Diabetes mellitus (DM) is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body, including in the eye. Diabetic retinopathy (DR), present in one-third of patients with diabetes, is a vision-threatening complication caused by uncontrolled diabetes, which greatly affects the retinal blood vessels and the light-sensitive inner retina, eventually leading to blindness. Several epidemiological studies elucidate that DR can vary by age of onset, duration, types of diabetes, and ethnicity. Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia. The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging. This review throws light on the pathological processes behind DR, the cascade of events that follow it, as well as the available and emerging treatment options.

Long-term consumption of a high-fat diet (HFD) disrupts energy homeostasis and leads to weight gain. The fat mass and obesity-associated (FTO) gene has been consistently identified to be associated with HFD-induced obesity. The hypothalamus is crucial for regulating energy balance, and HFD-induced hypothalamic leptin resistance contributes to obesity. FTO, an N6-methyladenosine (m6A) RNA methylation regulator, may be a key mediator of leptin resistance. However, the exact mechanisms remain unclear. Therefore, the present study aims to investigate the association between FTO and leptin resistance. After HFD or standard diet (SD) feeding in male mice for 22 weeks, m6A-sequencing and western blotting assays were used to identify target genes and assess protein level, and molecular interaction changes. CRISPR/Cas9 gene knockout system was employed to investigate the potential function of FTO in leptin resistance and obesity. Our data showed that chemokine (C-X3-C motif) ligand 1 (CX3CL1) was a direct downstream target of FTO-mediated m6A modification. Furthermore, upregulation of FTO/CX3CL1 and suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus impaired leptin-signal transducer and activator of transcription 3 signaling, resulting in leptin resistance and obesity. Compared to wild-type (WT) mice, FTO deficiency in leptin receptor-expressing neurons of the hypothalamus significantly inhibited the upregulation of CX3CL1 and SOCS3, and partially ameliorating leptin resistance under HFD conditions. Our findings reveal that FTO involved in the hypothalamic leptin resistance and provides novel insight into the function of FTO in the contribution to hypothalamic leptin resistance and obesity.

It has been almost 70 years since the discovery of nerve growth factor (NGF), a period of a dramatic evolution in our understanding of dynamic growth, regeneration, and rewiring of the nervous system. In 1953, the extraordinary finding that a protein found in mouse submandibular glands generated a halo of outgrowing axons has now redefined our concept of the nervous system connectome. Central and peripheral neurons and their axons or dendrites are no longer considered fixed or static "wiring." Exploiting this molecular-driven plasticity as a therapeutic approach has arrived in the clinic with a slate of new trials and ideas. Neural growth factors (GFs), soluble proteins that alter the behavior of neurons, have expanded in numbers and our understanding of the complexity of their signaling and interactions with other proteins has intensified. However, beyond these "extrinsic" determinants of neuron growth and function are the downstream pathways that impact neurons, ripe for translational development and potentially more important than individual growth factors that may trigger them. Persistent and ongoing nuances in clinical trial design in some of the most intractable and irreversible neurological conditions give hope for connecting new biological ideas with clinical benefits. This review is a targeted update on neural GFs, their signals, and new therapeutic ideas, selected from an expansive literature.

Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPβ, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPβ overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPβ can be a promising therapeutic approach.

Food intake and energy expenditure are regulated by peripheral signals providing feedback on nutrient status and adiposity to the central nervous system. One of these signals is the pancreatic hormone, insulin. Unlike peripheral administration of insulin, which often causes weight gain, central administration of insulin leads to a reduction in food intake and body weight when administered long-term. This is a result of feedback processes in regions of the brain that regulate food intake. Within the hypothalamus, the arcuate nucleus (ARC) contains subpopulations of neurones that produce orexinergic neuropeptides agouti-related peptide (AgRP)/neuropeptide Y (NPY) and anorexigenic neuropeptides, pro-opiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART). Intracerebroventricular infusion of insulin down-regulates the expression of AgRP/NPY at the same time as up-regulating expression of POMC/CART. Recent evidence suggests that insulin activity within the amygdala may play an important role in regulating energy balance. Insulin infusion into the central nucleus of the amygdala (CeA) can decrease food intake, possibly by modulating activity of NPY and other neurone subpopulations. Insulin signalling within the CeA can also influence stress-induced obesity. Overall, it is evident that the CeA is a critical target for insulin signalling and the regulation of energy balance.

