Central Nervous System Insulin Resistance Research Articles

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy.

Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling. We tested whether lowering brain GRK2 abundance may reverse insulin-resistance. We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA. Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance. These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Central nervous system insulin signaling can influence the rate of insulin influx into brain

BackgroundInsulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer’s disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD.MethodsWe investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice.ResultsWe found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus.ConclusionsThese results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.

Lifestyle impacts on insulin transport at the blood‐brain barrier in mice

AbstractBackgroundThe blood‐brain barrier (BBB) is a regulatory interface, controlling the blood‐to‐brain transport of many substances, resulting in nutrient delivery to the central nervous system (CNS) and communication between the periphery and CNS. There are structural and functional changes within the BBB in Alzheimer’s disease, which may contribute to the detrimental effects occurring within the CNS. CNS insulin resistance is one of many detrimental features of Alzheimer’s disease. As the BBB is responsible for the delivery of insulin to the CNS, alterations in insulin BBB transport could be a cause of CNS insulin resistance. Indeed, various lifestyle factors are known to impact insulin BBB pharmacokinetics, including diet and exercise, which have also been shown to impact Alzheimer’s disease progression.MethodsUtilizing sensitive radiotracer methods of substrate transport at the BBB in young male and female mice, we investigated the impact of exposure to a voluntary running wheel and what role CNS insulin resistance has on insulin BBB pharmacokinetics.ResultsAcute exercise increased insulin BBB transport and CNS insulin resistance decreased insulin brain uptake.ConclusionCNS insulin resistance decreases insulin BBB transport in mice, particularly in females. We found a lifestyle intervention, such as exercise, is able to enhance insulin BBB transport, which may be able to attenuate CNS insulin resistance. Future work is necessary to determine if exercise can reverse the insulin BBB transport deficiencies observed due to CNS insulin resistance.

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites.

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.

Insulin blood-brain barrier transport and interactions are greater following exercise in mice.

Exercise has multiple beneficial effects including improving peripheral insulin sensitivity, improving central function such as memory, and restoring a dysregulated blood-brain barrier (BBB). Central nervous system (CNS) insulin resistance is a common feature of cognitive impairment, including Alzheimer's disease. Delivery of insulin to the brain can improve memory. Endogenous insulin must cross the BBB to directly act within the CNS and this transport system can be affected by various physiological states and serum factors. Therefore, the current study sought to investigate whether exercise could enhance insulin BBB transport as a mechanism for the underlying benefits of exercise on cognition. We investigated radioactive insulin BBB pharmacokinetics following an acute bout of exercise in young, male and female CD-1 mice. In addition, we investigated changes in serum levels of substrates that are known to affect insulin BBB transport. Finally, we measured the basal level of a downstream protein involved in insulin receptor signaling in various brain regions as well as muscle. We found insulin BBB transport in males was greater following exercise, and in males and females to both enhance the level of insulin vascular binding and alter CNS insulin receptor signaling, independent of changes in serum factors known to alter insulin BBB transport.NEW & NOTEWORTHY Central nervous system (CNS) insulin and exercise are beneficial for cognition. CNS insulin resistance is present in Alzheimer's disease. CNS insulin levels are regulated by transport across the blood-brain barrier (BBB). We show that exercise can enhance insulin BBB transport and binding of insulin to the brain's vasculature in mice. There were no changes in serum factors known to alter insulin BBB pharmacokinetics. We conclude exercise could impact cognition through regulation of insulin BBB transport.

