Brain Insulin Research Articles

Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus.

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.

Effects of Chronic Secondhand Smoke (SHS) Exposure on Cognitive Performance and Metabolic Pathways in the Hippocampus of Wild-Type and Human Tau Mice.

Background:Exposure to secondhand smoke (SHS) is a risk factor for developing sporadic forms of sporadic dementia. A human tau (htau) mouse model is available that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at an early age (3–4 months) and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline.Objective:The goal of this study was to assess the effects of chronic SHS exposure (10 months’ exposure to ) on behavioral and cognitive function, metabolism, and neuropathology in mice.Methods:Wild-type (WT) and htau female and male mice were exposed to SHS (90% side stream, 10% main stream) using the SCIREQ® inExpose™ system or air control for 168 min per day, for 312 d, 7 d per week. The exposures continued during the days of behavioral and cognitive testing. In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in gene expression.Results:Mice exposed to chronic SHS exposure showed the following genotype-dependent responses: a) lower body weights in WT, but not htau, mice; b) less spontaneous alternation in WT, but not htau, mice in the Y maze; c) faster swim speeds of WT, but not htau, mice in the water maze; d) lower activity levels of WT and htau mice in the open field; e) lower expression of brain PHF1, TTCM1, , and HSP90 protein levels in WT male, but not female, mice; and f) more profound effects on hippocampal metabolic pathways in WT male than female mice and more profound effects in WT than htau mice.Discussion:The brain of WT mice, in particular WT male mice, might be especially susceptible to the effects of chronic SHS exposure. In WT males, independent pathways involving ascorbate, flavin adenine dinucleotide, or palmitoleic acid might contribute to the hippocampal injury following chronic SHS exposure. https://doi.org/10.1289/EHP8428

Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus.

Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.

Combination of human tau and islet amyloid polypeptide exacerbates metabolic dysfunction in transgenic mice.

Amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau are important contributors to Alzheimer's disease (AD). Tau also impacts pancreatic beta cell function and glucose homeostasis. Amyloid deposits composed of islet amyloid polypeptide (IAPP) are a pathological feature of type 2 diabetes (T2D). The current study investigates the role of human tau (hTau) in combination with human IAPP (hIAPP) as a potential mechanism connecting AD and T2D. Transgenic mice expressing hTau and hIAPP in the absence of murine tau were generated to determine the impact of these pathological factors on glucose metabolism. Co-expression of hIAPP and hTau resulted in mice with increased hyperglycaemia, insulin resistance, and glucose intolerance. The hTau-hIAPP mice also exhibited reduced beta cell area, increased amyloid deposition, impaired insulin processing, and reduced insulin content in islets. Tau phosphorylation also increased after stimulation with high glucose. In addition, brain insulin content and signalling were reduced, and tau phosphorylation was increased in these animals. These data support a link between tau and IAPP amyloid, which seems to act co-ordinately to impair beta cell function and glucose homeostasis, and suggest that the combined pathological actions of these proteins may be a potential mechanism connecting AD and T2D. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cross-sectional investigation of insulin resistance in youths with autism spectrum disorder. Any role for reduced brain glucose metabolism?

The autism spectrum disorder (ASD) is an etiologically heterogeneous disorder. Dysfunctions of the intermediate metabolism have been described in some patients. We speculate these metabolic abnormalities are associated with brain insulin resistance (IR), i.e., the reduced glucose metabolism at the level of the nervous central system. The Homeostasis model assessment of insulin resistance (HOMA-IR) is very often used in population studies as estimate of peripheral IR and it has been recently recognized as proxy of brain IR. We investigated HOMA-IR in 60 ASD patients aged 4–18 years and 240 healthy controls, also aged 4–18 years, but unmatched for age, sex, body weight, or body mass index (BMI). At multivariable linear regression model, the HOMA-IR was 0.31 unit higher in ASD individuals than in controls, after having adjusted for sex, age, BMI z-score category, and lipids that are factors known to influence HOMA-IR. Findings of this preliminary study suggest it is worth investigating brain glucose metabolism in larger population of patients with ASD by using gold standard technique. The recognition of a reduced glucose metabolism in some areas of the brain as marker of autism might have tremendous impact on our understanding of the pathogenic mechanisms of the disease and in terms of public health.

Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits.

It is well accepted that PI3k/Akt signaling pathway is a potential therapeutic window which regulates metabolism and energy homeostasis within the brain, and is an important mediator of normal neuronal physiological functions. Dysregulation of this pathway results in impaired insulin signaling, learning and memory and neuronal survival. Elucidating the role of everolimus in intracerebroventricular (ICV) streptozotocin induced Insulin/IGF-1 dependent PI3K/Akt/mTOR pathway dysregulation and associated neurobehavioral deficits. Rats were administered with streptozotocin (3mg/kg) intracerebroventricular, followed by administration of everolimus (1mg/kg) orally for 21days. After that, Morris water maze and passive avoidance tests were performed for assessment of memory. Animals were sacrificed to evaluate brain insulin pathway dysfunction, neurotrophic, apoptotic, inflammatory, and biochemical markers in rat brain. To elucidate the mechanism of action of everolimus, PI3K inhibitor, wortmannin was administered in the presence of everolimus in one group. Streptozotocin administration resulted in a significant decrease of brain insulin, insulin growth factor-1 levels, and alterations in behavioral, neurotrophic (BDNF), inflammatory (TNF-α), apoptotic (NF-κB, Bcl2 and Bax) and biochemical (AChE and ChAT assay) parameters in comparison to sham group rats. Everolimus significantly mitigated the deleterious behavioral, biochemical, and molecular changes in rats having central insulin dysfunction. However, the protective effect of everolimus was completely abolished when it was administered in the presence of wortmannin. Findings from the study reveal that mTOR inhibitors can be an important treatment strategy for neurobehavioral deficits occurring due to central insulin pathway dysfunction. Protective effect of drugs is via modulation of PI3K/Akt pathway.

Neuroprotective Efficacy of Co-Encapsulated Rosiglitazone and Vorinostat Nanoparticle on Streptozotocin Induced Mice Model of Alzheimer Disease.

Anomalies in brain insulin signaling have been demonstrated to be involved in the pathology of Alzheimer disease (AD). In this context, the neuroprotective efficacy of an insulin sensitizer, rosiglitazone, has been confirmed in our previous study. In the present study, we hypothesize that a combination of an epigenetic modulator, vorinostat, along with rosiglitazone can impart improved gene expression of neurotrophic factors and attenuate biochemical and cellular alteration associated with AD mainly by loading these drugs in a surface modified nanocarrier system for enhanced bioavailability and enhanced therapeutic efficacy. Hence, in this study, rosiglitazone and vorinostat were loaded onto a poloxamer stabilized polymeric nanocarrier system and administered to mice in the intracerebroventricular streptozotocin (3 mg/kg) induced model of AD. Treatment with the free drug combination (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) for 3 weeks attenuated the behavioral, biochemical, and cellular alterations as compared to either treatment alone (rosiglitazone 10 mg/kg, vorinostat 50 mg/kg). Further, the coencapsulated nanoformulation (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) exerted better neuroprotective efficacy than the free drug combination as evidenced by improved behavioral outcome, reduced oxidative stress, and elevated levels of neurotrophic factors. In conclusion, the synergistic neuroprotective efficacy of rosiglitazone and vorinostat has been increased through the poloxamer stabilized polymeric nanocarrier system.

Brain insulin signaling and cerebrovascular disease in human postmortem brain

Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS616IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.

Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.

Alcohol consumption and cognitive aging: can it be beneficial?

We present a literature review which summarizes the data supporting one of the alternative perspectives on the effect of alcohol consumption on cognitive aging – the possible positive effect of low to moderate drinking. Some of the main theories about aging, the mechanisms of brain aging, and the pathogenesis of cognitive decline and dementia are briefly described. In this context, the putative mechanisms of the protective action of non-alcoholic components in alcoholic beverages or low doses of ethanol against oxidative stress, inflammation, mitochondrial dysfunction, brain insulin resistance, and production of amyloid-β peptides are presented. The review article does not favor the data selected and highlighted, but it aims at inspiring more interest and further research on the topic.