Alzheimer's disease is associated with biochemical and histopathological changes characterized by molecular abnormalities. Due to the lack of effective treatments for Alzheimer's disease, many attempts have been made to find potential therapies to reduce or even return neuronal loss after disease initiation. Alzheimer's disease is also touted as type III diabetes, showing an association with insulin signaling. The large distribution of the insulin receptor on the cell surface and its regulatory role in the central nervous system suggests that the pathogenesis of Alzheimer's disease could be ascribed to insulin signaling. The interference of opioids, such as morphine with insulin signaling pathways, is thought to occur via direct crosstalk between the signaling pathways of the insulin receptor and the mu-opioid receptor. In this review article, we discuss the possible crosstalk between the mu-opioid receptor and insulin signaling pathways. The association of these two signaling pathways with Alzheimer's disease is also debated.

The characterization of the hypothalamic neuronal network, that controls food intake and energy expenditure, has provided great advances in the understanding of the pathophysiology of obesity. Most of the advances in this field were obtained thanks to the development of a number of genetic and nongenetic animal models that, at least in part, overtook the anatomical constraints that impair the study of the human hypothalamus. Despite the undisputed differences between human and rodent physiology, most seminal studies undertaken in rodents that have unveiled details of the neural regulation of energy homeostasis were eventually confirmed in humans; thus, placing experimental studies in the forefront of obesity research. During the last 15 years, researchers have provided extensive experimental proof that supports the existence of hypothalamic dysfunction, which leads to a progressive whole-body positive energy balance, and thus, to obesity. Here, we review the experimental work that unveiled the mechanisms behind hypothalamic dysfunction in obesity.

Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS is presented. This classification includes the use of formulations administered systemically that can elicit transcytosis-mediated transport by interacting with transporters expressed by transvascular endothelial cells. Neurotherapeutics can also be delivered to the CNS by means of surgical intervention using specialized catheters or implantable reservoirs. Strategies for delivering drugs to the CNS have evolved tremendously during the last two decades, yet, some factors can affect the quality of data generated in preclinical investigation, which can hamper the extension of the applications of these strategies into clinically useful tools. Here, we disclose some of these factors and propose some solutions that may prove valuable at bridging the gap between preclinical findings and clinical trials.

Cancer is a complex group of diseases where different signaling pathways have been found to be deregulated, mainly related to cell proliferation, angiogenesis, metastasis, evasion of apoptosis and insensitivity to anti-growth sings among others. Diet plays a fundamental role in the treatment of the oncological patients, we must be aware that food can interact with certain types of cancer therapy. On the other hand, cancer therapies sometimes affect the patient's sense of smell, taste, appetite, gastric capacity or nutrient absorption, which often results in malnutrition due to the lack of essential nutriments. In this chapter we will review the effect of different metabolic disorders in cancer and mechanisms of action of some phytochemicals found in different foods like resveratrol, EGCG, curcumin and lycopene.

Ischemic stroke and diabetes are vascular risk factors for the development of impaired memory such as dementia and/or Alzheimer's disease. Clinical studies have demonstrated that minor striatal ischemic lesions in combination with β-amyloid (Aβ) load are critical in generating cognitive deficits. These cognitive deficits are likely to be associated with impaired insulin signaling. In this study, we examined the histological presence of insulin-like growth factor-I (IGF-1) and insulin receptor substrate (IRS-1) in anatomically distinct brain circuits compared with morphological brain damage in a co-morbid rat model of striatal ischemia (ET1) and Aβ toxicity. The results demonstrated a rapid increase in the presence of IGF-1 and IRS-1 immunoreactive cells in Aβ + ET1 rats, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion. These regions included subcortical white matter, motor cortex, thalamus, dentate gyrus, septohippocampal nucleus, periventricular region and horizontal diagonal band of Broca in the basal forebrain. The alteration in IGF-1 and IRS-1 presence induced by ET1 or Aβ rats alone was not severe enough to affect the entire brain circuit. Understanding the causal or etiologic interaction between insulin and IGF signaling and co-morbidity after ischemia and Aβ toxicity will help design more effective therapeutics.

Diabetic polyneuropathy (DPN) is a common but intractable degenerative disorder of peripheral neurons. DPN first results in retraction and loss of sensory terminals in target organs such as the skin, whereas the perikarya (cell bodies) of neurons are relatively preserved. This is important because it implies that regrowth of distal terminals, rather than neuron replacement or rescue, may be useful clinically. Although a number of neuronal molecular abnormalities have been examined in experimental DPN, several are prominent: loss of structural proteins, neuropeptides, and neurotrophic receptors; upregulation of "stress" and "repair" proteins; elevated nitric oxide synthesis; increased AGE-RAGE signaling, NF-κB and PKC; altered neuron survival pathways; changes of pain-related ion channel investment. There is also a role for abnormalities of direct signaling of neurons by insulin, an important trophic factor for neurons that express its receptors. While evidence implicating each of these pathways has emerged, how they link together and result in neuronal degeneration remains unclear. However, several offer interesting new avenues for more definitive therapy of this condition.

Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight. mTOR integrates signals from a variety of "energy balancing" hormones such as leptin, insulin, and ghrelin, although its action varies in response to these distinct hormonal stimuli as well as across different neuronal populations. In this review, we summarize and highlight recent findings regarding the functional roles of mTOR complex 1 (mTORC1) in the hypothalamus specifically in its regulation of body weight, energy expenditure, and glucose/lipid homeostasis. Understanding the role and underlying mechanisms behind mTOR-related signaling in the brain will undoubtedly pave new avenues for future therapeutics and interventions that can combat obesity, insulin resistance, and diabetes.

Here we asked if insulin activation of the nucleus accumbens in vitro is reflected by an increase in (3)H-deoxyglucose ([(3)H]DG) uptake, thus subserving a new model to study molecular mechanisms of central insulin actions. Additionally, we investigated the dependence of this insulin effect on endocannabinoids and corticosteroids, two major culprits in insulin resistance. We found that in acute accumbal slices, insulin (3 and 300nM but not at 0.3nM) produced an increase in [(3)H]DG uptake. The synthetic cannabinoid agonist, WIN55212-2 (500nM) and the glucocorticoid dexamethasone (10μM), impaired insulin (300nM) action on [(3)H]DG uptake. The glucocorticoid receptor (GcR) antagonist, mifepristone (10μM) prevented dexamethasone from inhibiting insulin's action. Strikingly, this anti-insulin action of dexamethasone was also blocked by two CB1 cannabinoid receptor (CB1R) antagonists, O-2050 (500nM) and SR141716A (500nM), as well as by tetrahydrolipstatin (10μM), an inhibitor of diacylglycerol lipases-the enzymes responsible for the synthesis of the endocannabinoid, 2-arachidonoyl-glycerol (2-AG). On the other hand, the blockade of the post-synaptic 2-AG metabolizing enzymes, α,β-serine hydrolase domain 6/12 by WWL70 (1μM) also prevented the action of insulin, probably via increasing endogenous 2-AG tone. Additionally, an anti-insulin receptor (InsR) antibody immunoprecipitated CB1Rs from accumbal homogenates, indicating a physical complexing of CB1Rs with InsRs that supports their functional interaction. Altogether, insulin stimulates glucose uptake in the nucleus accumbens. Accumbal GcR activation triggers the synthesis of 2-AG that in turn binds to the known CB1R-InsR heteromer, thus impeding insulin signaling.

Diabetic polyneuropathy in humans is of gradual, sometimes insidious onset, and is more likely to occur if glucose control is poor. Arguments that the disorder arises chiefly from glucose toxicity however ignore the greater complexity of a unique neurodegenerative disorder. For example, sensory neurons regularly thrive in media with levels of glucose at or exceeding those of poorly controlled diabetic persons. Also, all of the linkages between hyperglycemia and neuropathy develop in the setting of altered insulin availability or sensitivity. Insulin itself is recognized as a potent growth, or trophic factor for adult sensory neurons. Low doses of insulin, insufficient to alter blood glucose levels, reverse features of diabetic neurodegeneration in animal models. Insulin resistance, as occurs in diabetic adipose tissue, liver, and muscle, also develops in sensory neurons, offering a mechanism for neurodegeneration in the setting of normal or elevated insulin levels. Other interventions that "shore up" sensory neurons prevent features of diabetic polyneuropathy from developing despite persistent hyperglycemia. More recently evidence has emerged that a series of subtle molecular changes in sensory neurons can be linked to neurodegeneration including epigenetic changes in the control of gene expression. Understanding the new complexity of sensory neuron degeneration may give rise to therapeutic strategies that have a higher chance of success in the clinical trial arena.

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

Bacopa monnieri extract has been implicated in the recovery of memory impairments due to various neurological disorders in animal models and humans. However, the precise molecular mechanism of the role of CDRI-08, a well characterized fraction of Bacopa monnieri extract, in recovery of the diabetes mellitus-induced memory impairments is not known. Here, we demonstrate that DM2 mice treated orally with lower dose of CDRI-08 (50- or 100 mg/kg BW) is able to significantly enhance spatial memory in STZ-DM2 mice and this is correlated with a significant decline in oxidative stress and up regulation of the AMPA receptor GluR2 subunit gene expression in the hippocampus. Treatment of DM2 mice with its higher dose (150 mg/kg BW or above) shows anti-diabetic effect in addition to its ability to recover the spatial memory impairment by reversing the DM2-induced elevated oxidative stress and decreased GluR2 subunit expression near to their values in normal and CDRI-08 treated control mice. Our results provide evidences towards molecular basis of the memory enhancing and anti diabetic role of the Bacopa monnieri extract in STZ-induced DM2 mice, which may have therapeutic implications.

Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 × 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this positive regulation. This evidence might serve in further elucidating the mechanism behind ME-induced cognitive gain.

Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

The prevalence of Alzheimer's disease is increasing rapidly in the absence of truly effective therapies. A promising strategy for developing such therapies is the treatment of brain insulin resistance, a common and early feature of Alzheimer's disease, closely tied to cognitive decline and capable of promoting many biological abnormalities in the disorder. The proximal cause of brain insulin resistance appears to be neuronal elevation in the serine phosphorylation of IRS-1, most likely due to amyloid-β-triggered microglial release of proinflammatory cytokines. Preclinically, the first line of defense is behavior-lowering peripheral insulin resistance (e.g., physical exercise and a Mediterranean diet supplemented with foods rich in flavonoids, curcumin and ω-3 fatty acids). More potent remediation is required, however, at clinical stages. Fortunately, the US FDA-approved antidiabetics exenatide (Byetta; Amylin Pharmaceuticals, Inc., CA, USA) and liraglutide (Victoza; Novo Nordisk A/S, Bagsvaerd, Denmark) are showing much promise in reducing Alzheimer's disease pathology and in restoring normal brain insulin responsiveness and cognitive function.

Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow-derived cells or only in bone marrow-derived cells. We show that a functional TLR4 in bone marrow-derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow-derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.

IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-κB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.

Obesity is considered as a risk factor for mood disorders including depression. Nevertheless, the mechanisms underlying this association are not clearly understood. To address this issue, we investigated the impact of high-fat (HF)-diet-induced obesity on depressive-like behavior and on serotonin (5-HT)-dependent Akt/glycogen synthase kinase 3β (GSK3β) signaling in the dentate gyrus (DG) of the hippocampus, which has been associated with mood regulation. We first showed that a HF diet induced significant overweight and hyperglycemia as well as a depressive-like behavior in adult Wistar rats. By using an ex vivo approach on brain slices, we demonstrated that 5-HT activates the Akt/GSK3β cascade in the DG of control chow (C) diet-fed animals and that a 16-week HF diet feeding abolishes this activation, concurrently with a desensitization of leptin and insulin signaling in the same region. Furthermore, depressive-like behavior inversely correlated with 5-HT-induced phosphorylation of GSK3β in the subgranular neurons of the DG. Interestingly, a substitution of HF with C diet for 6 weeks induced a total loss of depressive symptoms, whereas body weight and glycemia remained significantly higher compared to control rats. In addition, food restoration led to a recovery of the Akt/GSK3β signaling pathway activation in the DG. In parallel, we observed a negative correlation between body weight and cell proliferation in the subgranular zone of the DG. To conclude, we provide evidence for a desensitization of 5-HT-induced Akt/GSK3β signaling and an impaired cell proliferation in the DG by HF diet, suggesting novel molecular mechanisms linking obesity to depression.

Alzheimer's disease (AD) is an age-related neurodegenerative disease leading over the course of decades to the most common form of dementia. Many of its pathologic features and cognitive deficits may be due in part to brain insulin resistance recently demonstrated in the insulin receptor→insulin receptor substrate-1 (IRS-1) signaling pathway. The proximal cause of such resistance in AD dementia and amnestic mild cognitive impairment (aMCI) appears to be serine inhibition of IRS-1, a phenomenon likely due to microglial release of inflammatory cytokines triggered by oligomeric Aβ. Studies on animal models of AD and on human brain tissue from MCI cases at high risk of AD dementia have shown that brain insulin resistance and many other pathologic features and symptoms of AD may be greatly reduced or even reversed by treatment with FDA-approved glucagon-like peptide-1 (GLP-1) analogs such as liraglutide (Victoza). These findings call attention to the need for further basic, translational, and clinical studies on GLP-1 analogs as promising AD therapeutics.

Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

Recently published work and emerging research efforts have suggested that the olfactory system is intimately linked with the endocrine systems that regulate or modify energy balance. Although much attention has been focused on the parallels between taste transduction and neuroendocrine controls of digestion due to the novel discovery of taste receptors and molecular components shared by the tongue and gut, the equivalent body of knowledge that has accumulated for the olfactory system, has largely been overlooked. During regular cycles of food intake or disorders of endocrine function, olfaction is modulated in response to changing levels of various molecules, such as ghrelin, orexins, neuropeptide Y, insulin, leptin, and cholecystokinin. In view of the worldwide health concern regarding the rising incidence of diabetes, obesity, and related metabolic disorders, we present a comprehensive review that addresses the current knowledge of hormonal modulation of olfactory perception and how disruption of hormonal signaling in the olfactory system can affect energy homeostasis.

Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action, or neuropeptide expression in the hypothalamus of mice fed with a high-fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhancing the leptin-induced leptin receptor/Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin-induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice. These effects were independent of body weight. TPM also raised anorexigenic neuropeptides such as POMC, TRH, and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in peroxisome proliferator-activated receptor-coactivator α and uncoupling protein 1 protein levels in brown adipose tissue. Furthermore, TPM increased AMP-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation in peripheral tissues, which may help improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity.

Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development.

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

The beneficial effects of insulin and insulin-like growth factor I on cognition have been documented in humans and animal models. Conversely, obesity, hyperinsulinemia, and diabetes increase the risk for neurodegenerative disorders including Alzheimer's disease (AD). However, the mechanisms by which insulin regulates synaptic plasticity are not well understood. Here, we report that complete disruption of insulin receptor substrate 2 (Irs2) in mice impairs long-term potentiation (LTP) of synaptic transmission in the hippocampus. Basal synaptic transmission and paired-pulse facilitation were similar between the 2 groups of mice. Induction of LTP by high-frequency conditioning tetanus did not activate postsynaptic N-methyl-D-aspartate (NMDA) receptors in hippocampus slices from Irs2(-/-) mice, although the expression of NR2A, NR2B, and PSD95 was equivalent to wild-type controls. Activation of Fyn, AKT, and MAPK in response to tetanus stimulation was defective in Irs2(-/-) mice. Interestingly, IRS2 was phosphorylated during induction of LTP in control mice, revealing a potential new component of the signaling machinery which modulates synaptic plasticity. Given that IRS2 expression is diminished in Type 2 diabetics as well as in AD patients, these data may reveal an explanation for the prevalence of cognitive decline in humans with metabolic disorders by providing a mechanistic link between insulin resistance and impaired synaptic transmission.

Painful diabetic neuropathy (PDN) induces neuronal hyperactivity at the spinal cord and periaqueductal gray (PAG), a key area in descending nociceptive modulation. Since the PAG uses relay stations at serotoninergic and noradrenergic brainstem areas, we determined the serotonin and noradrenaline levels at the spinal cord of streptozotocin-diabetic rats and at those brainstem areas (serotoninergic rostroventromedial medulla and noradrenergic A(5) and A(7) cell groups). Since, during diabetes, the levels of insulin growth factor 1 (IGF1) decrease, reducing its neurotrophic effect in the brain, we also studied the effects of IGF1 treatment. One week after diabetes induction, subcutaneous injections of IGF1 (2.5mg/kg) were performed during 3 weeks. Body weights, glycemia, and mechanical nociception were weekly evaluated until the end of the study, the time when the animals were subjected to a modified formalin test to study chemical allodynia. Serotonin and noradrenaline levels were quantified by ELISA at the spinal cord, whereas at the brainstem, the quantification was performed by immunohistochemistry against, respectively, tryptophan hydroxylase (TpH) or tyrosine hydroxylase (TH). STZ-diabetic rats exhibited mechanical hyperalgesia and chemical allodynia, along with higher spinal levels of serotonin and noradrenaline and higher numbers of neurons expressing TpH at the RVM and TH at the A(5) noradrenergic cell group. Treatment with IGF1 prevented the behavioral signs of PDN and reversed the neuronal hyperactivity at the spinal cord and ventrolateral PAG and the neurochemical changes at the spinal cord and at the brainstem. Based on the facilitatory role of serotoninergic and noradrenergic descending modulation during chronic pain, the increased serotonin and noradrenaline innervation of the dorsal horn in STZ-diabetic rats may probably account for enhanced pain during PDN. The benefits of IGF1 in PDN are probably due to blockade of the increased peripheral input to the somatosensory system, but direct central actions cannot be discarded. The value of IGF1 in PDN treatment deserves further evaluation.

The function of the brainstem Hap1-Ahi1 complex in the regulation of feeding behavior was investigated. When mice were fasted or treated with 2-deoxy-D-glucose (2-DG), Hap1-Ahi1 was significantly upregulated. By using streptozotocin (STZ) to decrease the circulating insulin in mice, Hap1-Ahi1 was significantly increased. Furthermore, intra-brain injection of insulin decreased the expression of Hap1-Ahi1 in the brainstem. Moreover, when we knocked down the expression of brainstem Hap1 by RNAi, the mice showed decreased food intake and lower body weights. Collectively, our results indicate that the Hap1-Ahi1 complex in the brainstem works as a sensor for insulin signals in feeding control.

