Insulin, cognition, and dementia

doi:10.1016/j.ejphar.2013.08.008

European Journal of Pharmacology

Volume 719, Issues 1–3, 5 November 2013, Pages 170-179

https://doi.org/10.1016/j.ejphar.2013.08.008 Get rights and content

Abstract

Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly Alzheimer's disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer's disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer's disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain's insulin sensitivity.

Introduction

Insulin, long considered to be a hormone that primarily exerts its influence in the periphery, is now known to have potent effects in the brain. Insulin resistance refers to the reduced ability of insulin to exert its action on target tissues and is associated with neuropathological processes that underlie cognitive aging and dementia. Several risk factors implicated in cognitive decline, including diabetes, hyperlipidemia, hypertension, and obesity are closely linked to underlying insulin dysfunction. Given the rise in such chronic conditions, in combination with a rapidly aging population, the prevalence of Alzheimer's disease and other cognitive disorders is likely to continue to rise exponentially. Recent clinical trials have focused on identification of novel potential therapeutic mechanisms aimed at improving insulin sensitivity in the brain; with the expectation that these mechanisms may represent promising treatments for cognitive disorders of aging. This review will focus on the effects of insulin in the central nervous system, the relationship between insulin-associated conditions and dementia, and potential mechanisms for the pharmacological treatment of insulin resistance in brain.

Section snippets

The role of insulin in the brain

Insulin, a peptide secreted by pancreatic beta cells, is readily transported into the central nervous system across the blood brain barrier by a saturable, receptor-mediated process (Banks et al., 1997a, Baskin et al., 1987, Baura et al., 1993). Insulin receptors are abundant in the synapses of both astrocytes and neurons, and are selectively distributed in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, amygdala, and septum (Baskin et al., 1987, Havrankova et al., 1978a,

Insulin resistance and Alzheimer's disease pathology

While acute hyperinsulinemia may produce beneficial effects on cognition, persistently high levels of circulating insulin may conversely exert a negative influence on memory and other cognitive functions. Raising peripheral insulin levels acutely elevates brain and cerebrospinal fluid insulin levels, whereas prolonged peripheral hyperinsulinemia down-regulates insulin receptors at the blood–brain barrier and reduces insulin transport into the brain (Schwartz et al., 1990, Wallum et al., 1987).

Insulin resistance-related conditions and dementia

Above, we provide compelling evidence that insulin resistance alone is a viable candidate risk factor for Alzheimer's disease. Indeed, recent studies have associated insulin resistance with Alzheimer-consistent impairments on functional imaging scans. For example, insulin resistance (defined as having high levels of fasting plasma insulin) in middle-aged women was associated with reduced activity in the prefrontal cortex and hippocampal regions, which corresponded with reductions in performance

Intranasal insulin

One innovative therapeutic strategy currently under investigation is the normalization of brain insulin levels through intranasal insulin administration. As reviewed in the previous sections, insulin has pleiotropic effects on pathways implicated in Alzheimer's disease pathogenesis. As such, augmenting central nervous system insulin, in contrast to the majority of therapeutic approaches that focus on narrowly defined mechanisms such as acetylcholine modulation or amyloid accumulation, may have

Conclusions

With an aging population and concurrent rise in chronic health conditions comes a rapid escalation in the incidence of dementia. Although notable strides have been made with regard to discerning the pathophysiological processes associated with Alzheimer's disease and other dementias, pharmacological treatment trials to date have generally produced minimal or disappointing results. Fortunately, many of the processes that underlie the neuropathological features of dementia may be related to risk

References (143)

K.J. Anstey et al.
Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis
American Journal of Geriatric Psychiatry
(2008)
K.V. Axen et al.
High dietary fat promotes syndrome X in nonobese rats
Journal of Nutrition
(2003)
W.A. Banks et al.
Transport of insulin across the blood–brain barrier: saturability at euglycemic doses of insulin
Peptides
(1997)
W.A. Banks et al.
Selective, physiological transport of insulin across the blood–brain barrier: novel demonstration by species-specific radioimmunoassays
Peptides
(1997)
C. Benedict et al.
Intranasal insulin improves memory in humans
Psychoneuroendocrinology
(2004)
D.M. Bravata et al.
Two measures of insulin sensitivity provided similar information in a U.S. population
Journal of Clinical Epidemiology
(2004)
G.A. Bray et al.
The influence of different fats and fatty acids on obesity, insulin resistance and inflammation
Journal of Nutritional
(2002)
B.L. Burgess et al.
Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma
Neurobiology of Disease
(2006)
D. Cao et al.
Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease
Journal of Biological Chemistry
(2007)
D.G. Cook et al.
Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele
American Journal of Pathology
(2003)

