expressing IRS-2 repopulated the pancreas, restoring sufficient β cell function to compensate for insulin resistance, supporting the aforementioned hypothesis about possible compensation of function/structure of damaged insulin producing/secreting cells in the brain. Furthermore, insulin infusion in the third cerebral ventricle suppresses glucose production at the periphery independent of circulating levels of insulin, which suggests that hypothalamic insulin resistance can contribute to hyperglycemia that may lead to type 2 diabetes (36,73). This indicates that a decrease in the IR number, defects in IR function and signaling, and insulin lack or resistance in the brain may lead to the development of type 2 diabetes even when pancreatic β-cells are normal.

CONCLUSION

Brain insulin resistant state is characterized by a dysfunction of the neuronal IR signaling cascade demonstrated in the PI3 kinase pathway, the consequences being manifested mostly as disturbed APP/Aβs metabolism and tau-protein hyperphosphorylation, cognitive deficits in learning and memory, and altered feeding behaviour. Accumulating data demonstrate that insulin resistant brain state is associated with conditions like aging, obesity, sporadic Alzheimer’s disease, and type 2 diabetes mellitus. Aging and sporadic Alzheimer’s disease may represent insulin resistance primarily in neuronal, non-classical target tissue, while obesity and type 2 diabetes may represent insulin resistance primarily in non-neuronal, classical insulin target tissue. Current knowledge suggests a bi-directional communication of central and peripheral insulin resistant state, respectively, one may increase the risk for development of another and vice versa. However, proposed mechanisms of insulin resistance, like AGEs accumulation and oxidative stress found both centrally and peripherally, do not offer plausible answer for the questions which tissue, neuronal or non-neuronal, becomes first resistant to the insulin, and why the central and peripheral insulin resistance do not develop simultaneously if their cause is present in both tissue types and body compartments. Various genetic, metabolic, nutritional and environmental factors certainly have an important role in this issue. However, the thin line that has to be crossed for both insulin resistant states to be developed and clinically manifested still remains to be discovered providing a challenging subject for further research.

Acknowledgements: Partly supported by The Ministry of Science, Technology and Sport, Republic of Croatia (No. 108134). Professor Peter Riederer and Professor Siegfried Hoyer are thanked for a fruitful discussion realised through a collaborative project “Stability Pact for South Eastern Europe” supported by Deutscher Akademischer Austausch Dienst (DAAD).

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Fig. 1. Intracellular insulin receptor signaling pathway. Insulin binding to insulin receptor (IR) activates receptor tyrosine kinase (TK) activity, and among other molecules recruits insulin receptor substrate (IRS) protein. IRS becomes phosphorylated at tyrosine residues (Tyr-P) and capable of recruiting various signaling molecules including enzymes like phosphoinositide-3 kinase (PI3-K), or different adapters, among which one transduces the signal to the serine/threonine kinase MAPK (mitogen activated protein kinase) pathway via monomeric G protein Ras. Ras/MAPK pathway is related to insulin-induced effects on growth and proliferation. Downstream to the PI3-K pathway is protein kinase B (PKB/Act) that is related to insulin-induced metabolic events, like translocation of glucose transporter GLUT4 to the cell membrane to facilitate cellular glucose uptake. PKB/Act may also phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3), leading thus to activation of glycogen synthase and increased glycogen synthesis. In the brain, GSK-3 α is related to regulation of the metabolism of amyloid precursor protein (APP) and amyloid-β proteins (Aβs), while GSK-3 β balances the phosphorylation of tau protein. Amonth others, IR signal transduction may be reduced by decreasing the binding of insulin to IR via Aβs, by reducing the TK activity of IR via cortisol and catecholamine, or by inducing the serine/threonine phosphorylation (S/T-P) of IRS via free fatty acids (FFA), cytokines and inflammatory products like tumor necrosis factor α (TNF-α), or advanced glycation end products (AGEs). Simplified scheme modified according to Hoyer S, 2004 (47).

IR

Aβs

reduced insulin binding

cortisol, catecholamines... insulin

reduced TK activity TK activity

FFA, TNF-α, AGEs... insulin

reduced initiation of

insulin signal transduction insulin signal transduction

↓ ↓

PKB/Act

MAPK

↓ ↓

regulation of metabolic effects regulation of mitogenic effects

↓ ↓

GLUT4 translocation GSK-3 → glycogen synthesis

glucose uptake α β

APP/Aβ tau protein

metabolism phosphorylation

23

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