Peripheral insulin and brain structure in early Alzheimer disease

Burns, Jeffrey M.; Donnelly, Joseph E.; Anderson, Heather S.; Mayo, Matthew S.; Spencer-Gardner, Luke; Thomas, George P.; Cronk, Benjamin; Haddad, Zeina; Klima, David A.; Hansen, Daniela; Brooks, William M.

doi:10.1212/01.wnl.0000276952.91704.af

Cited by 100 publications

(81 citation statements)

References 63 publications

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“…Retention of some large molecules, such as amyloid and Tau proteins, may contribute to the development of Alzheimer disease, which is characterized by intracellular neurofibrillary tangles and extracellular deposits in the form of senile plaques (43)(44)(45)(46). That may be why hyperinsulinemia and insulin resistance is inseparable from Alzheimer disease (12,13). Retention of large molecules may contribute to the hypertrophy of tissues/organs.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin resistance is either a precursor or a key component of numerous diseases including obesity, metabolic syndrome, T2DM, cardiovascular disorders (including strokes), Alzheimer disease, depression, asthma, chronic inflammatory diseases, cancers, and aging (11)(12)(13)(14)(15)(16)(17)(18)(19). Insulin resistance is primarily caused by the positive energy imbalance between the intake and expenditure of calories.…”

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confidence: 99%

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Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Liu

Han

Cao

et al. 2009

Journal of Biological Chemistry

344

260

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Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.Macroautophagy (autophagy) is a catabolic process whereby long lived large molecules and cellular organelles, such as mitochondria and endoplasmic reticulum (ER), 3 are degraded by lysosomes for an alternative energy source during starvation (1, 2). Autophagy is normally activated by glucagon or deprivation of amino acids during starvation (1) but inhibited by amino acids and/or insulin through the mTOR-or/and Akt-dependent pathways after food intake (3, 4). Thus, autophagy activity fluctuates with food intakes and fasts. Importantly, autophagy is also essential for maintaining cellular health by removing misfolded large molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (1, 5). In other words, decreased autophagy will inevitably slow the removal of misfolded large molecules and aged/dysfunctional cellular organelles. Accumulation of these molecules and dysfunctional cellular organelles may not only contribute to the development of cancers (1) but also contribute to the development of metabolic diseases, such as insulin resistance. For example, the accumulation of dysfunctional mitochondria will most likely cause increased mitochondrion-derived oxidative stress, which is known to contribute to the development of insulin resistance (6 -10).Insulin resistance is either a precursor or...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Liu

Han

Cao

et al. 2009

Journal of Biological Chemistry

344

260

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“…A low acute insulin response in an intravenous glucose tolerance test in midlife was associated with an increased risk of Alzheimer's disease during a 32-year follow-up [9]. Furthermore, decreased peripheral insulin levels were associated with Alzheimer's disease-related brain atrophy in a cross-sectional study [10], and such patients have also been found to have reduced insulin concentrations in the brain and the cerebrospinal fluid [11]. On the other hand, it has been suggested that features of the insulin resistance syndrome may imply an increase in the risk of vascular dementia, but the association with Alzheimer's disease is still controversial [12,13].…”

Section: Introductionmentioning

confidence: 90%

Glucose metabolism and the risk of Alzheimer’s disease and dementia: a population-based 12 year follow-up study in 71-year-old men

et al. 2009

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Aims/hypothesis Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. Methods The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. Results Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. Conclusions/interpretation In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.

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“…A trained psychometrician administered a psychometric battery including standard measures of memory, language, executive function, and visuospatial ability at baseline and at 24 months (tests described in detail elsewhere 12 ). Cognitive performance scores were converted to Z scores based on the mean and SD of a larger cohort of individuals without dementia.…”

Section: Demographics Subjects Without Dementia Aged 60 and Overmentioning

confidence: 99%

“…Cognitive performance scores were converted to Z scores based on the mean and SD of a larger cohort of individuals without dementia. 12 The mean of each participant's Z scores was determined to create an index of global cognitive performance, and the mean of each participant's Z scores on memory tests were used to create an index of global memory performance. Z scores from baseline and 24 months were used to calculate cognitive change scores for each individual.…”

Section: Demographics Subjects Without Dementia Aged 60 and Overmentioning

confidence: 99%

Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease

Honea

Swerdlow²,

Vidoni³

et al. 2011

Neurology

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Objective: Beyond age, having a family history is the most significant risk factor for Alzheimer disease (AD). This longitudinal brain imaging study examines whether there are differential patterns of regional gray matter atrophy in cognitively healthy elderly subjects with (FHϩ) and without (FHϪ) a family history of late-onset AD.Methods: As part of the KU Brain Aging Project, cognitively intact individuals with a maternal history (FHm, n ϭ 11), paternal history (FHp, n ϭ 10), or no parental history of AD (FHϪ, n ϭ 32) similar in age, gender, education, and Mini-Mental State Examination (MMSE) score received MRI at baseline and 2-year follow-up. A custom voxel-based morphometry processing stream was used to examine regional differences in atrophy between FH groups, controlling for age, gender, and APOE ⑀4 (APOE4) status. We also analyzed APOE4-related atrophy.Results: Cognitively normal FHϩ individuals had significantly increased whole-brain gray matter atrophy and CSF expansion compared to FHϪ. When FHϩ groups were split, only FHm was associated with longitudinal measures of brain change. Moreover, our voxel-based analysis revealed that FHm subjects had significantly greater atrophy in the precuneus and parahippocampus/ hippocampus regions compared to FHϪ and FHp subjects, independent of APOE4 status, gender, and age. Individuals with an 4 allele had more regional atrophy in the frontal cortex compared to 4 noncarriers. Conclusions:We conclude that FHm individuals without dementia have progressive gray matter volume reductions in select AD-vulnerable brain regions, specifically the precuneus and parahippocampal gyrus. These data complement and extend reports of regional cerebral metabolic differences and increases in amyloid-␤ burden in FHm subjects, which may be related to a higher risk for developing AD. Late-onset Alzheimer disease (AD) is a neurodegenerative disease caused by complex genetic and environmental mechanisms.1 Age is the most significant risk factor for developing AD, followed by a family history of AD, 2 with maternal transmission significantly more frequent than paternal transmission.3 First-degree relatives of individuals with AD are at a 4-to 10-fold higher risk for AD compared to individuals with no family history.2 Since it is unknown how familial transmission of AD biologically increases susceptibility for AD, clarifying mechanisms of familial risk for AD are a step toward developing enhanced treatment and prevention strategies.Various forms of neuroimaging have attempted to characterize genetic and familial risk factors for late-onset AD by studying heritable traits in healthy individuals with no cognitive impairment.1 There are several studies showing that individuals without dementia who are

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Peripheral insulin and brain structure in early Alzheimer disease

Abstract: Increased peripheral insulin is associated with reduced Alzheimer disease (AD)-related brain atrophy, cognitive dysfunction, and dementia severity, suggesting that insulin signaling may play a role in the pathophysiology of AD.

Cited by 100 publications

References 63 publications

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Glucose metabolism and the risk of Alzheimer’s disease and dementia: a population-based 12 year follow-up study in 71-year-old men

Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease

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