A New Approach to Model Sporadic Alzheimer's Disease by Intracerebroventricular Streptozotocin Injection in APP/PS1 Mice.

Alzheimer's disease (AD) is the most common cause of dementia among elderly people. Majority of AD cases are sporadic (SAD) with unknown cause. Transgenic animal models closely reflect the familial (genetic) aspect of the disease but not the sporadic type. However, most new drug candidates which are tested positive in transgenic animal models failed in clinical studies so far. Herein, we aim to develop an AD animal model that combines most of the neuropathological features seen in sporadic AD in humans with amyloid plaques observed in transgenic mice. Four-month-old wild-type and APP/PS1 AD mice were given a single intracerebroventricular (ICV) injection of 3 mg/kg streptozotocin (STZ), a diabetogenic agent. Three weeks later, their cognitive behavior was assessed, and their brain tissues were collected for biochemical and histological analysis. STZ produced cognitive deficits in both non-transgenic mice and AD mice. Biochemical analysis showed a severe decline in synaptic proteins, increase in tau phosphorylation, oxidative stress, disturbed brain insulin signaling with extensive neuroinflammation, and cell death. Significant increase was also observed in the level of the soluble beta amyloid precursor protein (APP) fragments and robust accumulation of amyloid plaques in AD mice compared to the control. These results suggest that STZ ICV treatment causes disturbance in multiple metabolic and cell signaling pathways in the brain that facilitated amyloid plaque accumulation and tau phosphorylation. Therefore, this animal model can be used to evaluate new AD therapeutic agents for clinical translation.

The Importance of the Mechanisms by Which Insulin Regulates Meal-Associated Liver Glucose Uptake in the Dog.

Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein-to-arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels fivefold in healthy dogs. In one group (n = 7), the physiologic response was allowed to fully occur, while in another (n = 7), insulin's indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothalamic insulin signaling for 4 h. In contrast to the indirect hepatic effects of insulin, which were previously shown capable of independently generating a half-maximal stimulation of HGU, direct hepatic insulin action was by itself able to fully stimulate HGU. This suggests that under hyperinsulinemic/hyperglycemic conditions insulin's indirect effects are redundant to direct engagement of hepatocyte insulin receptors.

Role of insulin receptor substance-1 modulating PI3K/Akt insulin signaling pathway in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, also regarded as "type 3 diabetes" for the last few years because of the brain insulin resistance (IR) and dysregulation of insulin signaling in the brain, which can further promote pathological progression of AD. IRS-1/PI3K/Akt insulin signaling pathway disorder and its downstream cascade reaction are responsible for cognitive decline in the brain. In recent years, a growing number of studies has documented that dysregulation of insulin signaling is a key feature of AD and has crucial correlations with serine/tyrosine (Ser/Tyr) phosphorylation of insulin receptor substance-1(IRS-1). Phosphorylation of this protein has been identified as an important molecule involved in the process of amyloid-β (Aβ) deposition into senile plaques (SPs) and tau hyperphosphorylation into neurofibrillary tangles (NFTs). In this paper, we review the links between IRS-1 and the PI3K/Akt insulin signaling pathway, and highlight phosphorylated IRS-1 which negatively regulated by downstream effector of Akt such as mTOR, S6K, and JNK, among others in AD. Furthermore, anti-diabetic drugs including metformin, thiazolidinediones, and glucagon-like peptide-1 (GLP-1) analogue could modulate IRS-1 phosphorylation, brain IR, PI3K/Akt insulin signaling pathway, and other pathologic processes of AD. The above suggest that anti-diabetic drugs may be promising strategies for AD disease-modifying treatments.

Brain insulin, insulin-like growth factor 1 and glucagon-like peptide 1 signalling in Alzheimer's disease.