Regulation of insulin transport across the blood‐brain barrier by CNS insulin receptor signaling

AbstractBackgroundImpairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer’s disease (AD), age‐related cognitive decline, and mild cognitive impairment (MCI). Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood‐brain barrier (BBB). CNS insulin is derived from the blood and crosses the BBB by a saturable transport system. Therefore, the insulin resistance observed in the CNS and at the neurovascular unit in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Much focus has been placed on the peripheral mediators of insulin transport, with the direct role of the CNS often ignored. Therefore, the goal of this study was to investigate the communication of the neurovascular unit (NVU) in mediating CNS insulin levels in AD.MethodWe utilized the multiple‐time regression analysis technique to measure 125I‐insulin pharmacokinetics at the BBB. We were able to define the transport rate for 125I‐insulin and amount of vascular binding due to changes in CNS insulin receptor signaling. First, we inhibited CNS insulin receptor signaling by administering 1 μg S961 by intracerebroventricular (icv) injection. Second, we evaluated 125I‐insulin transport in mice lacking the insulin receptor in astrocytes.ResultAcute, broad inhibition of the CNS insulin receptor following icv delivery of S961, a selective antagonist, led to decreased 125I‐insulin transport across the BBB that was sex specific in CD‐1 mice. Follow‐up studies revealed the astrocytic insulin receptor may be responsible for this decreased transport as mice lacking the insulin receptor in astrocytes, GFAP insulin receptor knock‐out (GIRKO) mice, also have decreased 125I‐insulin BBB transport.ConclusionThese studies suggest the insulin receptor present on specific cell types within the CNS have a regulatory role in mediating insulin uptake by the brain.

Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance.

The blood-brain barrier (BBB) mediates the communication between the periphery and the central nervous system (CNS). Recently, CNS insulin resistance has been elucidated to play a role in neurodegenerative disease. This has stimulated a wealth of information on the molecular impact of insulin in the brain, particularly in the improvement of cognition. Since the BBB regulates the transport of insulin into the brain and thus, helps to regulate CNS levels, alterations in the BBB response to insulin could impact CNS insulin resistance. In this review, we summarize the effect of insulin on some of the cell types that make up the BBB, including endothelial cells, neurons, astrocytes, and pericytes. We broadly discuss how these changes in specific cell types could ultimately impact the BBB. We also summarize how insulin can regulate levels of the pathological hallmarks of Alzheimer’s disease, including amyloid beta (Aβ) and tau within each cell type. Finally, we suggest interventional approaches to overcome detrimental effects on the BBB in regards to changes in insulin transport.

Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review.

Research in animals and humans has shown that type 2 diabetes and its prodromal state, insulin resistance, promote major pathological hallmarks of Alzheimer's disease (AD), such as the formation of amyloid plaques and neurofibrillary tangles (NFT). Worrisomely, dysregulated amyloid beta (Aβ) metabolism has also been shown to promote central nervous system insulin resistance; although the role of tau metabolism remains controversial. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted insulin signaling. They also provide strong support for the hypothesis that pharmacologically restoring brain insulin signaling could represent a promising strategy to curb the development and progression of AD. In this context, great hopes have been attached to the use of intranasal insulin. This drug delivery method increases cerebrospinal fluid concentrations of insulin in the absence of peripheral side effects, such as hypoglycemia. With this in mind, the present review will also summarize current knowledge on the efficacy of intranasal insulin to mitigate major pathological symptoms of AD, i.e., cognitive impairment and deregulation of Aβ and tau metabolism.

Ageing: Improvement in age-related cognitive functions and life expectancy by ketogenic diets.

Rodent studies have indicated that low-carbohydrate diets prevent age-related cognitive decline and extend lifespan due to increased circulating levels of ketone bodies. A possible physiological mechanism for how ketone bodies exert this effect might be by improving central nervous system insulin resistance, which makes this finding interesting with regards to the prevention of cognitive decline and dementia in patients with type 2 diabetes mellitus.

The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins.

A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes.

Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study.

Epidemiological studies have identified a robust association between type II diabetes mellitus and Alzheimer disease (AD), and neurobiological studies have suggested the presence of central nervous system insulin resistance in individuals with AD. Given this association, we hypothesized that the central nervous system-penetrant insulin-sensitizing medication metformin would be beneficial as a disease-modifying and/or symptomatic therapy for AD, and conducted a placebo-controlled crossover study of its effects on cerebrospinal fluid (CSF), neuroimaging, and cognitive biomarkers. Twenty nondiabetic subjects with mild cognitive impairment or mild dementia due to AD were randomized to receive metformin then placebo for 8 weeks each or vice versa. CSF and neuroimaging (Arterial Spin Label MRI) data were collected for biomarker analyses, and cognitive testing was performed. Metformin was found to be safe, well-tolerated, and measureable in CSF at an average steady-state concentration of 95.6 ng/mL. Metformin was associated with improved executive functioning, and trends suggested improvement in learning/memory and attention. No significant changes in cerebral blood flow were observed, though post hoc completer analyses suggested an increase in orbitofrontal cerebral blood flow with metformin exposure. Further study of these findings is warranted.

