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INSULIN RESISTANCE AND METABOLIC FAILURE UNDERLIE ALZHEIMER DISEASE
SUZANNE M. DE LA MONTE1–4 AND MING TONG4
1Departments of Pathology (Neuropathology), 2Neurology, 3Neurosurgery, and
4Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
Abstract: Alzheimer disease (AD) is the most common cause of dementia in North America. Despite 30+ years of intensive research, gaps remain in our understanding of AD pathogenesis and approaches to treatment. However, the recent rapid shift to a paradigm that focuses on the roles of metabolic dysfunction and insulin and insulin-like growth factor (IGF) resistance as causal agents of cognitive impairment and neurodegeneration holds promise. The overarching hypothesis, that AD is a brain diabetes (type 3), accounts for the impairments in neuronal survival, myelin maintenance, energy metabolism, synaptic integrity, and plasticity, and the well-recognized neuropathological processes including, tau hyper-phosphorylation, amyloid-beta (APPβ-Aβ) accumulation, oxidative and endoplasmic reticulum stress, and cerebral microvascular disease. Herein, we discuss the roles of aging, lifestyle choices, peripheral insulin resistance diseases, including obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and metabolic syndrome, nitrosamine exposures, and familial/genetic factors as mediators of brain diabetes, cognitive impairment, and neurodegeneration. The data suggest that neurodegeneration can be initiated and propagated by the buildup of agents consequential to peripheral insulin resistance, i.e. toxic lipids (ceramides), and predicts that toxic ceramides generated in liver or visceral fat, cross the blood-brain barrier and cause brain insulin resistance, stress, and inflammation. This extrinsic mechanism of neurodegeneration accounts for the strikingly concurrent and overlapping increases in prevalence of all insulin resistance diseases. Yet, there is evidence that AD/type 3 diabetes occurs as the dominant or only manifestation of insulin resistance. The predicted intrinsic pathway of neurodegeneration is nearly identical to the extrinsic pathway, except its underlying basis is direct toxic/metabolic injury to the brain, or familial AD-associated mutations and gene variants that accelerate the trajectory to brain insulin resistance with aging. Finally, we propose that progressive cognitive impairment and neurodegeneration in AD are effectuated by a positive feedback mal-signaling cascade, whereby declining function of insulin/IGF networks dysregulate lipid metabolism and increase local levels of toxic ceramides. Toxic ceramides promote inflammation, endoplasmic reticulum and oxidative stress, and mitochondrial dysfunction, all of which exacerbate brain insulin/IGF resistance. Over time and with aging, adducts accumulate in DNA, RNA, protein, and lipids, causing continuous multi-modal molecular failure, leading to disruption of cytoskeletal function, AβPP-Aβ secretion, synaptic plasticity, cell survival mechanisms, and myelin maintenance. Once established, the reverberating loop must be targeted using multi-pronged approaches to disrupt spiraling progression of the AD neurodegeneration cascade.
1.1 INTRODUCTION
The mature brain requires intact insulin and insulin-like growth factor (IGF) signaling for homeostasis, neuronal plasticity, and myelin integrity. Resistance and deficiency of insulin and IGF disrupt energy balances and signaling networks that are needed to support a broad range of functions, including cell survival. In recent years, considerable evidence has accumulated showing that in Alzheimer disease (AD), cognitive impairment and neurodegeneration are associated with insulin and IGF resistance and impairments in signaling through pro-growth and pro-survival pathways. Furthermore, studies have linked the sharply increased incidence and prevalence rates of AD to other chronic insulin resistance disease states, including obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and metabolic syndrome. On the other hand, there is ample evidence that sporadic AD very frequently occurs in the absence of peripheral insulin resistance diseases. In addition, because familial forms of AD, although relatively uncommon, have nearly identical clinical and neuropathological features as sporadic AD, their disease mechanisms ultimately should be shared with those of sporadic AD. This review focuses on two major questions: (1) how do peripheral insulin resistance diseases contribute to the pathogenesis of cognitive impairment and neurodegeneration; and (2) do the same pathogenic factors mediate AD neurodegeneration, whether or not peripheral insulin resistance diseases or mutations in the amyloid precursor protein or presenilin genes exist?
These concepts share in common the theme of insulin resistance with dysregulated lipid metabolism. Consequences include increased local tissue and peripheral blood levels of cytotoxic ceramides. Cytotoxic ceramides promote inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and worsened insulin resistance. We propose that peripheral insulin resistance diseases promote or exacerbate cognitive impairment and neurodegeneration by causing brain insulin resistance. Mechanistically, toxic ceramides generated in liver or visceral fat leak into the peripheral circulation due to local cellular injury or death. The lipid-soluble nature of the toxic ceramides enables them to cross the blood-brain barrier, and either initiate or propagate a cascade of neurodegeneration mediated by brain insulin resistance, inflammation, stress, and cell death (extrinsic pathway).