Although the brain was once considered an insulin-independent organ, insulin signalling is now recognised as being central to neuronal health and to the function of synapses and brain circuits. Defective brain insulin signalling, as well as related signalling by insulin-like growth factor 1 (IGF-1), is associated with neurological disorders, including Alzheimer's disease, suggesting that cognitive impairment could be related to a state of brain insulin resistance. Here, I briefly review key epidemiological/clinical evidence of the association between diabetes, cognitive decline and AD, as well as findings of reduced components of insulin signalling in AD brains, which led to the initial suggestion that AD could be a type of brain diabetes. Particular attention is given to recent studies illuminating mechanisms leading to neuronal insulin resistance as a key driver of cognitive impairment in AD. Evidence of impaired IGF-1 signalling in AD is also examined. Finally, we discuss potentials and possible limitations of recent and on-going therapeutic approaches based on our increased understanding of the roles of brain signalling by insulin, IGF-1 and glucagon-like peptide 1 in AD.

Insulin on the brain: The role of central insulin signalling in energy and glucose homeostasis.

Insulin signals to the brain where it coordinates multiple physiological processes underlying energy and glucose homeostasis. This review explores where and how insulin interacts within the brain parenchyma, how brain insulin signalling functions to coordinate energy and glucose homeostasis and how this contributes to the pathogenesis of metabolic disease.

Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ1-42 -Induced AD-Like Mice and SH-SY5Y Cells.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome. AD mice model built through intracerebroventricular injection of Aβ1-42 and AD cell model developed through the SH-SY5Y cell line and Aβ1-42 are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in Aβ1-42 -injected mice and relieves apoptosis in Aβ1-42 -treated SH-SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorates Aβ accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses Aβ1-42 -induced cognitive impairment. Besides, Q3G restores Aβ1-42 -induced reduction of short-chain fatty acids (SCFAs) and gut microbiota dysbiosis. Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ1-42 -induced cognitive dysfunction.

Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome

Dysregulation of brain insulin signaling with reduced downstream neuronal survival and plasticity mechanisms are fundamental abnormalities observed in Alzheimer disease (AD). This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the inhibition of IRS1. Since Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration in DS and whether they contribute to early onset AD in DS.We evaluated levels and activation of proteins belonging to the insulin signaling pathway (IR, IRS1, BVR-A, MAPK, PTEN, Akt, GSK3β, PKCζ, AS160, GLUT4) in the frontal cortex of Ts65dn (DS model) (n = 5–6/group) and euploid mice (n = 6/group) at different ages (1, 3, 9 and 18 months). Furthermore, we analyzed whether changes of brain insulin signaling were associated with alterations of: (i) proteins regulating brain energy metabolism (mitochondrial complexes, hexokinase-II, Sirt1); (ii) oxidative stress (OS) markers (iii) APP cleavage; and (iv) proteins mediating synaptic plasticity mechanisms (PSD95, syntaxin-1 and BDNF).Ts65dn mice showed an overall impairment of the above-mentioned pathways, mainly characterized by defects of proteins activation state. Such alterations start early in life (at 1 month, during brain maturation). In particular, accumulation of inhibited IRS1, together with the uncoupling among the proteins downstream from IRS1 (brain insulin resistance), characterize Ts65dn mice. Furthermore, reduced levels of mitochondrial complexes and Sirt1, as well as increased indices of OS also were observed. These alterations precede the accumulation of APP-C99 in Ts65dn mice. Tellingly, oxidative stress levels were negatively associated with IR, IRS1 and AS160 activation as well as mitochondrial complexes levels in Ts65dn mice, suggesting a role for oxidative stress in the observed alterations.We propose that a close link exists among brain insulin resistance, mitochondrial defects and OS that contributes to brain dysfunctions observed in DS, likely favoring the development of AD in DS.

Intranasal insulin.