Studies have suggested that insulin resistance plays a role in cognitive impairment in individuals with type 2 diabetes. We aimed to determine whether an improvement in insulin resistance could explain cognitive performance variations over 36 weeks in older individuals with mild cognitive impairment (MCI) and type 2 diabetes.

A total of 97 older individuals (mean +/- SD age 76 +/- 6 years) who had recently (<2 months) started an antidiabetes treatment of metformin (500 mg twice a day) (n = 30) or metformin (500 mg/day)+rosiglitazone (4 mg/day) (n = 32) or diet (n = 35) volunteered. The neuropsychological test battery consisted of the Mini-Mental State Examination (MMSE), Rey Verbal Auditory Learning Test (RAVLT) total recall, and Trail Making Tests (TMT-A and TMT-B) performed at baseline and every 12 weeks for 36 weeks along with clinical testing.

At baseline, no significant differences were found between groups in clinical or neuropsychological parameters. Mean +/- SD values in the entire population were as follows: A1C 7.5 +/- 0.5%, fasting plasma glucose (FPG) 8.6 +/- 1.3 mmol/l, fasting plasma insulin (FPI) 148 +/- 74 pmol/l, MMSE 24.9 +/- 2.4, TMT-A 61.6 +/- 42.0, TMT-B 162.8 +/- 78.7, the difference between TMT-B and TMT-A [DIFFBA] 101.2 +/- 58.1, and RAVLT 24.3 +/- 2.1. At follow-up, ANOVA models tested changes in metabolic control parameters (FPI, FPG, and A1C). Such parameters improved in the metformin and metformin/rosiglitazone groups (P(trend) < 0.05 in both groups). ANCOVA repeated models showed that results for the metformin/rosiglitazone group remained stable for all neuropsychological tests, and results for the diet group remained stable for the MMSE and TMT-A and declined for the TMT-B (P(trend) = 0.024), executive efficiency (DIFFBA) (P(trend) = 0.026), and RAVLT memory test (P(trend) = 0.011). Results for the metformin group remained stable for the MMSE and TMTs but declined for the RAVLT (P(trend) = 0.011). With use of linear mixed-effects models, the interaction term, FPI x time, correlated with cognitive stability on the RAVLT in the metformin/rosiglitazone group (beta = -1.899; P = 0.009).

Rosiglitazone may protect against cognitive decline in older individuals with type 2 diabetes and MCI.

Glutamate AMPA receptors are critical for sensory transmission at the spinal cord dorsal horn (DH). Plasma membrane AMPA receptor endocytosis that can be induced by insulin may underlie long term modulation of synaptic transmission. Insulin receptors (IRs) are known to be expressed on spinal cord DH neurons, but their possible role in sensory transmission has not been studied. In this work the effect of insulin application on fast excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors evoked in DH neurons was evaluated. Acute spinal cord slices from 6 to 10 day old mice were used to record EPSCs evoked in visually identified superficial DH neurons by dorsal root primary afferent stimulation. AMPA EPSCs could be evoked in all of the tested neurons. In 75% of the neurons the size of the AMPA EPSCs was reduced to 62.1% and to 68.9% of the control values when 0.5 or 10 microM insulin was applied. There was no significant change in the size of the AMPA EPSCs in the remaining 25% of DH neurons. The membrane permeable protein tyrosine kinase inhibitor, lavendustin A (10 microM), prevented the insulin induced AMPA EPSC depression. Our results suggest a possible role of the insulin pathway in modulation of sensory and nociceptive synaptic transmission in the spinal cord.

The insulin-like growth factor receptor type 1 (IGF1R) signalling pathway is activated in the mammalian nervous system from early developmental stages. Its major effect on developing neural cells is to promote their growth and survival. This pathway can integrate its action with signalling pathways of growth and morphogenetic factors that induce cell fate specification and selective expansion of specified neural cell subsets. This suggests that during developmental and adult neurogenesis cellular responses to many signalling factors, including ligands of Notch, sonic hedgehog, fibroblast growth factor family members, ligands of the epidermal growth factor receptor, bone morphogenetic proteins and Wingless and Int-1, may be modified by co-activation of the IGF1R. Modulation of cell migration is another possible role that IGF1R activation may play in neurogenesis. Here, I briefly overview neurogenesis and discuss a role for IGF1R-mediated signalling in the developing and mature nervous system with emphasis on crosstalk between the signalling pathways of the IGF1R and other factors regulating neural cell development and migration. Studies on neural as well as on non-neural cells are highlighted because it may be interesting to test in neurogenic paradigms some of the models based on the information obtained in studies on non-neural cell types.

The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Insulin is neuroprotective following transient global brain ischemia; however, the mechanisms by which insulin exerts its salutary effects remain unclear.