S. Craft et al.

Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype

Psychoneuroendocrinology

(2003)

S. Craft et al.

Memory improvement following induced hyperinsulinemia in Alzheimer's disease

Neurobiology of Aging

(1996)

S. Craft et al.

Insulin and neurodegenerative disease: shared and specific mechanisms

Lancet Neurology

(2004)

S. Cuzzocrea et al.

Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation

European Journal of Pharmacology

(2004)

P. Escher et al.

Peroxisome proliferator-activated receptors: insight into multiple cellular functions

Mutation Research

(2000)

D.P. Figlewicz et al.

Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus

Brain Research

(1993)

K. Gerozissis et al.

Basal and hyperinsulinemia-induced immunoreactive hypothalamic insulin changes in lean and genetically obese Zucker rats revealed by microdialysis

Brain Research

(1993)

M. Hong et al.

Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons

Journal of Biological Chemistry

(1997)

C. Iadecola et al.

Hypertension and cerebrovascular dysfunction

Cell Metabolism

(2008)

L. Illum

Nasal drug delivery: new developments and strategies

Drug Discovery Today

(2002)

H. Kenna et al.

Fasting plasma insulin and the default mode network in women at risk for Alzheimer's disease

Neurobiology of Aging

(2013)

S.P. Kennelly et al.

Blood pressure and the risk for dementia: a double edged sword

Ageing Research Reviews

(2009)

S.R. Kopf et al.

Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism

Neurobiology of Learning and Memory

(1999)

I.V. Kurochkin et al.

Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme

FEBS Letters

(1994)

L.J. Launer et al.

Midlife blood pressure and dementia: the Honolulu-Asia aging study

Neurobiology of Aging

(2000)

C.C. Lee et al.

Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation

Neurobiology of Aging

(2009)

S.B.B. López et al.

Distinctive postprandial modulation of beta cell function and insulin sensitivity by dietary fats: monounsaturated compared with saturated fatty acids

American Journal of Clinical Nutrition

(2008)

J.A. Luchsinger

Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease: an epidemiological perspective

European Journal of Pharmacology

(2008)

J.A. Luchsinger et al.

Body mass index, dementia, and mortality in the elderly

Journal of Nutrition Health and Aging

(2008)

D. Luo et al.

Effect of pioglitazone on altered expression of Abeta metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance

European Journal of Pharmacology

(2011)

E. Mannucci et al.

Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials

International Journal of Cardiology

(2010)

J.H. Paik et al.

Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways

Journal of Biological Chemistry

(2000)

C.R. Park et al.

Intracerebroventricular insulin enhances memory in a passive-avoidance task

Physiology and Behavior

(2000)

E.J. Park et al.

15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia

Journal of Biological Chemistry

(2003)

A.R. Pathan et al.

Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats

Life Sciences

(2006)

H. Petrovitch et al.

Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging study

Neurobiology of Aging

(2000)

M.A. Abbott et al.

The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses

Journal of Neuroscience

(1999)

J. Apelt et al.

Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain

Journal of Neuroscience Research

(1999)

Z. Arvanitakis et al.

Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function

Archives of Neurology

(2004)

F. Authier et al.

Insulin-degrading enzyme

Clinical & Investigative Medicine

(1996)

Z. Bagi et al.

PPAR{gamma} activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes

American Journal of Physiology-Heart and Circulatory Physiology

(2004)

H. Baker et al.

Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat

Experimental Brain Research

(1986)

L.D. Baker et al.

Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes

Archives of Neurology

(2011)

B.J. Balin et al.

Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey

Journal of Comparative Neurology

(1986)

D.G. Baskin et al.

Insulin in the brain

Annual Review of Physiology

(1987)

G.D. Baura et al.

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain

Journal of Clinical Investigation

(1993)

M.S. Beeri et al.

Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology

Neurology

(2008)

C. Benedict et al.

Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin

The Journal of Clinical Endocrinology and Metabolism

(2008)

E.M. Bingham et al.