Antidiabetic Drugs in Alzheimer’s Disease: Mechanisms of Action and Future Perspectives

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.

Alcohol, insulin resistance and the liver–brain axis

Chronic alcohol exposure inhibits insulin and insulin-like growth factor signaling in the liver and brain by impairing the signaling cascade at multiple levels. These alterations produced by alcohol cause severe hepatic and central nervous system insulin resistance as the cells fail to adequately transmit signals downstream through Erk/mitogen-activated protein kinase (MAPK), which is needed for DNA synthesis and liver regeneration, and phosphatidylinositol 3-kinase (PI3K), which promotes growth, survival, cell motility, glucose utilization, plasticity, and energy metabolism. The robust inhibition of insulin signaling in liver and brain is augmented by additional factors involving the activation of phosphatases such as phosphatase and tensin homologue (PTEN), which further impairs insulin signaling through PI3K/Akt. Thus, intact insulin signaling is important for neuronal survival. Chronic alcohol consumption produces steatohepatitis, which also promotes hepatic insulin resistance, oxidative stress and injury, with the attendant increased generation of "toxic lipids" such as ceramides that increase insulin resistance. The PI3K/Akt signaling cascade is altered by direct interaction with ceramides as well as through PTEN upregulation as a downstream target gene of enhanced p53 transcriptional activity. Cytotoxic ceramides transferred from the liver to the blood can enter the brain due to their lipid-soluble nature, and thereby exert neurodegenerative effects via a liver-brain axis. We postulate that the neurotoxic and neurodegenerative effects of liver-derived ceramides activate pro-inflammatory cytokines and increase lipid adducts and insulin resistance in the brain to impair cognitive and motor function. These observations are discussed in the context of insulin sensitizers as potential cytoprotective agents against liver and brain injury induced by alcohol.

Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions

Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood–brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood–brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.

Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism

In recent years, the central nervous system (CNS) has emerged as a principal site of insulin action. This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and by experiments in humans that make use of the intranasal pathway of insulin administration to the brain. Employing neurobehavioural and metabolic measurements as well as functional imaging techniques, these studies have provided insight into a broad range of central and peripheral effects of brain insulin. The present review focuses on CNS effects of insulin administered via the intranasal route on cognition, in particular memory function, and whole-body energy homeostasis including glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer's disease where CNS insulin resistance might contribute to cognitive dysfunction.

Overview of Newer Agents: Where Treatment Is Going

Impaired insulin secretion (β-cell), increased hepatic glucose production (liver), and decreased peripheral (muscle) glucose utilization constitute the traditional primary defects responsible for the development and progression of type 2 diabetes mellitus. β-Cell failure, ultimately leading to decreased insulin secretion, is now known to occur much earlier in the natural history of type 2 diabetes than originally believed. Additionally, a better understanding of the pathophysiology of type 2 diabetes reveals other etiologic mechanisms beyond the classic triad, now referred to as the ominous octet. In addition to the β-cell, liver, and muscle, other pathogenic mechanisms include adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity (gastrointestinal), increased glucagon secretion (α-cell), enhanced glucose reabsorption (kidney), and central nervous system insulin resistance resulting from neurotransmitter dysfunction (brain). Currently, the management of type 2 diabetes focuses on glucose control via lowering of blood glucose (fasting and postprandial) and hemoglobin A 1c. However, the goal of therapy should be to delay disease progression and eventual treatment failure. Treatment should target the known pathogenic disturbances of the disease (i.e., reducing the deterioration of β-cell function and improving insulin sensitivity). In recent years, treatment strategies have focused on the development of novel therapeutic options that affect many of the defects contributing to type 2 diabetes and that provide durable glucose control through a blunting of disease progression. Optimal management of type 2 diabetes should include early initiation of therapy using multiple drugs, with different mechanisms of action, in combination.