The intranasal (IN) route enables the delivery of insulin to the central nervous system in the relative absence of systemic uptake and related peripheral side effects. Intranasally administered insulin is assumed to travel along olfactory and adjacent pathways and has been shown to rapidly accumulate in cerebrospinal fluid, indicating efficient transport to the brain. Two decades of studies in healthy humans and patients have demonstrated that IN insulin exerts functional effects on metabolism, such as reductions in food intake and body weight and improvements of glucose homeostasis, as well as cognition, ie, enhancements of memory performance both in healthy individuals and patients with mild cognitive impairment or Alzheimer's disease; these studies moreover indicate a favourable safety profile of the acute and repeated use of IN insulin. Emerging findings suggest that IN insulin also modulates neuroendocrine activity, sleep-related mechanisms, sensory perception and mood. Some, but not all studies point to sex differences in the response to IN insulin that need to be further investigated along with the impact of age. "Brain insulin resistance" is an evolving concept that posits impairments in central nervous insulin signalling as a pathophysiological factor in metabolic and cognitive disorders such as obesity, type 2 diabetes and Alzheimer's disease, and, notably, a target of interventions that rely on IN insulin. Still, the negative outcomes of longer-term IN insulin trials in individuals with obesity or Alzheimer's disease highlight the need for conceptual as well as methodological advances to translate the promising results of proof-of-concept experiments and pilot clinical trials into the successful clinical application of IN insulin.

A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease.

Brain insulin system dysfunction has been proposed as a key player in the pathogenesis of sporadic Alzheimer's disease (sAD). Given this fact, an adult rat model for sAD has been developed by intracerebroventricular injection of a subdiabetogenic streptozotocin dosage (icv-STZ). A low dose of icv-STZ in adult rats leads to a subclinical model of Alzheimer's disease. According to the brain developmental origin for sAD occurrence, the present study evaluated the effect of neonatal injection of icv-STZ on the development and progression of Alzheimer's disease later in the adult animals treated with a low dose of icv-STZ. Although no alteration was observed in the rats receiving an adult low dose of icv-STZ, these animals displayed cognitive deficits if they were also treated neonatally with icv-STZ. These impairments were associated with altered gene expression of insulin receptor, tau and choline acetyltransferase, along with increased astrocyte and dark neuron densities in the hippocampus. This study highlights neonatal brain insulin system dysfunction in the programming of brain insulin signaling sensitivity and provides more evidence for the developmental origin of sAD.

γ-PGA-Rich Chungkookjang, Short-Term Fermented Soybeans: Prevents Memory Impairment by Modulating Brain Insulin Sensitivity, Neuro-Inflammation, and the Gut-Microbiome-Brain Axis.

Fermented soybean paste is an indigenous food for use in cooking in East and Southeast Asia. Korea developed and used its traditional fermented foods two thousand years ago. Chungkookjang has unique characteristics such as short-term fermentation (24–72 h) without salt, and fermentation mostly with Bacilli. Traditionally fermented chungkookjang (TFC) is whole cooked soybeans that are fermented predominantly by Bacillus species. However, Bacillus species are different in the environment according to the regions and seasons due to the specific bacteria. Bacillus species differently contribute to the bioactive components of chungkookjang, resulting in different functionalities. In this review, we evaluated the production process of poly-γ-glutamic acid (γ-PGA)-rich chungkookjang fermented with specific Bacillus species and their effects on memory function through the modulation of brain insulin resistance, neuroinflammation, and the gut–microbiome–brain axis. Bacillus species were isolated from the TFC made in Sunchang, Korea, and they included Bacillus (B.) subtilis, B. licheniformis, and B. amyloliquefaciens. Chungkookjang contains isoflavone aglycans, peptides, dietary fiber, γ-PGA, and Bacillus species. Chungkookjangs made with B. licheniformis and B. amyloliquefaciens have higher contents of γ-PGA, and they are more effective for improving glucose metabolism and memory function. Chungkookjang has better efficacy for reducing inflammation and oxidative stress than other fermented soy foods. Insulin sensitivity is improved, not only in systemic organs such as the liver and adipose tissues, but also in the brain. Chungkookjang intake prevents and alleviates memory impairment induced by Alzheimer’s disease and cerebral ischemia. This review suggests that the intake of chungkookjang (20–30 g/day) rich in γ-PGA acts as a synbiotic in humans and promotes memory function by suppressing brain insulin resistance and neuroinflammation and by modulating the gut–microbiome–brain axis.