The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study

Diabetes

(2002)

J. Born et al.

Sniffing neuropeptides: a transnasal approach to the human brain

Nature Neuroscience

(2002)

Cited by (169)

Individual and dual trajectories of insomnia symptoms and body mass index before and after retirement and their associations with changes in subjective cognitive functioning
2024, Preventive Medicine
We examined individual and dual trajectories of insomnia symptoms and body mass index (BMI) before and after retirement, and their associations with changes in subjective cognitive functioning after retirement.
We used the Helsinki Health Study's (n = 2360, 79% women, aged 40–60 at baseline, Finland) repeated surveys to identify the developmental patterns of insomnia symptoms and BMI (2000–2017) and changes in subjective cognitive functioning (2017–2022). We analysed the data using latent group-based dual trajectory modelling and logistic regression analysis.
Three latent groups were identified for insomnia symptoms (stable low, decreasing and increasing symptoms) and BMI (stable healthy weight, stable overweight and stable obesity). Insomnia symptoms were associated with declining subjective cognitive functioning and largely explained the effects in the dual models. Conclusion:
The association between dual trajectories of insomnia symptoms and BMI with subjective cognitive decline is dominated by insomnia symptoms.
Diabetes-Alzheimer's connection in older age: SGLT2 inhibitors as promising modulators of disease pathways
2023, Ageing Research Reviews
Late-onset Alzheimer's disease (LOAD) is the most frequent cause of dementia in older persons. Subjects affected by type 2 diabetes mellitus (T2DM) are at higher risk of vascular disease, cognitive decline, and dementia. LOAD has many characteristics shared with impaired insulin signaling pathways, and substantial evidence has demonstrated a pivotal role in dysregulated glucose metabolism in its pathogenesis. Recent studies have shown that some anti-diabetic drugs, other than regulating the metabolism of peripheral tissues, can also modulate the brain's metabolism, reduce inflammation, and have a direct neuroprotective effect. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a newer class with many pleiotropic effects that may have strong neuroprotective potential. After a summary of the principal "anti-diabetic" drugs acting as suitable candidates in treating LOAD, this narrative review explored the potential role of SGLT2i on cognition from pre-clinical to clinical studies.
High fat diet allows food-predictive stimuli to energize action performance in the absence of hunger, without distorting insulin signaling on accumbal cholinergic interneurons
2023, Appetite
Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of the insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CINs does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.
Neurology
2023, Ketogenic: The Science of Therapeutic Carbohydrate Restriction in Human Health
The brain is a metabolically demanding organ and thus sensitive to nutrient availability. It is not ordinarily conceived to be predisposed to metabolic syndromes, though research postulates insulin resistance and chronic hyperglycaemia may be behind most neurological disorders, redefining them from a metabolic perspective. High-carbohydrate diets also have an important psychological impact. The brain has been evolutionarily programmed to treat carbohydrates as a reward, activating dopaminergic cascades due to their historical scarcity. This neurobiology has disadvantages in an age of carbohydrate abundance. While the brain is perceived as a glucose-dependent organ, ketone bodies are an alternative and possibly superior fuel, allowing patients with Alzheimer’s disease (AD), dementia, and mood disorders to improve their glucose hypometabolic states and associated symptoms. Ketogenic diets (KDs) are an accepted standard of treatment for refractory epilepsies and alleviate neuroinflammation in other neuropathologies. Research on the KD in the treatment of these disorders is in its infancy, yet has demonstrable restorative potential begging further investigation.
Does the regulation of skeletal muscle influence cognitive function? A scoping review of pre-clinical evidence
2023, Journal of Orthopaedic Translation
Cognitive impairment is a major challenge for elderlies, as it can progress in a rapid manner and effective treatments are limited. Sarcopenic elderlies have a higher risk of dementia. This scoping review aims to reveal whether muscle is a mediator of cognitive function from pre-clinical evidence.
PubMed, Embase, and Web of Science were searched to Feb 2nd, 2022, using the keywords (muscle) AND (cognition OR dementia OR Alzheimer) AND (mouse OR rat OR animal). The PRISMA guideline was used in this study.
A total of 17 pre-clinical studies were selected from 7638 studies. 4 studies reported that muscle atrophy and injury harmed memory, functional factors, and neurons in the brain for rodents with or without Alzheimer's disease (AD). 3 studies observed exercise induced muscle to secrete factors, including lactate, fibronectin type III domain-containing protein 5 (FNDC5), and cathepsin B, which plays essential roles in the elevation of cognitive functions and brain-derived neurotrophic factor (BDNF) levels. Muscle-targeted treatments including electrical stimulation and intramuscular injections had effective remote effects on the hippocampus. 6 studies showed that muscle-specific overexpression of scFv59 and Neprilysin, or myostatin knockdown alleviated AD symptoms. 1 study showed that muscle insulin resistance also led to deficient hippocampal neurogenesis in MKR mice.
The skeletal muscle is involved in the mediation of cognitive function. The evidence was established by the response in the brain (altered number of neurons, functional factors, and other AD pathological characteristics) with muscle atrophy or injury, muscle secretory factors, and muscle-targeted treatments.
This study summarizes the current evidence in how muscle affects cognition in molecular levels, which supports muscle-specific treatments as potential clinical strategies to prevent cognitive dysfunction.
Hyper-glycemia and insulinemia induce morphological changes and modulate secretion of S100B, S100A8, amyloid β 1–40 and amyloid β 1–42, in a model of human dopaminergic neurons
2022, Biomedicine and Pharmacotherapy
Glucose metabolism in neuronal tissue declines during neurodegenerative disorders in a progressive, region-specific, and disease-specific manner. Studies have shown that extracellular hyper-glycemia affects the functioning of adenosine triphosphate (ATP) sensitive potassium channels located in neurons and astrocytes. Also, hyper-insulinemia contributes to the formation and progression of Alzheimer’s disease (AD) via competition with amyloid β (Aβ) for insulin-degrading enzyme. Aβ disruption is phosphatidylinositol 3-kinase pathway dependent, and increased circulatory insulin concentrations lead to Aβ accumulation. In 2008, based on assessment of brain glucose utilization disorders and insulin signaling disruptions, it was proposed that AD could be called "type III diabetes". Proteins from the S100 family are actively secreted during metabolic and oxidative stress, but their role in neuronal cells has yet to be clarified. However, it has been demonstrated that they act in a dose-dependent manner, which may be crucial in the modulation of glucose and insulin metabolism in the brain. The goal of this paper was to elucidate the association between high glucose and insulin concentrations with extra- and intracellular S100B and S100A8 proteins levels as well as the correlation with toxic (Aβ₄₂) and physiologic (Aβ₄₀) forms of Aβ. Medium and high glucose concentrations mimicking pre-diabetic and diabetic state, caused statistically significant discharge of S100b and S100A8 protein to the extracellular compartment. Similar effect was observed after 50 nM insulin incubation. Furthermore, the correlation coefficient patterns between those proteins shows similar associations which highlights possible effective and modulating role of S100 family in the metabolic disturbances occurring in neuropathological disorders.