We assessed insulin's effect on the PI3K-Akt survival system and consequent modulation of the pro-apoptotic proteins Bim, Bad and FoxO3a.

We utilized rats subjected to 10 minutes of global brain ischemia, with or without insulin administered at the onset of reperfusion.

In sham-operated animals, minimal pAkt immunofluorescence was detected in the CA1. Moreover, at 30 minute reperfusion, there was no change in pAkt in CA1 neurons. Single bolus high-dose insulin treatment resulted in an early increase in pAkt after 30 minutes, preservation of CA1 neurons to 14 days of reperfusion and preservation of spatial learning ability. Insulin treatment increased cytoplasmic and nuclear staining for pAkt in both CA1 and cortex. Insulin-induced Akt phosphorylation was suppressed by the PI3K inhibitor wortmannin. Neither reperfusion nor insulin induced any change in the phosphorylation or subcellular localization of FoxO3a, Bim or Bad. A single bolus of high-dose insulin reduced CA1 neuronal cell death and thus represents a potential therapeutic intervention for global brain ischemia.

These results reveal that proximal elements of a known cell-survival pathway are triggered by high-dose insulin during early reperfusion. Insulin induces robust PI3K-dependent phosphorylation of Akt by 30 minute reperfusion and results in improvement of hippocampal structure and function. However, the Akt substrates FoxO3a, Bim and Bad do not undergo corresponding changes in phosphorylation or subcellular localization in this model of global brain ischemia. The downstream components of insulin-induced Akt survival signaling after transient global brain ischemia remain to be identified.

The highly efficient formation of phosphatidic acid from exogenous 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) in rat brain synaptic nerve endings (synaptosomes) from cerebral cortex and hippocampus is reported. Phosphatidic acid synthesized from SAG or 1,2-dipalmitoyl-sn-glycerol (DPG) was 17.5 or 2.5 times higher, respectively, than from endogenous synaptosomal diacylglycerides. Insulin increased diacylglycerol kinase (DAGK) action on endogenous substrate in synaptic terminals from hippocampus and cerebral cortex by 199 and 97%, respectively. Insulin preferentially increased SAG phosphorylation from hippocampal membranes. In CC synaptosomes insulin increased phosphatidic acid (PA) synthesis from SAG by 100% with respect to controls. Genistein (a tyrosine kinase inhibitor) inhibited this stimulatory insulin effect. Okadaic acid or cyclosporine, used as Ser/Threo protein phosphatase inhibitors, failed to increase insulin effect on PA formation. GTP gamma S and particularly NaF were potent stimulators of PA formation from polyunsaturated diacylglycerol but failed to increase this phosphorylation when added after 5 min of insulin exposure. GTP gamma S and NaF increased phosphatidylinositol 4,5 bisphosphate (PIP2) labeling with respect to controls when SAG was present. On the contrary, they decreased polyphosphoinositide labeling with respect to controls in the presence of DPG. Our results indicate that a DAGK type 3 (DAGKepsilon) which preferentially, but not selectively, utilizes 1-acyl-2-arachidonoyl-sn-glycerol and which could be associated with polyphosphoinositide resynthesis, participates in synaptic insulin signaling. GTP gamma S and NaF appear to be G protein activators related to insulin and the insulin receptor, both affecting the signaling mechanism that augments phosphatidic acid formation.

Postburn alterations in the morphology and metabolism of brain tissue have been previously reported. It was demonstrated in our previous study that thermal injury decreased glucose usage in rat brain during the ebb phase. The cellular and molecular signaling events that trigger the pathophysiologic alterations, however, have not yet been characterized. In the present report, the authors have examined the effect of burn injury on mitogen-activated protein kinases (MAPKs) activities and insulin signaling in the brain tissue. Rats were subjected to 50% total body surface area full thickness scald injury. Brain samples were collected at 6 hours after injury. Tissue lysates were analyzed for MAPKs activities, insulin receptor substrate (IRS)-1 expression, and Akt activity which were determined by western blot and immunoprecipitation. Burn injury stimulated the stress-responsive components, SAPK/JNK, p38 MAP kinase and p44/42 MAP kinase, and increased IRS-1 expression and Akt activity. There was no change, however, on the phosphorylation of Ser307 of IRS-1 in brain tissue. The present data is consistent with the hypothesis that activation of the three major MAPKs pathways appears to be events involved in the mechanisms of burn injury induced insulin resistance and encephalopathy. Changes in signal transduction pathways in the brain after burn injury provide the underlying molecular mechanism of neurologic abnormalities (burn encephalopathy) that occur in burn patients.