Acetylcholinesterase inhibition and insulin resistance in late onset Alzheimer's disease

Insulin resistance (IR) may play a role in most pathogenic processes that promote the development of late onset Alzheimer's disease (LOAD). This study was designed to evaluate whether galantamine influenced peripheral IR in LOAD. Ninety-five consecutive elderly patients, 40 LOAD and 55 non-demented patients were evaluated. IR was calculated with HOMA and modified-HOMA. All the patients were evaluated through comprehensive geriatric assessments at baseline and at 6, 12 and 18 months. Over three 6-month periods of galantamine treatment, compared to the baseline values, there was a significant increase at 6 and 12 months in the MMSE and at 6 months in the IADL scores (t = 3.25, p = 0.002 and t = 2.69, p = 0.011 for MMSE; t = 2.03, p = 0.049; for IADL, respectively). Although, there was an improvement in MMSE and IADL scores of galantamine-treated patients, there was no significant change in IR indexes and correlation between IR indexes and cognitive status in both groups during the treatment period. This study showed no relation between cognitive improvement and IR by galantamine therapy in AD. In conclusion, peripheral IR and central nervous system IR may be different, and galantamine itself may show its effects without affecting the insulin-signaling pathway.

Associations between postprandial insulin and blood glucose responses, appetite sensations and energy intake in normal weight and overweight individuals: a meta-analysis of test meal studies

It is unclear whether postprandial blood glucose or insulin exerts a regulatory function in short-term appetite regulation in humans. The aim of this study was to investigate, by use of meta-analysis, the role of blood glucose and insulin in short-term appetite sensation and energy intake (EI) in normal weight and overweight participants. Data from seven test meal studies were used, including 136 healthy participants (ALL) (92 normal weight (NW) and 44 overweight or obese (OW)). All meals were served as breakfasts after an overnight fast, and appetite sensations and blood samples were obtained frequently in the postprandial period. Finally, an ad libitum lunch was served. Data were analysed by fixed effects study level (SL) meta-regression analysis and individual participant data (IPD) regression analysis, using STATA software. In SL analysis, postprandial insulin response was associated with decreased hunger in ALL, NW and OW (P < 0.019), and with increased satiety in NW (P = 0.004) and lower subsequent EI in OW (P = 0.022). Multivariate IPD analysis showed similar associations, but only in NW for hunger, satiety and EI (P < 0.028), and in ALL for EI (P = 0.016). The only association involving blood glucose was the multivariate IPD analysis showing an inverse association between blood glucose and EI in ALL (P = 0.032). Our results suggest that insulin, but not glucose, is associated with short-term appetite regulation in healthy participants, but the relationship is disrupted in the overweight and obese. We conclude that the postprandial insulin response may be an important satiety signal, and that central nervous system insulin resistance in overweight might explain the blunted effect on appetite.

Fast Food, Central Nervous System Insulin Resistance, and Obesity

Rates of obesity and insulin resistance have climbed sharply over the past 30 years. These epidemics are temporally related to a dramatic rise in consumption of fast food; until recently, it was not known whether the fast food was driving the obesity, or vice versa. We review the unique properties of fast food that make it the ideal obesigenic foodstuff, and elucidate the mechanisms by which fast food intake contributes to obesity, emphasizing its effects on energy metabolism and on the central regulation of appetite. After examining the epidemiology of fast food consumption, obesity, and insulin resistance, we review insulin's role in the central nervous system's (CNS) regulation of energy balance, and demonstrate the role of CNS insulin resistance as a cause of leptin resistance and in the promotion of the pleasurable or "hedonic" responses to food. Finally, we analyze the characteristics of fast food, including high-energy density, high fat, high fructose, low fiber, and low dairy intake, which favor the development of CNS insulin resistance and obesity.