View all citing articles on Scopus

View full text

ReviewInsulin, cognition, and dementia

Abstract

Introduction

Section snippets

The role of insulin in the brain

Insulin resistance and Alzheimer's disease pathology

Insulin resistance-related conditions and dementia

Intranasal insulin

Conclusions

American Journal of Geriatric Psychiatry

Journal of Nutrition

Peptides

Peptides

Psychoneuroendocrinology

Journal of Clinical Epidemiology

Journal of Nutritional

Neurobiology of Disease

Journal of Biological Chemistry

American Journal of Pathology

Psychoneuroendocrinology

Neurobiology of Aging

Lancet Neurology

European Journal of Pharmacology

Mutation Research

Brain Research

Brain Research

Journal of Biological Chemistry

Cell Metabolism

Drug Discovery Today

Neurobiology of Aging

Ageing Research Reviews

Neurobiology of Learning and Memory

FEBS Letters

Neurobiology of Aging

Neurobiology of Aging

American Journal of Clinical Nutrition

European Journal of Pharmacology

Journal of Nutrition Health and Aging

European Journal of Pharmacology

International Journal of Cardiology

Journal of Biological Chemistry

Physiology and Behavior

Journal of Biological Chemistry

Life Sciences

Neurobiology of Aging

The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses

Journal of Neuroscience

Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain

Journal of Neuroscience Research

Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function

Archives of Neurology

Insulin-degrading enzyme

Clinical & Investigative Medicine

PPAR{gamma} activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes

American Journal of Physiology-Heart and Circulatory Physiology

Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat

Experimental Brain Research

Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes

Archives of Neurology

Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey

Journal of Comparative Neurology

Insulin in the brain

Annual Review of Physiology

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain

Journal of Clinical Investigation

Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology

Neurology

Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin

The Journal of Clinical Endocrinology and Metabolism

The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study

Diabetes

Sniffing neuropeptides: a transnasal approach to the human brain

Nature Neuroscience

Review
Insulin, cognition, and dementia