Adult neurogenesis in dentate gyrus (DG) is an evolutionarily preserved trait in most mammals examined thus far. Neuronal proliferation and subsequent integration of new neurons into the hippocampal circuit are regulated processes that can have profound effects on an animal's behaviour. A streptozotocin model of type I diabetes, characterized by low insulin and high plasma glucose levels, affects not only body's overall metabolism but also brain activity.

Neurogenesis was measured within the DG of the hippocampus using immunohistochemical markers Ki67, Doublecortin, Calbindin (CaBP) and bromodeoxyuridine (BrdU).

Cell proliferation, measured with the endogenous marker Ki67, was reduced by 45%, and cell survival, measured with BrdU, was reduced by 64% of the control. Combined effects on proliferation and survival produced dramatically lower neuronal production. Among the surviving cells only 33% matured normally as judged by the co-labelling of BrdU and CaBP.

Such a reduction lowered the number of surviving cells with neuronal phenotype by over 80% of the control values and this is expected to cause a significant functional impairment of learning and memory in diabetic animals. These results may shed light on causes of diabetic neuropathology and provide an explanation for the memory deficiencies seen in some diabetic patients.

We previously reported that insulin accumulated in the retina of diabetic rats after topical insulin eye drop treatment. In light of insulin's reported benefits to the retina, we hypothesized that the delivery of insulin to the retina by eye drop application might be efficacious in preventing diabetic retinopathy.

We applied daily, uni-ocular porcine insulin drops (0.75%) to diabetic rats for 14 months and then analyzed their retinas for vascular pathology.

Our data showed that high-dose insulin eye drop treatment increased the number of retinal acellular capillaries, with many of these capillaries exhibiting a degenerated, threadlike appearance. The retinas also showed extensive capillary obliteration and had tangled masses of vascular cells. The glycated hemoglobin levels of eye drop-treated rats were similar to those found in control, vehicle-treated diabetic animals at sacrifice. Retinal insulin levels remained elevated after a 2-week regimen of daily insulin eye drops, suggesting that our treatment protocol resulted in the pooling of insulin in the retina. A similar treatment regimen was also found to have no effect on retinal glucose concentration.

Our results showed that treatment of diabetic rats with daily, high-dose insulin eye drops intensified their retinal pathology.

The olfactory bulb (OB) contains the highest concentration of the insulin receptor (IR) kinase in the central nervous system; however, its functional role and modulation in this region remains poorly understood. IR kinase contains a number of proline-rich motifs, making it an excellent candidate for modulation by SH(3) domain-containing adaptor proteins. Kv1.3, a voltage-gated Shaker potassium channel and tyrosine phosphorylation substrate of IR kinase, contains several proline-rich sequences and a canonical post-synaptic density 95 (PSD-95)/discs large/zO-1 domain (PDZ) recognition motif common to most Shaker family members. We sought to determine if a functional relationship existed between Kv1.3, IR kinase, and the SH(3)/PDZ adaptor protein PSD-95. Through patch-clamp electrophysiology, immunochemistry, and co-immunoprecipitation, we found that while Kv1.3 and PSD-95 alone interact via the canonical C-terminal PDZ recognition motif of the channel, this molecular site of interaction acts to cluster the channels but the PSD-95 SH(3)-guanylate kinase domain functionally modulates Kv1.3 activity via two proline-rich domains in its N- and C-terminal. Therefore, these data suggest that adaptor domains responsible for ion-channel clustering and functional modulation are not necessarily coupled. Moreover, IR kinase and Kv1.3 can only be co-immunoprecipitated in the presence of PSD-95 as the adapting linker. Functionally, insulin-dependent Kv1.3 phosphorylation that causes channel current suppression is blocked via interaction with the PSD-95 SH(3)-guanylate kinase domain. Because all the three proteins co-localize in multiple lamina of the OB that are known to be rich in synaptic connections, membrane excitability and synaptic transmission at critical locations in the OB have the capacity to be finely regulated.

Diabetes targets the peripheral nervous system with several different patterns of damage and several mechanisms of disease. Diabetic polyneuropathy (DPN) is a common disorder involving a large proportion of diabetic patients, yet its pathophysiology is controversial. Mechanisms considered have included polyol flux, microangiopathy, oxidative stress, abnormal signaling from advanced glycation endproducts and growth factor deficiency. Although some clinical trials have demonstrated modest benefits in disease stabilization or pain therapy in DPN, robust therapy capable of reversing the disease is unavailable. In this review, general aspects of DPN and other diabetic neuropathies are examined, including a summary of recent therapeutic trials. A particular emphasis is placed on the evidence that the neurobiology of DPN reflects a unique yet common and disabling neurodegenerative disorder.