Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Burillo, Jesús; Marqués, Patricia; Jiménez, Beatriz; González-Blanco, Carlos; Benito, Manuel; Guillén, Carlos

doi:10.3390/cells10051236

Cited by 100 publications

(72 citation statements)

References 435 publications

(465 reference statements)

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“…Thus, under physiological conditions, insulin acts as a protective factor for brain function and contributes to the prevention of cognitive decline. On the other hand, a dysregulated brain insulin signaling, defined as “brain insulin resistance”, has been proposed among factors responsible for AD progression [ 19 ], and the impaired activity of several mediators in the insulin-signaling pathways may contribute to neurodegeneration and AD symptoms [ 51 , 52 ].…”

Section: Insulin-signaling Impairment and Neurodegenerationmentioning

confidence: 99%

Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

et al. 2021

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A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.

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Section: Insulin-signaling Impairment and Neurodegenerationmentioning

confidence: 99%

Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

et al. 2021

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“…Alzheimer's disease (AD) is the most prevalent form of dementia [1] and it is also one of the most significant causes of morbidity and mortality in the elderly population worldwide [3]. AD prevalence is estimated to reach Pharmaceuticals 2021, 14, 890 2 of 22 115 million by 2050 due to an increased ageing population pattern, unless novel drugs are available to slow or cure this disease [2][3][4]. Neuropathological modifications of AD, such as tau hyperphosphorylation and Aβ toxicity, led to the main current hypothesis trying to explain neuronal and synapse loss, associated with cognitive and memory impairment [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, it has been shown that both T2DM and LOAD possess multifactorial risk profiles and a wide variety of molecular connections. The intersection between the molecular pathways of these two diseases could give birth to the appearance of the cognitive anomalies of LOAD patients with underlying T2DM [ 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

et al. 2021

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Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models.

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“…Similarly, brain insulin resistance may be defined as the failure of brain cells to respond to insulin [ 82 ]. Lack of response to insulin may be due to various causes, including downregulation of insulin receptors, the inability of IR to bind insulin or an impairment of the insulin cascade [ 83 ].…”

Section: Insulin Resistance and Alzheimer’s Diseasementioning

confidence: 99%

“…In brains characterized by AD, Tau protein demonstrates three times as much hyperphosphorylation than in normal brains [ 83 ]. Indeed, out of 85 phosphorylable residues, more than 40 phosphorylation sites have been identified in Tau from the brains of AD patients, and 28 sites are exclusively phosphorylated [ 95 ].…”

Section: Insulin Resistance and Alzheimer’s Diseasementioning

confidence: 99%

Insulin and Insulin Resistance in Alzheimer’s Disease

Sędzikowska

Szablewski

2021

IJMS

132

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Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood–brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer’s disease.

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Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cited by 100 publications

References 435 publications

Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

Insulin and Insulin Resistance in Alzheimer’s Disease

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