Human and experimental data indicate that sporadic AD occurs in the absence of diabetes, obesity, fatty liver disease, or metabolic syndrome. Yet, AD brains exhibit significant deficits in insulin and IGF signaling, which worsen as the disease progresses. Clues pertaining to the pathogenesis of disease stem from epidemiological and experimental studies. Epidemiological studies strongly support exposure rather than genetic factors as agents of disease. Experimental models highlight the role of nitrosamine and related toxins as mediators of insulin resistance diseases, including in the brain. Mechanistically, we propose that the nitrosamines (toxins) present in processed and preserved foods, cause oxidative damage, disrupt lipid metabolism, and impair insulin signaling. Toxic lipids (ceramides) accumulated directly in the brain promote inflammation, stress, and insulin resistance, which together activate a positive feedback mal-signaling cascade that causes AD-type neurodegeneration (intrinsic pathway). Familial forms of AD are discussed in light of how their gene mutations (AβPP, PS1, and PS2) or variants (ApoE-ε4) prematurely disrupt brain insulin/IGF signaling networks, and thereby accelerate brain aging. These concepts help delineate the strategies needed to detect, monitor, treat, and prevent AD, as well as other major insulin resistance diseases.
1.2 MEDIATORS OF INSULIN SIGNALING
1.2.1 Insulin, the Master Hormone
Insulin is a 5800 Dalton, 51 amino acid polypeptide, composed of an A (21 residues) chain and B (30 residues) chain linked by disulfide bonds. In the early 1920s, Banting and Best discovered insulin in pancreatic secretions [1,2], and shortly thereafter demonstrated that it reversed hyperglycemia in humans [3]. It took nearly 30 years to devise methods that could stabilize insulin, prolong its actions, and delay its absorption, and it took 50 years to produce 99% pure insulin, free of pro-insulin and other islet polypeptides [4]. Prior to 1980, insulin used to treat humans was extracted from bovine or porcine pancreas, but early in 1980, commercial sources of human insulin became available.
Advancement of molecular and biochemical technology, including genetic engineering, led to large-scale production of human insulin. Currently, human insulin is produced using Saccharomyces cerevisiae (yeast) technology, and insulin is continuously harvested from the supernatant during fermentation. Insulin is further purified, crystalized, esterified, and hydrolyzed to ensure purity [5]. However, efforts are currently underway to produce insulin that can be administered orally rather than by injection [6].
1.2.2 Insulin-Stimulated Effects
The main targets of insulin include skeletal muscle, adipose tissue, and liver, although virtually every organ, tissue, and cell type is responsive to insulin stimulation. Insulin regulates glucose uptake and utilization by cells and regulates free fatty acid levels in peripheral blood. Free fatty acids are substrates for generating complex lipids. In skeletal muscle, insulin stimulates glucose uptake by inducing translocation of the glucose transporter protein, GLUT4, from the Golgi to the plasma membrane [7]. In liver, insulin stimulates lipogenesis and triglyceride storage, and inhibits gluconeogenesis. In adipose tissue, insulin decreases lipolysis and fatty acid efflux [8]. These pro-metabolic effects of insulin on glucose and free fatty acid disposal help to maintain energy balance.
1.2.3 Insulin-Like Growth Factors (IGFs)
Insulin is closely related to another polypeptide, insulin-like growth factor 1 (IGF-1). IGF-1 is also referred to as somatomedin C or mechano growth factor [9,10]. IGF-1 regulates growth, particularly during development, and it exerts anabolic effects on mature organs and tissues. IGF-1 is composed of 70 amino acids (7649 Daltons) in a single chain that contains three intra-molecular disulfide bridges [9,10]. IGF-1 is abundantly produced in liver, and its supply and actions are regulated by interactions with IGF binding proteins (IGFBPs) [11].
1.2.4 Insulin and IGF Signaling in the Brain
Historically, most of the research concerning insulin and IGF actions focused on cells and tissues other than those of the central nervous system (CNS). However, within the last 15 to 20 years, information has steadily emerged about expression and function of insulin and IGF polypeptides and receptors in the CNS. In the brain, insulin and IGF signaling regulates a broad array of neuronal and glial activities, including growth, survival, metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, neurotransmitter function, and plasticity [12,13]. In addition, insulin and IGF pathways have critical roles in maintaining cognitive function. Insulin, IGF-1, and IGF-2 polypeptide and receptor genes are expressed in neurons [12] and glial cells [14,15] throughout the brain, but their highest levels of expression are in structures that are typically targeted by neurodegenerative diseases [12, 16, 17]. The fact that genes encoding insulin, IGFs, and insulin-like peptides and their receptors are expressed in human, rodent, and drosophila brains [18] suggests that the corresponding signaling networks permit local control of diverse functions, including energy metabolism.
1.2.5 Insulin and IGF Signal Transduction: Steps in Pathwa...
